Skip to content
naulon
Get started

No retraction, correction or concern found when last checked on Oct 17, 2026.

GSK-3 as potential target for therapeutic intervention in cancer

James A. McCubrey, Linda S. Steelman, Fred E. Bertrand and 15 more

Oncotarget · 2014 · Review

doi:10.18632/oncotarget.2037

Abstract

// James A. McCubrey 1 , Linda S. Steelman 1 , Fred E. Bertrand 2 , Nicole M. Davis 1 , Melissa Sokolosky 1 , Steve L. Abrams 1 , Giuseppe Montalto 3 , Antonino B. D’Assoro 4 , Massimo Libra 5 , Ferdinando Nicoletti 5 , Roberta Maestro 6 , Jorg Basecke 7,8 , Dariusz Rakus 9 , Agnieszka Gizak 9 Zoya Demidenko 10 , Lucio Cocco 11 , Alberto M. Martelli 11 and Melchiorre Cervello 12 1 Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University Greenville, NC, USA 2 Department of Oncology, Brody School of Medicine at East Carolina University Greenville, NC, USA 3 Biomedical Department of Internal Medicine and Specialties, University of Palermo, Palermo, Italy 4 Department of Medical Oncology, Mayo Clinic Cancer Center, Rochester, MN, USA 5 Department of Bio-Medical Sciences, University of Catania, Catania, Italy 6 Experimental Oncology 1, CRO IRCCS, National Cancer Institute, Aviano, Pordenone, Italy. 7 Department of Medicine, University of Göttingen, Göttingen, Germany 8 Sanct-Josef-Hospital Cloppenburg, Department of Hematology and Oncology, Cloppenburg, Germany 9 Department of Animal Molecular Physiology, Institute of Experimental Biology, Wroclaw University, Wroclaw, Poland 10 Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA 11 Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy 12 Consiglio Nazionale delle Ricerche, Istituto di Biomedicina e Immunologia Molecolare “Alberto Monroy”, Palermo, Italy Correspondence: James A. McCubrey, email: // Keywords : GSK-3, cancer stem cells, Wnt/beta-catenin, PI3K, Akt, mTOR, Hedgehog, Notch, Targeted Therapy, Therapy Resistance, Mutations, Rapamycin Received : April 24, 2014 Accepted : May 28, 2014 Published : May 28, 2014 Abstract The serine/threonine kinase glycogen synthase kinase-3 (GSK-3) was initially identified and studied in the regulation of glycogen synthesis. GSK-3 functions in a wide range of cellular processes. Aberrant activity of GSK-3 has been implicated in many human pathologies including: bipolar depression, Alzheimer’s disease, Parkinson’s disease, cancer, non-insulin-dependent diabetes mellitus (NIDDM) and others. In some cases, suppression of GSK-3 activity by phosphorylation by Akt and other kinases has been associated with cancer progression. In these cases, GSK-3 has tumor suppressor functions. In other cases, GSK-3 has been associated with tumor progression by stabilizing components of the beta-catenin complex. In these situations, GSK-3 has oncogenic properties. While many inhibitors to GSK-3 have been developed, their use remains controversial because of the ambiguous role of GSK-3 in cancer development. In this review, we will focus on the diverse roles that GSK-3 plays in various human cancers, in particular in solid tumors. Recently, GSK-3 has also been implicated in the generation of cancer stem cells in various cell types. We will also discuss how this pivotal kinase interacts with multiple signaling pathways such as: PI3K/PTEN/Akt/mTORC1, Ras/Raf/MEK/ERK, Wnt/beta-catenin, Hedgehog, Notch and others.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 17, 2026. Paragraph numbers are ours, so an answer can point at one.

Multiple Roles of GSK-3 in Cellular Physiology and Human Health

GSK-3 is a serine (S) /threonine (T) kinase. GSK-3 was initially isolated and purified from rat skeletal muscle as a kinase that phosphorylated and inactivated glycogen synthase (GS), the last enzyme in glycogen biosynthesis. Thus GSK-3 was identified initially to have important roles in metabolism. GSK-3 is believed to be an important regulatory enzyme in many diseases and disorders such as: cancer and aging (cancer stem cells, cellular senescence, control of stem cell pluripotency and differentiation), immune disorders, metabolic disorders (atherosclerosis, diabetes, and heart disease), neurological disorders (Alzheimer's, amyotrophic lateral sclerosis [ALS], bipolar disorder, mood disorders, Parkinson's, and schizophrenia), and other maladies. GSK-3 may be a key therapeutic target for these and other diseases.

GSK-3 has been implicated to play roles in cancers which are resistant to chemo-, radio-, and targeted therapy. Targeting GSK-3 may be a means to overcome the resistance of these cancers to certain chemotherapeutic drugs, radiation and small molecule inhibitors.

GSK-3alpha and GSK-3beta

The GSK-3 gene family consists of two highly conserved kinases GSK-3alpha and GSK-3beta. However, the two molecules have distinct roles and one can not compensate for the loss of the other. In fact, expression of GSK-3alpha did not rescue embryonic lethality in mice in which GSK-3beta gene has been disrupted. GSK3A and GSK3B encode 51 and 47 kDa proteins respectively. The GSK-3alpha isoform has a glycine-rich extension at its amino terminus. GSK-3alpha and GSK-3beta display 98% sequence identity in their kinase domains but only 36% identity in their carboxyl termini. GSK-3alpha and GSK-3beta are considered active in non-stimulated cells. Both GSK-3-alpha and GSK-3beta exhibit strong preferences for primed substrates; this means they prefer substrates which have already been phosphorylated by other kinases [(e.g., casein kinase-1 (CK1), mitogen activate protein kinases (MAPK) [extracellular regulated kinase (ERK), pMAPK, and c-Jun N-terminal kinase (JNK)], 5' adenosine monophosphate-activated protein kinase (AMPK)] and others. The GSK-3 kinases phosphorylate greater than 40 proteins including over 12 transcription factors. Figure 1 presents a diagram indicating some of the substrates of GSK-3.

Differences between GSK-3alpha and GSK-3beta

GSK-3alpha and GSK-3beta are structurally similar, however, they are not functionally identical and they have some different substrate specificities. These GSK-3beta knock-out mice die around embryonic day 16 due to liver degeneration caused by hepatocyte apoptosis. Furthermore, GSK-3beta activity was essential for TNF-alpha-induced NF-kappaB activation in hepatocytes. In contrast GSK-3alpha knockout mice are viable but exhibited enhanced glucose and insulin sensitivity and reduced fat mass. GSK-3alpha knock-out mice elicited metabolic and neuronal developmental abnormalities. GSK-3alpha and GSK-3beta have different substrate preferences in the brain and likely other tissues. Thus, GSK-3 isoforms exhibit tissue-specific physiologically important functions which are may not be overlapping and sometimes may be different. These and other studies indicate that there are rationales for the specific targeting of GSK-3alpha or GSK-3beta in certain diseases.

Most biochemical studies have focused on GSK-3beta; however, some studies have demonstrated roles for GSK-3alpha in drug resistance and cancer stem cells. GSK-3alpha was recently identified as a key target in acute myeloid leukemia (AML). Thus the generation of isoform specific inhibitors could result in more specific treatments.

GSK-3 Activity is Controlled by Phosphorylation/Dephosphorylation

GSK-3alpha and GSK-3beta are expressed ubiquitously and highly conserved. Their activities are regulated by diverse stimuli and signaling pathways. The activity of GSK-3alpha is extinguished by phosphorylation at S21, while GSK-3beta activity is silenced by phosphorylation at S9. These phosphorylation events at S21 and S9 inhibit GSK-3 activity by inducing a pseudosubstrate conformation in the substrate docking motifs of GSK-3alpha and GSK-3beta respectively. Phosphorylation of GSK-3beta at S9 leads to its inactivation by proteasomal degradation and has been associated with many pathological conditions, including cancer. Various kinases phosphorylate GSK-beta at S9 including protein kinase A (PKA), protein kinase B (PKB a.k.a Akt), p90 ribosomal S6 kinase (p90Rsk), p70 ribosomal S6 kinase (p70S6K). A diagram depicting sites of regulation of GSK-3beta is presented in Figure 2.

Insulin signaling results in activation of Akt and subsequent phosphorylation and inactivation of GSK-3beta (S9) and GSK-3alpha (S21). Epidermal growth factor (EGF), platelet derived growth factor (PDGF) and other growth factors also induce the phosphorylation of GSK-3beta (S9) and GSK-3alpha (S21) by the activated Raf/MEK/ERK/p90Rsk1 signaling pathway. Other signaling pathways induce the phosphorylation and inactivation of GSK-3beta and GSK-3alpha by phosphorylation at S9 and S21 respectively. Thus GSK-3 activity is often shut off after exposure to mitogenic/growth factors.

Elucidation of the crystal structure of GSK-3 has helped to reveal how the phosphorylation of GSK-3beta and GSK-3alpha at S9 and S21 respectively results in their inhibition. When either S9 or S21 of GSK-3beta or GSK-3alpha respectively, are phosphorylated, a primed pseudosubstrate is created which folds and binds the positively-charged pocket. This folding prevents the phosphorylation of substrates as the catalytic groove is blocked. This is a competitive mechanism of inhibition and if elevated concentrations of the substrates are present, they will out-compete the pseudosubstrate and the substrates will be phosphorylated.

Arginine 96 of GSK-3beta is a critical component of the positive pocket which binds primed substrates. Mutation of arginine (R) 96 of GSK-3beta to alanine (A) (R96A) has consequences on the ability of GSK-3beta to phosphorylate primed vs. unprimed substrates. Priming of substrates usually occur N+4 from the site where GSK-3 phosphorylates the substrate. Namely if the substrate is primed, which is a preference of the GSK-3s; they will not be phosphorylated when R96 is mutated to A, whereas if they are not primed they will be phosphorylated. The R96A mutation disrupts the GSK-3beta pocket of positive charge and prevents the phosphorylation of the primed substrates. The R96A mutation prevented the S9-phosphorylated GSK-3beta pseudosubstrate from folding back and resulted in the phosphorylation of unprimed substrates even when GSK-3beta was phosphorylated at S9. A peptide of eleven amino acids corresponding to the phosphorylated amino terminal of GSK-3beta inhibited competitively the phosphorylation of both primed and unprimed substrates. In contrast, a truncated version of this peptide only inhibited phosphorylation of primed substrates. These results point to different approaches to specifically inhibit the ability of GSK-3beta to phosphorylate different substrates.

Phosphorylation of GSK-3beta at tyrosine (Y) 216 also regulates it activity and may activate GSK-3beta. This may be due to autophosphorylation but it may also be mediated by kinases such as Src. Y279 is the corresponding residue present in GSK-3alpha. Phosphorylation of GSK-3beta at Y216 may be constitutive in resting cells. Apoptotic stimuli can increase Y216 phosphorylation of GSK-3beta indicating roles for GSK-3beta in cell death. The proline-rich tyrosine kinase 2 (PYK2) may phosphorylate GSK-3alpha and GSK-3beta at Y216 and Y270 respectively. PYK2 controls lysophosphatidic acid-induced activation of GSK-3 which regulates the phosphorylation of microtubule-associated proteins. PYK2-mediated activation of GSK-3 destabilized microtubules during actinomyosin-driven neurite retraction. The Fyn tyrosine kinase also phosphorylates GSKs. The MAPK family also regulates the activity of GSK-3s. p38MAPK phosphorylates GSK-3beta at S389/T390. ERK phosphorylation of GSK-3beta at T43 has been proposed to induce a conformational change in GSK-3 which alters its activity. Finally protein phosphatases (e.g., PP2A, PP1) have important roles in regulation of GSK-3 activity by removing the phosphate on S9 as well as other regulatory residues. In addition, GSK-3s likely have protein phosphatases as substrates (e.g., PP1G).

Biochemical Functions of GSK-3

GSK-3beta represses the expression of certain immediate response genes in quiescent cells. GSK-3 can alter the activity of proteins important in RNA translation such as p70S6K. The GSK-3-related yeast protein Mck1 can inhibit the activity of the major mitotic cyclin-Cdk complex Clb2-Cdk1 and regulate cellular division. A diagram illustrating some of the targets of GSK-3 was presented in Figure 1.

Cell cycle arrest at the G1 phase occurs upon inhibition of GSK-3 and subsequent activation of p27Kip-1. GSK-3 can also phosphorylate p21Cip1 at T57. This phosphorylation event lead to the proteasomal degradation of p21Cip1. In contrast, lack of GSK-3-mediated phosphorylation of cyclin D1 at T286 and cyclin E at S380 suppressed their nuclear export and degradation.

GSK-3 has many direct and indirect effects on cell proliferation. GSK-3 can regulate the activity of transcription factors. Thus it can has important regulatory roles on cellular growth. The growth arrest and DNA damage 45 (GADD45) and GADD153 genes encode tumor suppressors which are checkpoint inhibitors. GSK-3beta can regulate the activity of the tumor suppressor TP53, which can modulate GADD45 transcription. GADD45 is induced by DNA damage and its expression is regulated by TP53. The cell cycle is arrested when GADD45 is induced. c-Myc can also influence the expression of the GADD43 and GADD153 genes. GSK-3 can regulate c-Myc activity. c-Myc can also modulate the expression of cell division cycle 25A (CDC25) gene which encodes an important cell cycle regulator gene.

GSK-3 regulates the activity of other transcription factors including NF-kappaB, Snail, Notch, forkhead, CAAT-enhancer binding protein (C/EBP). GSK-3 modifies the activity of other transcription factors frequently implicated in cancer including: activation protein 1 (AP1) and c-Myc. GSK-3beta can phosphorylate NF-kappaB at S468 which promoted its proteasomal degradation. GSK-3beta also interacted with I-kappaBalpha in epithelial cells. Other studies have indicated that GSK-3beta suppressed NF-kappaB activity by preventing the degradation of IkapaBalpha. Thus GSK-3beta can regulate NF-kappaB activity by multiple mechanisms.

GSK-3beta also affected TP53 activity. TP53 and miRNA34 can in turn regulate Snail, which is also regulated by GSK-3. Loss of TP53 activity resulted in decreased miRNA34 levels which bound to the 3'ends of Snail mRNA and suppressed its expression. Hence in the absence of functional TP53, Snail activity was increased and epithelial-mesenchymal transition (EMT) was promoted. GSK-3 regulated this axis. TP53 and miRNA34 are normally suppressors of Wnt/beta catenin signaling.

NF-kappaB and GSK-3 regulate the focal adhesion kinase (FAK). Some extracellular matrix proteins are indirect targets of Snail, c-Myc and NF-kappaB. Certain matrix metalloproteinases are transcriptionally regulated by NF-kappaB, C/EBPs and Snail. Furthermore Snail represses E-cadherin transcription. GSK-3 phosphorylates Snail which leads to its nuclear export. Phosphorylation of Snail by GSK-3 can result in the cytoplasmic translocation of Snail and lead to increased E-cadherin expression in oral cancer. Stabilization of Snail protein, by increased GSK-3beta phosphorylation, is also observed during EMT in different solid cancer types. Snail stabilization and EMT, through enhanced Akt activity and subsequent GSK-3β phosphorylation, is induced by hepatitis B virus X protein (HBx) in HBV-associated hepatocarcinogenesis and in hepatocellular carcinoma (HCC) patients which have amplification and overexpression of the novel oncogene Maelstrom (MAEL).

The activity of apoptotic and anti-apoptotic family members are also regulated by GSK-3. Bcl-2 expression is inhibited by GSK-3beta phosphorylation of CREB. The myeloid cell leukemia sequence 1 (Mcl-1) anti-apoptotic factor is also regulated by GSK-3. However, some studies indicate that GSK-3 activity may not be required for Mcl-1 degradation. GSK-3 stabilizes the expression of certain anti-apoptotic Bcl-2 family members. Gsk-3beta can regulate BCL2L12a anti-apoptotic signaling. BCL2L12A is an anti-apoptotic Bcl-2 family member which is expressed at high levels in glioblastoma. When BCL2L12A is phosphorylated at S156 by GSK-3beta, it is stabilized and has increased anti-apoptotic effects with regards to treatment with the drug staurosporin. The effects of BCL2L12A expression on apoptosis were inhibited when the cells were treated with the GSK-3 inhibitor lithium chloride. Interestingly, GSK-3beta and Mcl-1 inactivation have been shown to be part of the mechanism of action of the anesthetic propofol.

The expression of the myeloblastosis transcription factor (c-Myb) is also regulated by GSK-3beta. c-Myb is important in the regulation of BCL2 transcription. Suppression of GSK-3beta inhibited the expression of c-Myb. c-Myc can form a complex with the lymphoid enhancer-binding factor 1 (LEF-1) transcription factor and bind the promoter regions of the BCL2 and BIRC5 (survivin) genes which leads to the prevention of apoptosis.

Pro-apoptotic Bim is also a target of GSK-3beta. Suppression of GSK-3beta resulted in increased expression of Bim in pancreatic cancer cells, but not in non-transformed pancreatic epithelial cells. This regulation of Bim is thought to occur via JNK-dependent mechanisms which involve Bim transcription.

Bcl-2-associated X protein (Bax) can be phosphorylated by GSK-3beta in neuronal cells. Bax phosphorylation by GSK-3beta stimulated the mitochondrial localization of Bax. This localization of Bax had pro-apoptotic consequences. TP53 activity in colorectal cancer cells (CRCs) can be in part regulated by GSK-3beta. These effects of GSK-3beta on TP53 lead to increased levels of Bax. GSK-3 can activate the v-maf musculoaponeurotic fibrosarcoma oncogene homolog (MAF) transcription factor which enhanced its transforming activity. GSK-3 also serves to regulate the levels of beta-catenin, a key molecule involved in normal development as well as cancer progression.

Thursday Inhibtition of GSK-3beta activity was also shown to be critical for association of two metabolic enzymes: hexokinase II [ PMID: 21430642] and muscle isoform of fructose-1,6-bisphosphatase (FBP2) [ PMID: 22154964] with mitochondria which results in the protection of the organella against stress stimuli and the promotion of ATP synthesis.

GSK-3 as a Tumor-Promoter

GSK-3 has various roles in cancer which even after years of study remain complex and controversial. GSK-3 may play positive roles in cell proliferation and its aberrant expression as a tumor promoter. GSK-3 is overexpressed in various tumor types including; colon, liver, ovarian and pancreatic tumors.

Suppression of GSK-3beta expression inhibited pancreatic cancer growth and angiogenesis. Decreased levels of Bcl-2 and vascular endothelial growth factor (VEGF) were detected in cells which had GSK-3beta knocked-down. GSK-3 inhibitors may be appropriate for treatment of these types of tumors exhibiting GSK-3 overexpression in which GSK-3 is acting as a tumor promoter.

GSK-3 as a Tumor-Suppressor

GSK-3 also functions as a tumor suppressor. GSK-3 can suppress the Wnt/beta-catenin pathway by phosphorylating beta-catenin which results in the ubiquitin/proteasome-dependent degradation of beta-catenin. Introduction of kinase-inactive (KI), GSK-3beta mutants which presumably functioned as inhibitors of the endogenous wild-type (WT) GSK-3beta protein stimulated Wnt signaling and mammary tumorigenesis. Enforced expression of kinase-dead (KD) GSK-3beta, which presumably functioned as inhibitors of the WT GSK-3beta protein, promoted tumorigenesis of breast and skin tumors. Overexpression of constitutively-active GSK-3beta mutants, in some studies, increased chemosensitivity, cell cycle arrest, and reduced tumorigenicity of breast cancers. Pharmacological inhibition of GSK-3 induced EMT and invasion in breast cancer. In these studies suppression of GSK-3 lead to stabilization of beta-catenin which resulted in elevated c-Myc, cyclin-B1 and survivin expression and promoted proliferation and tumorigenesis. There is perhaps a fine balance with GSK-3 whether it functions a tumor suppressor or tumor inducer.

Expression of KI GSK-3beta in murine mammary glands can function as DN mutation and promote breast cancer development by stabilizing beta-catenin protein expression. The GSK-3beta KI construct stabilized beta-catenin expression and increased its nuclear localization and upregulated the expression of beta-catenin target genes such as cyclin D1. The GSK-3beta KI gene was driven by a mouse mammary tumor virus long terminal repeat (LTR) which contains sequences that promoted high level expression of the introduced gene in the mammary tissue. Expression of the GSK-3beta KI mutant resulted in stabilized beta-catenin expression, beta-catenin nuclear localization, activation of a TCF/LEF-dependent reporter construct and increased cyclin-D mRNA and protein levels.

Cyclin D1 was detected at high levels in approximately 50% of breast cancer patients examined. However only 15-20% of these patient samples had amplification of cyclin D1. beta-catenin transactivation has been associated with cyclin D1 overexpression in breast cancer. Aberrant GSK-3beta expression may lead to increased beta-catenin transcription which increases cyclin D1 expression. Cyclin D1 expression is increased in certain breast cancer patients as GSK-3beta regulates cyclin D1 turnover.

Overexpression of the tumor suppressor Axin gene in transgenic mice lead to decreased expression of cyclin D1 and increased apoptosis in mammary epithelia. In addition, impaired lymphoid development was observed in these. CK2alpha overexpression in transgenic mice resulted in mammary tumorigenesis as under these circumstances CK2alpha promoted Wnt signaling.

We observed that the GSK-3(KD) mutant induced doxorubicin resistance in MCF-7 breast cancer cells. However, in the same experiments the constitutively-active A9 GSK-3beta also made the cells slightly more doxorubicin resistant than cells transfected with the GSK-3beta (WT) construct. Moreover, the GSK-3beta(KD) construct made the MCF-7 cells more resistant to tamofixen than the cells transfected with the GSK-3beta(WT) construct. However different results were observed with rapamycin which blocks mTORC. MCF-7 cells transfected with the GSK-3beta(KD) construct were hypersensitive to rapamycin while cells transfected with the constitutively-active GSK-3beta (A9) construct were resistant to rapamycin. The cells containing the GSK-3beta(KD) construct were more sensitive to the GSK-3 inhibitor lithium than cells harboring GSK-3beta(WT) construct.

Mutations in GSK-3 Targets

Since GSK-3 is a kinase with a specific recognition motif present in substrate proteins that it phosphorylates, mutations can occur in certain genes which prevent GSK-3-mediated phosphorylation of the proteins they encode. The mutant proteins may have altered half-lifes as compared to the WT proteins as they may not be subject to proteasomal degradation. For example, mutations changing T58 of c-Myc prevented the ability of GSK-3 to phosphorylate c-Myc and thus suppressed its proteasomal degradation. Genetic mutations changing the GSK-3 phosphorylation sites S33, S37, S45 or T41 present in beta-catenin prevented the ability of GSK-3beta to phosphorylate beta-catenin and thus inhibited its proteasomal degradation. Likewise mutations at S45 of beta-catenin prevented CKI from performing the priming phosphorylation, thus GSK-3 was unable to phosphorylate the other residues of beta-catenin. Thus mutations at GSK-3 or CKI phosphorylation sites which prevent the ability of GSK-3 or CKI to phosphorylate target proteins which can under certain circumstances be oncogenic.

The PI3K/PTEN/Akt/mTOR Pathway and GSK-3

The PI3K/PTEN/Akt/mTOR pathway and GSK-3 can cross-regulate each other at various points. Some of the interactions between GSK-3 and the PI3K/PTEN/Akt/mTOR pathway are presented in Figure 3. As stated previously, GSK-3beta is negatively by Akt when it is phosphorylated on S9. GSK-3beta is then inactive.

The PI3K/PTEN/mTOR pathway is also involved in cancer initiation, metastasis, drug resistance, and sensitivity to therapy. PI3K p110 catalytic subunit (PIK3CA) mutations may be driver mutations in certain cancers responsible for metastasis. Novel PI3K-alpha inhibitors have been isolated and they inhibit metastasis. Most PI3K inhibitors are cytostatic rather than cytotoxic and it has been questioned whether treatment with a single PI3K inhibitor will be effective.

The PI3K/PTEN/Akt/mTORC1 pathway is important in c-Myc expression in Burkitt's lymphomagenesis in germinal center B cells. The PI3K/PTEN/Akt/mTORC1 pathway is also an emerging target for mantle cell lymphoma as this cascade is upregulated in this cancer. Disruption of PTEN and TP53 activity in the thyroid has recently been shown to result in murine models of anaplastic thyroid carcinomas. This model could be important for the development of approaches to target human thyroid carcinomas. The PI3K/PTEN/Akt/mTORC1 pathway is a key pathway involved in many cancers including gliomas often due to aberrant PTEN expression. Recently it has been shown that reduction of PIK3CA or PI3K p85 regulatory subunit (PIK3RA) cell proliferation impedes proliferation, migration, and invasion in glioblastoma multiforme cells. In contrast to PIK3CA, PIK3CB (PI3K p110-beta catalytic subunit) is oncogenic in its WT configuration when it is overexpressed in certain conditions. PIK3CB can act like an oncogenic mutant of PIK3CA.

PIK3CD (PI3K-delta p110 catalytic subunit) has been shown to have roles in BCR-ABL-mediated chronic lymphocytic leukemia (CLL) by turning off breakpoint cluster region (BCR) signaling. Elevated PI3K signaling has been detected in certain breast cancer subtypes and is believed to drive their abnormal proliferation. Novel lipid phosphatases have been shown to be important in regulation of this pathway. Inositol polyphosphate 4-phosphatase type II (INPP4B), is a tumor suppressor gene implicated in many cancers including: breast, ovarian and prostate cancers.

mTORC1 and mTORC2 Complexes

The S/T mTOR kinase is a critical component of two complexes, mTORC1 and mTORC2. In the mTORC1 complex, mTOR complexes with Raptor (Regulatory associated protein of mTOR) adaptor protein, DEP domain containing mTOR-interacting protein (DEPTOR) and mLST8, a member of the Lethal-with-Sec-Thirteen gene family, first identified in yeast, FK506 Binding Protein 38 (FKBP38) and proline-rich Akt substrate 40 kDa protein (PRAS40). DEPTOR may be a tumor suppressor gene as decreased expression of DEPTOR results in increased mTORC1 activity. mTORC2 can function as the elusive PDK-2 which phosphorylates Akt-1 on S473 in response to growth factor stimulation.

LKB1/AMPK Network Interactions with GSK-3 and PI3K/Akt/mTORC1 Pathway

The LKB1/AMP activated protein kinase (LMPK) pathway is a key pathway initially investigated in metabolic diseases such as diabetes. However, the LMPK pathway is now recognized to play important roles in cancer and other diseases. The LKB1/AMPK pathway can be stimulated by the commonly prescribed drugs, such as N,N-dimethylimidodicarbonimidic diamide (metformin) and 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR). AICAR is used to prevent cardiac ischemic injury and is also used in diabetes care. Activation of LKB1/AMPK in various tumor types results in cell cycle arrest, caspase-dependent apoptosis or autophagy in various tumors. Metformin inhibits mTORC1-controlled protein translation. Many of the targeted proteins are important in the growth of malignant cells. The translation of these proteins is not as well inhibited with allosteric mTORC1 inhibitors, such as rapamycin and its derivatives. Recently it was shown that metformin also targets the cancer initiating cells (CICs), the critical target for cancer eradication. Thus the LKB1/AMPK pathway is critically involved in regulating diseases such as diabetes as well as the proliferation and survival of malignant cells. Drugs targeting and activating LKB1/AMPK maybe a novel, less toxic and cost effective treatment option for certain malignancies.

The ability of metformin to suppress the proliferation of T-acute lymphoblastic leukemias (T-ALL) cell lines and primary T-ALL patient samples displaying mTORC1 activation was examined. Metformin induced autophagy and apoptosis and inhibited proliferation. The effects of metformin on control CD4+ T-lymphocytes were examined. Metformin was much less toxic against CD4+ T-lymphocytes from healthy donors than against either the T-ALL cell lines or primary patient cells. These studies documented the dephosphorylation of downstream targets of mTORC1. In addition, inhibition of mRNA translation in metformin-treated T-ALL cells was observed. In contrast, a similar inhibition of translation was not observed after rapamycin treatment. Importantly in primary patient samples, metformin targeted the side population of T-ALL cell lines as well as a putative leukemia initiating cell (LIC) subpopulation (CD34+, CD7-, CD4-). Metformin exhibited anti-leukemic activity, which supports further development of LKB1/AMPK pathway activators as potential clinical candidates for T-ALL therapy. AMPK is also important in BCR-ABL-induced chronic myeloid leukemia (CML) and AMPK pathway activators may prove useful as combination drug therapy (with BCR-ABL inhibitors) for this disease. AMPK can also be activated by rapamycin.

LKB1 is an important tumor suppressor and gatekeeper mutations of LKB1 cause the rare Peutz-Jeghers Syndrome (PJS) which is a cancer-prone syndrome. LKB1 is a critical regulator of cell polarity and energy/metabolism control and exerts it vast effects via diverse effectors. AMPK is considered a metabolic gatekeeper important in many diseases including diabetes, cancer and neurologic disorders. Inhibiting mTORC1 activity by drugs such as metformin and other drugs (including rapamycin) may not only aid in the treatment of diabetics, but also improve cancer therapies and increase longevity.

The plant natural product berberine has recently been shown to inhibit the growth of drug-resistant breast cancer cells whereas the parental drug sensitive line was not as growth inhibited. Berberine may also target LKB1/AMPK. Cells overexpressing neutrophil gelatinase-associated lipocalin (NGAL) were more sensitive to berberine than parental cells which did not over express NGAL.

Regulation of mTORC by GSK-3, TSC1/TSC2 and Other Molecules

The activity of the mTORC1 complex is regulated by many different molecules. Akt can suppress tuberous sclerosis 2 (TSC2 or tuberin) function by phosphorylation. TSC2 is a GTPase activating protein (GAP). TSC2 functions in association with TSC1 (hamartin) to regulate mTORC1 activity. TSC1/TSC2 inactivate the small G protein Ras homolog enriched in brain (Rheb). TSC2 phosphorylation by Akt represses GAP activity of the TSC1/TSC2 complex, allowing Rheb to accumulate in a GTP-bound state. Rheb-GTP then activates the protein kinase activity of mTOR present in the mTORC1 complex.

GSK-3 plays key roles in this regulatory circuit. The TSC1/TSC2 complex can negatively-regulate proliferation through mTORC1 inhibition and GSK-3beta activation. GSK-3 can also interact with TSC1/TSC2 by phosphorylating TSC2 and activating it. This regulatory loop would result in suppression of mTORC1 activity.

Akt also phosphorylates the proline-rich Akt substrate of 40 kDa (PRAS40), another inhibitor of mTORC1. When PRAS40 is phosphorylated by Akt, it can not suppress mTORC1 signalling. Thus, this is another mechanism by which Akt activates mTORC1. To complicate matters, PRAS40 is a substrate of mTORC1 itself, and mTORC1-mediated phosphorylation of PRAS40 prevents inhibition of additional mTORC1 signaling. The Ras/Raf/MEK/ERK signaling pathway also regulates mTORC1. TSC2 is phosphorylated by both ERK and p90Rsk-1. When TSC2 is phosphorylated by either ERK or p90Rsk-1, its inhibitory function is suppressed. Moreover, inhibition of mTORC1 can result in ERK1/2 activation, through p70S6K/PI3K/Ras/Raf/MEK.

The mechanism(s) by which Rheb-GTP activates mTORC1 are not fully elucidated. However for Rheb to activate mTORC1, Rheb must be farnesylated and farnesylation can be suppressed by farnesyl transferase (FT) inhibitors. Rheb-GTP may relieve the inhibitory function of FK506-binding protein 8 (FKBP38) on mTOR, thus leading to mTORC1 activation.

mTORC1 also inhibits Akt via a negative feedback loop which involves p70S6K and potentially other molecules. p70S6K can exert negative effects on insulin receptor substrate-1 (IRS-1). p70S6K can phosphorylate IRS-1 on S312 and/or S636/S639. This results in the targeting of IRS-1 to the proteasome where it is degraded. Hence PI3K/Akt signaling downstream of IRS-1 is downregulated when p70S6K is active. Rapamycin blocks mTORC1 and p70S6K activation, thus this loop is broken upon rapamycin was added and Akt is activated.

GSK-3 can regulate this pathway by phosphorylation of S371 on p70S6K. GSK-3 interacts with mTORC1 to regulate p70S6K activity. GSK-3beta can have negative effects on p70S6K activity. GSK-3 can phosphorylate TSC2 which results in inhibition of mTORC1 and prevents the phosphorylation of p70S6K at T389. Little is known about the interactions of GSK-3 and mTORC2 in oncogenesis. mTORC2 stabilizes cyclin D1 through prevention of GSK3- dependent and FBX4-mediated cyclin D1 degradation Thursday

Involvement of GSK-3 in Hematopoietic Stem Cell (HSC) Homeostasis

To maintain a balanced number of self-renewing cells or to generate the required lineage-differentiated progeny cells necessary to fulfill the loss of mature blood cells, normal HSCs exit quiescence under the appropriate circumstances. GSK-3 plays key roles in HSC homeostasis by regulating the quiescent HSC pool. Depletion of functional GSK-3 activity in bone marrow (BM) transiently expanded HSC in a beta-catenin-dependent fashion, indicating roles for GSK-3 and Wnt/beta-catenin signaling in homeostasis. Depletion of GSK-3 activity in the HSC pool resulted in their depletion by activation of mTORC1. Loss of the HSCs in the GSK-3-deficient BM could be suppressed by treatment with mTORC1 inhibitors. GSK-3 is a master regulatory switch which controls both Wnt/beta-catenin and mTORC1 signaling which in turn regulates HSC self renewal and lineage commitment respectively. This important study has suggested a potential therapeutic approach to expand HSCs in vivo by using already approved drugs for treatment of other diseases (rapamycin/rapalogs to inhibit mTORC1 and lithium to inhibit GSK-3).

As stated previously, GSK-3 phosphorylates TSC2 which in turn inhibits Rheb and mTORC1 activity. The PTEN phosphatase is upstream of GSK-3. PTEN negatively regulates Akt activity by de-phosphorylating phosphatidylinositol (3,4,5)-trisphosphate (PIP3) which Akt requires for membrane localization. PTEN and TSC1 knock-out mice have similar hematopoietic phenotypes. Increases in HSC were transiently observed which were followed by HSC depetion and lineage commitment. The authors suggested that there were additional tumor suppressors which were induced in PTEN-mutant mice indicating the complicated interacting genetic factors between PTEN loss and mTOR activation. Knock-down of GSK-3alpha and GSK-3beta induced a similar HSC phenotype as observed in PTEN−/− and TSC-1−/− mice as the HSCs initially increased and then they were progressively depleted. Thus GSK-3 plays critical roles in HSC homeostasis and regulating the decision between self-renewal and differentiation. These pathways often have competing functions in HSC self renewal and differentiation. Wnt signaling can induce mTORC1 activity by preventing the inhibitory effects that GSK-3 has on mTORC activity. Thus there is a division of the canonical Wnt pathway with Wnt or GSK-3 inducing opposing signal pathways. Wnt and GSK-3 can activate potentially opposing processes (HSC renewal vs. differentiation). Other factors and molecules may also be discovered that may modify the balance and modify HSC homeostasis.

Nutrient-sensing pathways interact to regulate HSC homeostasis. HSCs reside in the BM in a nutrient and oxygen-deprived niche. Both the mTORC1 and LKB1 pathways are important nutrient-sensing pathways. Dysregulation of these pathways alters HSC homeostasis. Increased mTORC1 activity or decreased LKB1 activity stimulates the proliferation of committed progenitors and decreases HSCs. Low nutrient availability is a critical component which controls HSC homeostasis.

Suppression of this pathway by rapamycin combined with activation of Wnt/beta-catenin pathway by GSK-3 inhibitors permitted ex vivo maintenance of human and mouse HSCs in the absence of exogenous cytokines. These studies demonstrated that two drugs (GSK inhibitor CHIR99021 and the mTOR blocker rapamycin) increased the number of long-term HSC in vivo. Thus GSK-3 plays roles in HSC homeostasis as a suppressor of Wnt/beta catenin self-renewal pathway and also as a suppressor of the mTORC1 pathway which would normally promote lineage commitment and stem-cell depletion. Inhibition of GSK-3 activated self renewal while suppression of mTORC1 prevented HSC depetion allowing the generation of long term HSC (but not the proportion) in vivo. This approach may also prove useful for both hematopoietic recovery and immune reconstitution in umbilical cord blood transplantation.

The promyelocytic leukemia (PML)–peroxisome proliferator-activated receptor-delta (PPAR-delta)–fatty-acid oxidation (FAO) pathway is another pathway which is important in HSC maintenance. GSK-3 regulates this pathway. PPARs are regulated by GSK-3 phosphorylation. Loss of HSC maintenance can occur after suppression of PPAR-delta or inhibition of mitochondria FAO. Improved HSC maintenance was observed after treatment with PPAR-delta agonists. PML regulates PPAR signaling and FAO which have important roles in HSC maintenance. The asymmetric division of HSCs is controlled by this pathway. Thus the PPAR-FAO pathway is a metabolic regulatory switch for the control of HSC fate. PPARs are important transcription factors that regulate nutrient sensing and metabolic pathways including FAO and fatty acid transport. These studies have important therapeutic implications as small molecule PPAR activators and inhibitors have been developed and evaluated for the treatment of obesity and metabolic disorders.

The PML gene is a tumor suppressor gene originally cloned from the break point of the t(15;17) chromosomal translocation present in PML. PML has an important role in regulating the maintenance of HSCs and LIC quiescence. Suppressing the activity of PML eliminated certain LICs. PML-deficient CML-LICs became exhausted over time and lost their ability to generate CML in transplanted mice. PML also acted as a negative regulator of mTORC1 in a mouse CML model. Repressing or balancing mTORC1 activity is important in HSC maintenance. Elevated mTORC1 activity adversely affected LIC maintenance while the mTORC1 blocker rapamycin prevented the exhaustion of Pml−/− LICs. PML is targeted for degradation by arsenic trioxide. Arsenic trioxide treatment of murine CML models decreased PML expression and prevented maintenance of CML-LIC quiescence.

GSK-3 inhibition permitted mouse embryonic stem cells (ESC) to maintain pluripotency. ESCs prepared from mice lacking GSK-3alpha and GSK-3beta retained some markers of pluripotency even when they were cultured under differentiation-inducing conditions.

GSK-3 and mTORC1 may also regulate T cell memory. Importantly inhibition of GSK-3, mTORC1 or both may augment the number and competence of CD8+ memory T cells.

Involvement of GSK-3 and Wnt/beta-catenin Signaling

Essentially there are two Wnt signaling pathways, a canonical Wnt signaling pathway which is beta-catenin-dependent and a non-canonical Wnt signaling pathway which is beta-catenin-independent. Beta-catenin can play multiple roles in cell physiology. Different pools of beta-catenin likely exist at various subcellular locations. For example one pool of beta-catenin is associated with cadherins at the cell-cell junctions while another pool of beta-catenin is “free” and localized in the cytosol and nucleus where it can play important roles in regulating gene expression. “Free” beta-catenin exists at a low level and is regulated by rapid turn-over. GSK-3 is critical in regulating the turnover of beta-catenin. An overview of the interactions between GSK-3 and the Wnt/beta-catenin pathway is presented in Figure 5.

The Wnt gene family is comprised of approximately nineteen genes in mammals. Wnt genes are found in multicellular animals but not in single-cell organisms suggesting that the Wnt genes played essential roles in the evolution of multicellular organisms. When Wnt binds it's receptor, a conformation change of the receptor occurs resulting in the phosphorylation of target proteins. Wnt binds a member of the Frizzled (Fz) family which is comprised of approximately 10 family members. Fz proteins are membrane bound receptors which are G-protein coupled receptors (GPCRs). The low density lipoprotein receptor (LDR) related proteins 5/6 (LRP5 or LRP6) are transmembrane proteins which are co-receptors for Wnt. Additional proteins can interact with Wnt to transduce various signals, these include receptor tyrosine kinases (RTKs), such as receptor-tyrosine-kinase-like orphan receptor 1 (ROR1) and ROR2 as well as the RTK-like proteins.

The GSK-3 Drosophila homologue is zeste-white 3, a negative regulator of wingless (Wg) signaling which is critical for normal development. Wnt is the vertebrate homologue of Wg and the Wnts are responsive for embryonic patterning as well as many other processes and their dysregulation can result in cancer. Wnt signaling is complex as at least 19 different Wnts exist in mammals and depending on the cellular context, different Wnts can induce or suppress critical aspects of proliferation. Activation of the canonical Wnt/beta-catenin pathway results in the induction of T cell factor/lymphoid enhancer factor-1 (TCF/LEF)-responsive genes. beta-catenin serves as a transactivator which binds to TCF/LEFs which are bound to specific gene targets in the DNA.

GSK-3 normally inhibits this pathway as in the absence of Wnt ligands; GSK-3 phosphorylates the amino terminals domain of beta-catenin which targets it for ubiquitination and proteasomal degradation. However, when Wnt ligands are present, GSK-3 is inactivated. The disheveled (Dvl) phosphoprotein is required to transduce a signal from Wnt that results in the inactivation of GSK-3beta. As a result, beta-catenin is dephosphorylated and accumulates in the cytoplasm and translocates to the nucleus where it associates with TCF/LEFs to become a transcriptional co-activator.

Regulation of beta-Catenin Activity by GSK-3

In the absence of stimulation, CK1 phosphorylates beta-catenin at S45 which primes beta-catenin for subsequent phosphorylation by GSK-3 at S41, S37 and S33. These phosphorylation events target beta-catenin for ubiquitination and proteasomal degradation. A blow up of the Wnt/beta-catenin and beta catenin destruction complex is presented in Figure 5.

When Wnt ligand is present, it binds Fz, which signals through Dvl to suppress beta-catenin phosphorylation. beta-catenin is then able to complex with LEF/TCF and induces the transcription of genes. When beta-catenin is mutated at certain nucleotides it can act as an oncogene, as the beta-catenin proteins can not be phosphorylated by GSK-3 or CKI (depending on the residue). Other regulatory proteins are also involved in controlling the activity of the Wnt/beta-catenin complex. In many cases, they may be either oncogenes or tumor suppressor genes. GSK-3-binding protein (GBP), also known as, frequently rearranged in advanced T-cell lymphomas (FRAT), may regulate the binding of GSK-3 to Axin. Diversin (Div) is an ankyrin rich protein that interacts with both Dvl and Axin to promote Wnt signaling. The beta-catenin destruction complex consists of: beta-catenin, axin/conductin, adenomatous polyposis coli (APC), CK1, GSK-3 and GBP. APC is a tumor-suppressor gene and an essential component of the beta-catenin complex which controls cytoplasmic beta-catenin levels. Mutations at APC are detected in certain cancers such as colo-rectal cancer (CRC). Mutations at APC occur early in CRC and result in increased beta-catenin levels which lead to the expression of Wnt/beta-catenin responsive genes. The Axin and related conductin (Axil) proteins contain multiple protein:protein interaction domains. The Axin/Axil proteins interact with APC and form key components of the beta-catenin destruction complex. Axin and APC are both phosphorylated by GSK-3. Phosphorylation of Axin by GSK-3 increases it stability as well as its ability to bind to beta-catenin. CKI is a priming kinase by phosphorylating Axin, Dvl and APC. Once these proteins are phosphorylated by CK1, GSK-3 then phosphorylates them. The Div protein can recruit CKI to the beta-catenin destruction complex.

GBP plays key important roles in the interactions between GSK-3 and other proteins. The binding sites for Axin and GBP on GSK-3 are overlapping. When GSK-3 is bound to GBP, GSK-3 cannot bind Axin and thus GSK-3 does not phosphorylate beta-catenin. GBP can regulate the nuclear export of GSK-3 and control the accessibility of nuclear and cytoplasmic substrates to GSK-3.

Dvl attaches to the cytoplasmic portion of Fz. Wnt/Fz then associates with the Wnt-coreceptor LRP5 or LRP6. CKI phosphorylates and primes LRP6 on T1479. GSK-3beta then plays a positive role in Wnt signaling by phosphorylating LRP6 on S1490. These events are required for Axin to bind to the complex which results in beta-catenin stabilization. beta-catenin can then enter the nucleus and effect gene transcription. Figure 6 presents a diagram of the positive effects which CKI and GSK-3 exert on Wnt/beta-catenin signaling. Targeting GSK-3 may be effective in suppressing the growth of certain cancers.

Axin attaches to the cytoplasmic portion of LRP6. This complex sequesters beta-catenin away from the beta-catenin destruction complex and suppresses the ability of GSK-3beta to phosphorylate beta-catenin. If Wnt signaling is turned on, GSK-3-mediated phosphorylation of S33, S37 and T41 on beta-catenin is suppressed and beta-catenin is stabilized.

GSK-3 has two roles in regulation of Wnt/beta-catenin signaling. Phosphorylation of LRP5/6 stabilizes Axin while phosphorylation of beta-catenin targets it for proteasomal degradation. As stated previously, there may be multiple pools of GSK-3 in cells; one linked with Axin and is resistant to phosphorylation by Akt. Another pool of GSK-3 is regulated by Akt and when it is phosphorylated by Akt it is destabilized and degraded. Introduction of constructs encoding activated Akt did not activate beta-catenin signaling in the examined model system in terms of changes in levels of LEF1-dependent transcription. Wnt may induce GSK-3 and Axin translocation to the plasma membrane. These translocations may be dependent upon interactions with Fz and Dvl. Axin is required for GSK-3 to phosphorylate LRP5/6. Wnt signaling induces the association of CKI with LRP5/6. This association may also be involved in Wnt-induced Axin recruitment.

CKI phosphorylates beta-catenin on S45 when Wnt signaling is extinguished. GSK-3beta can then phosphorylate beta-catenin on S33, S37 and T41. The Axin/GSK-3/CK1/APC complex induces the degradation of beta-catenin. This occurs via ubiquitination by the SKP1/cullin1-F-box E3 ligase (beta-TrCP) complex in the 26S proteasome. The tumor suppressor APC interacts with both GSK-3 and beta-catenin. Axin serves as the scaffold of the destruction complex. APC binds directly to Axin. Axin is phosphorylated by CKI and then GSK-3. The affinity of beta-TrCP for beta-catenin is normally low. The Wilms tumor suppressor (WTX) protein increases the affinity of beta-TrCP for beta-catenin. A complex is formed consisting of and APC, Axin, beta-catenin, beta-TrCP and WTX, which promotes beta-catenin ubiquitination and subsequent proteasomal degradation.

Axin, Apc and WTX are tumor-suppressor proteins. APC increases the activity of GSK-3. GSK-3 phosphorylates conserved serines present in the PPPSP motif found in many Wnt signaling components such as beta-catenin, Axin, and APC.

GSK-3 and beta-Catenin Signaling and Hepatocarcinogenesis

The dysregulation of GSK-3beta phosphorylation and inhibition of GSK-3beta activity has been shown to be involved in hepatocarcinogenesis. In a recent study performed on 80 HCC patients, the expression of GSK-3beta protein in HCC tissues was found to be significantly lower than that in normal liver tissues and pericancerous tissues. In addition, low expression of GSK-3beta was correlated significantly with advanced clinicopathological characteristics and poor prognosis of HCC patients. GSK-3beta expression was also correlated with vascular invasion, histological grade, TNM classification and therefore could be involved in process of HCC metastasis.

In a different study, it was reported that some HCC cells expressed high basal levels of S9-phosphorylated GSK-3beta. As a result of the sustained phosphorylation of GSK-3beta, beta-catenin was stabilized and contributed to hepatic transformation.

Infection with either HBV or HCV are well known risk factors for HCC. HBx is one of the four proteins encoded by the HBV genome. Several studies have reported its involvement in liver carcinogenesis. Expression of HBx in hepatocytes activates the Ras/Raf/MEK/ERK signaling cascade. Interestingly, cross-talk between the Ras/Raf/MEK/ERK and Wnt/beta-catenin signaling has been observed in hepatoma cells. HBx activates ERK and as consequence it associates and primes GSK-3beta for its inactivation. In particular, activated ERK phosphorylated GSK-3beta at T43, which primers GSK-3beta for its subsequent phosphorylation at S9 by p90Rsk, resulting in inactivation of GSK-3beta. In turn, inactivation of GSK-3beta promoted beta-catenin stabilization and signaling. In other scenarios, ERK can collaborate with GSK-3 in the phosphorylation of paxillin and regulate cytoskeletal rearrangement.

Among the HCV encoded proteins, the core protein has been reported to contribute to HCC carcinogenesis. Interestingly, HCV core protein increases and stabilizes beta-catenin levels in hepatoma cells through inactivation of GSK-3beta by phosphorylation at S9. This results in stabilization of beta-catenin and enhancement of canonical Wnt/beta-catenin signaling activity. Downstream beta-catenin target genes, such as c-Myc, cyclin D1, WNT1-inducible-signaling pathway protein 2 (WISP2) and connective tissue growth factor (CTGF) are expressed at higher levels.

GSK-3beta/beta-catenin signaling plays roles in the Sirtuin 2 (SIRT2)-mediated transformation in HCC. SIRT2 is a member of sirtuin family, which is upregulated in about 50% of HCC patients. Increased SIRT2 expression is correlated with shorter overall survival. The sirtuins have been associated with oxidative stress and aging. The authors demonstrated that SIRT2 regulated activation of Akt by its deacetylation. Subsequently Akt phosphorylated and inactivated GSK-3beta. The beta-catenin-signaling cascade is enhanced and promoted EMT and cell migration of HCC cells. Together these results suggested that GSK-3beta is probably a tumor suppressor gene in HCC, and the loss of GSK-3beta expression and/or activity may contribute to development of HCC.

However, the roles of GSK-3beta in HCC remain controversial and several studies indicate that GSK-3beta is a potential therapeutic target for a broad spectrum of cancer types including HCC [.].

Inhibition of GSK-3beta activity with the GSK3beta inhibitors SB-216763 and AR-A014418 controled cancer cell survival and proliferation, in a manner unrelated to Wnt/beta-catenin signaling and Akt activation, through decreasing telomerase reverse transcriptase (hTERT) expression and telomerase activity. GSK-3beta inhibitors, lithium and SB-415286, have been also reported to overcome the inherent resistance of human hepatoma cells towards TRAIL-induced apoptosis. The inhibitors exerted their anticancer activity through a complex mechanism which involved the promotion of apoptotic signals (caspase-8, caspase-3 and TP53 activation) and of protective signals (JNK activation).

Wnt/GSK-3 Regulation of mTORC1 Pathway

Wnt signaling can regulate the mTORC1 pathway via GSK-3 by a beta-catenin-independent mechanism. GSK-3 can phosphorylate TSC2 after it has been phosphorylated (priming phosphorylation) by AMPK. This would lead to inhibition of mTORC1. In contrast, Wnt signaling suppresses GSK-3-mediated phosphorylation of TSC2 and the mTORC1 pathway is activated. Inhibition of Wnt-mediated activation of mTORC1 by rapamycin suppressed Wnt-mediated cellular proliferation. Activation of AMPK by metformin suppressed Wnt-mediated cellular proliferation. In addition to GSK-3, Dickkopf-related protein 1 (DKK1), Dvl and Axin also modulate the effects Wnt has on regulation of mTORC1 and cellular proliferation.

Wnt/GSK-3 Signaling in the Regulation of SMAD1

Mothers against decapentaplegic homolog 1 (SMAD1) is a mediator of the transforming growth factor-beta (TGF-beta)/bone morphogenetic protein (BMP) superfamily of ligands. Both MAPK and GSK-3 were determined to phosphorylate SMAD1 on its linker region which resulted in its polyubiquitinylation and transport to the centrosome where it was degraded by proteasomes. The priming phosphorylation mediated by MAPKs (ERK, JNK, p38MAPK) to phosphorylate SMAD1 was most likely required for GSK-3 activity. Wnt signaling decreased GSK-3 phosphorylation of SMAD1. Thus, the Wnt/GSK3/SMAD1 pathway plays an important role in embryonic pattern formation.

Overview of Hedgehog Pathway

The hedgehog (Hh) pathway is an important developmental pathway that controls segmental pattern formation. There are three Hh genes, desert hedgehog (DHH), Indian hedgehog (IHH) and sonic hedgehog (SHH). These hedgehogs function as ligands for the 12-pass transmembrane receptor patched (PTCH1) which controls many developmental signaling events. Hhs can function in some cases as mitogens, while in other cases they promote differentiation. An overview of the Hh pathway is presented in Figure 7.

Hh ligands bind their receptor PTCH1. This causes its internalization and degradation and release of Smoothened (SMO), a GPCR. SMO then promotes the dissociation of a suppressor of fused (SUFU)-glioma-associated oncogene homologue (GLI) complex. This allows the transcription factors GLI1 and GLI2 to translocate to the nucleus and ultimately induce the transcription of certain genes. In contrast, GLI3 is degraded during this process as it normally functions as a repressor.

GLI3 can be phosphorylated by PKA, GSK-3 and CK1 which results in GLI3 becoming a transcriptional repressor. Activated GLI proteins stimulate the transcription of Hh target genes, including: GLI1, GLI2, PTCH1, CCND1, IGF2, MYC, and BCL2. IGF-2 has been determined in some studies to subsequently induce the PI3K/PTEN/Akt/mTOR pathway and influence proliferation and survival as well as inhibit GSK-3beta.

The Hh pathway interacts with other signaling pathway regulators such as BMPs, parthyroid hormone and retinoids. The Hh pathway is aberrantly regulated in certain tumors. There is substantial interest in isolating inhibitors which can suppress its activity in various cancers and other disorders.

GSK-3 Regulation of Hh Signaling

The Hh pathway is regulated by GSK-3. The Hh pathway is inhibited when GSK-3 is suppressed. GSK-3beta is a specific binding partner of SUFU, a negative regulator of the Hh pathway. SUFU suppresses GLI activity by sequestering GLI in the cytoplasm. When GSK-3 phosphorylates SUFU, Hh pathway activity is increased. Hh pathway activation stimulates GSK-3beta to phosphorylate SUFU which induces the dissociation of SUFU from GLI3. GSK-3beta regulates the Hh pathway by phosphorylating GLI. The Hh pathway activates the GLI transcription factor by suppressing the function of SUFU. SUFU recruits GSK-3beta into a trimolecular complex of GLI3/SUFU/GSK-3beta. GSK-3beta then phosphorylates GLI3 which results in a SUFU/GLI3 transcriptional repressor. Shh then dissociates the GLI3/SUFU/GSK-3 beta complex from GLI3 which prevents GLI3 processing and results in GLI3 becoming a transcriptional activator instead of a transcriptional repressor.

Overview of Notch Signaling Pathway

Notch signaling is important in many processes including cellular fate decisions. Notch signaling is activated by cell to cell interactions which result in the step wise cleavage of Notch first by a TACE- metalloprotease, and then a gamma-secretase. This cleavage results in the release of the Notch intracellular domain (NICD). NICD can then translocate into the nucleus to bind transcription factors such as centromere binding factor (CBF1) which further recruits transcriptional co-activators including MAML1, histone acetyl transferases and cAMP response element-binding protein (CREB)-binding protein/p300.

GSK-3 and Notch Signaling Pathway

Notch signaling pathway is regulated by GSK-3. GSK-3beta phosphorylates the NICD. This phosphorylation event up-regulates NICD transcriptional activity by preventing its proteasomal degradation. In contrast to the effects of GSK-3, Akt negatively regulates NICD activity. GSK-3beta phosphorylates domains in the NICD of Notch1 (S/T-P-S/T) which are important for the nuclear localization of NICD. Phosphorylation of these domains by GSK-3beta increased the transcriptional activity of NICD. In contrast, other studies have shown that GSK-3 phosphorylation can decrease Notch1 protein levels and its transcriptional activity. beta-catenin could also modulate the transcriptional activity of Notch1/NICD. Beta-catenin levels are usually increased when GSK-3 is suppressed. Other studies have indicated that GSK-3beta phosphorylation of Notch downregulates Notch activity. Some of these differences in the effects of GSK-3 on the phosphorylation of Notch observed in the different studies may be related to the different cell lines utilized or culture conditions. Different culture conditions or cell lines containing different mutated activated oncogenes activated and tumor suppressor genes inactivatedmay affect Notch activity. These studies and others indicate the complex interactions between the GSK-3, Wnt/beta-catenin and Notch signaling pathways.

GSK-3 Inhibitors

One of the first described inhibitors of GSK-3 is lithium. Lithium carbonate has been used to treat mania patients since 1871. It was approved by the FDA in 1970 and it is currently used to treat many different types of patients with depressive disorders. Early clinical studies indicated that lithium had effects on HSCs and other hematopoietic cells. Lithium increased circulating HSCs and peripheral blood counts. In 1996, it was proposed that lithium could mobilize HSCs for BM transplantations. An important consequence of suppression of GSK-3 is stimulation of both the Wnt/beta-catenin and PI3K/PTEN/Akt/mTORC1 pathways. However, GSK-3 has many biological effects.

More than 50 GSK-3 inhibitors have been described including: lithium, AR-A014418 (beta, IC50 =104 nM), AZD1080 (alpha & beta, orally active, brain permeable, with Kis of 6.9 nM and 31 nM respectively), AZD2858 (alpha & beta IC50s of 68 nM), BIO (alpha & beta IC50 of 5 nM), CHIR-99021 (alpha & beta, IC50s of 10 nM/6.7 nM), CHIR-98014 (alpha & beta, IC50 of 0.65), LY2090314 (alpha & beta, IC50s of 1.5 nM and 0.9 nM respectively), SB-216763 (alpha & beta, IC50s of 34.3 nM), SB-415286 (alpha & beta IC50s of 78 nM and 31 nM respectively), TDZD-8 (beta, IC50 of 2 microM and TWS119 (beta, IC50s of 30 nM). Most GSK-3 inhibitors are ATP-competitive and do not differentiate between either GSK-3alpha or GSK-3beta. Tideglusib (NP031112) is an irreversible, non ATP-competitive GSK-3beta inhibitor with IC50 of 60 nM, which is in clinical trials. Table 1 present a listing of some GSK-3 inhibitors and their structures and references.

Clinical Trials with GSK-3 Inhibitors

Lithium carbonate has been in clinical trials with bipolar disorder patients. It is also involved in additional clinical trials for patients with Alzheimer disease (NCT01055392 & NCT00088387), bipolar disorder (NCT01543724, NCT00870311), spinocerebellar ataxia type 3 (NCT01096082) and Machado Joseph disease. Tideglusib has been in clinical trials for patients with Alzheimer's disease (NCT00948259) and progressive supranuclear palsy (NCT01049399). Divalproex (Valproate semisodium) is used for treatment of patients suffering from bipolar disorder, epilepsy and migraines. Divalproex has been in clinical trials in combination with lithium, for patients with Alzheimer's disease (NCT00088387), Valproic acid (VPA) is an anticonvulsant and mood-stabilizing drug which can inhibit GSK-3beta. It has been examined in clinical trials (NCT01548066) to determine whether it will prevent hair loss. It has also been examined in a clinical trial (NCT00385710) to determine if it can aid patients with progressive supranuclear palsy. LY2090314 has been in clinical trials for metastatic pancreatic cancer [NCT01632306], advanced or metastatic cancer in combination with pemetrexed and carboplatin [NCT01287520] and acute leukemia [NCT01214603].

GSK-3 Inhibitors in Pre-Clinical Anti-Cancer Studies

GSK-3 inhibitors may eventually be used in the treatment of certain cancers. GSK-3 is believed to exert pro-proliferative effects in solid cancers including: CRC, glioblastoma, pancreatic cancer and ovarian cancer and in blood cancers including MM, ALL, AML and CLL. Therefore it may be appropriate to treat these cancers and potentially others with GSK-3 inhibitors. Treatment of the KG1a, K562 and CMK leukemia cell lines with the GSK-3 inhibitor SB-415286 resulted in GSK-3beta S9 phosphorylation beta-catenin stabilization, cyclin B downregulation, cell growth inhibition, cell cycle arrest at G2/M and apoptosis. Blocking the death receptor pathway with an inhibitor of caspase 8 did not neutralize the effects of the GSK-3 inhibitor. The GSK-3 inhibitor treatment resulted in dephosphorylation of Bcl-2, downregulation of Bcl-XL and led to the depolarization of the mitochondrial membrane potential. The role of stabilized beta-catenin induced by the treatment of the leukemia cells with the GSK-3 inhibitor in the induction of apoptosis of these cells is not clear. The GSK-3 inhibitors SB-415286 and lithium as well as arsenic trioxide inactivated GSK-3beta in AML (APL) cells by inducing the phosphorylation of S9 on GSK-3beta. However, in other cancer types such as breast cancer and medulloblastoma, increased GSK-3 expression is associated with the induction of apoptosis. It remains controversial as to whether suppressing GSK-3 activity with small molecule inhibitors will inhibit or promote cancer growth.

1i is a selective ATP competitive inhibitor of GSK-3. 6-bromoindirubin-3-oxime (BIO) and TWS119 are also GSK-3 inhibitors. BIO inhibited GSK-3 and activated Wnt/beta catenin signaling, thereby maintaining the pluripotency of human and mouse ESCs. Continued GSK-3 inhibition or Wnt pathway activation promoted ESC differentiation into multipotent mesendodermal progenitors or their differential progenitors. As stated previously, GSK-3 interacts with the Wnt, Hh and Notch pathways. These interactions can under the appropriate conditions regulate cell fate determination and maintenance of stem cells. GSK-3 can phosphorylate the GLI2 transcription factor, which can effect differentiation. The self-renewal of ESCs was enhanced when they were cultured with leukemia inhibitory factor (LIF) and BMP3 and GSK-3 were suppressed. The mechanism responsible for the enhanced self-renewal is not clear. It was proposed that the expression of pluripotency factors such as Oct-4 and Nanog was prevented in these conditions. GSK-3 may phosphorylate and inactivate other transcription factors associated with pluripotency, such as c-Myc and c-Jun. 48 derivatives of the GSK-3 inhibitor 1i were synthesized by Bone and colleagues. The abilities of these GSK-3 inhibitors to maintain undifferentiated ESCs were determined. The effectiveness of these compounds on maintaining undifferentiated ESCs was linked with inhibition of GSK-3. Thus GSK-3 inhibitors may be used to both maintain stem cell pluripotency as well as to expand these cells. These inhibitors may also be effective with induced pluripotent stem cell generation (iPSC).

GSK-3 inhibitors may be appropriate for the treatment of certain diseases including: diabetes, obesity, ischemia, cancer, sepsis, colitis and neurological disorders. However, the evaluation of GSK-3 inhibitors in clinical trials has been hampered by the fear that inhibition of GSK-3 may stimulate or aid in malignant transformation as GSK-3 can phosphorylate such pro-oncogenic factors as beta-catenin, c-Jun and c-Myc which targets them for degradation. However, no studies have been reported suggesting that treatment of mice with GSK-3 inhibitors resulted in an increase in cancer incidence. In contrast, studies in prostate, pancreatic, ovarian, thyroid, melanoma, brain, pheochromocytoma, paraganglioma, colorectal, and hematopoietic cancers have indicated that GSK-3 inhibitors could suppress proliferation. In fact, many patients with bi-polar disorder have been treated with lithium for prolonged periods of time. There does not appear to be any evidence that these patients have increased incidences of cancer. In the studies by Wang et al, treatment on mice with mixed-lineage leukemia (MLL) like leukemia (see below) with lithium actually increased the survival of the mice approximately 50%.

Treatment of human leukemias containing MLL translocations with GSK-3 inhibitors GSK-3 IX, SB216763, and allsterpaullone inhibited their growth of. GSK-3beta activity was determined to be essential for the maintenance of MLL LSC. However GSK-3beta activity was not necessary for normal myeloid progenitors or progenitors transfected with other non-MLL fusions. GSK-3alpha and GSK-3beta performed similar functions in regulating the growth of MLL-transformed leukemias. p27Kip-1 was critical for the effectiveness of the GSK-3 inhibitors. Knock-down of p27Kip-1 prevented the growth arrest of the GSK-3 inhibitors specifically in MLL-transformed cells but not non-MLL fusion protein-transformed cells. GSK-3 is believed to support the maintenance of MLL-transformed leukemic cells by promoting p27Kip-1 degradation. Upon treatment of the MLL-transformed cells with GSK-3 inhibitors, p27Kip-1 accumulated specifically in the MLL-transformed cells and cell cycle arrest occurred.

Effects of Certain Small Molecule Inhibitors on GSK-3 Activity

Certain small molecule inhibitors synergized with GSK-3beta inhibition to result in cell death. The multi-kinase inhibitor sorafenib induced GSK-3beta which actually provides a survival signal in melanoma cells. When a constitutively-active form of GSK3B was introduced into the melanoma cells, elevated levels of anti-apoptotic Bcl-2, Bcl-XL and survivin were detected while decreased levels of pro-apoptotic Noxa were observed. Elimination of GSK-3beta activity increased the activity of sorafenib.

Summary

Many different biological processes are regulated by GSK-3 alpha and beta. GSK-3 interacts with many signaling pathways. Critical pathways often dysregulated in cancer are the PI3K/PTEN/Akt/mTORC1 and Wnt/beta-catenin pathways. GSK-3 interacts with both Akt, TSC2 to regulate mTORC1. Akt has a negative effect on GSK-3 as when GSK-3 is phosphorylated by Akt, GSK-3 can not phosphorylate TSC2. This has a pro-proliferative effect as mTORC1 is not suppressed by TSC2. GSK-3 has a negative effect on mTORC as it phosphorylates and promotes the activity of TSC2 which inhibits mTORC1. This has an anti-proliferative effect. mTORC1 and GSK-3 also interact to regulate p70S6K which can indirectly regulate Akt. GSK-3 interacts with the Wnt/beta-catenin pathway at multiple levels; in some circumstances it inhibits the activity of Wnt/beta-catenin pathway by phosphorylation of beta-catanin which results in its proteasomal degradation, while in other cases it promotes the pathway by phosphorylating LRP5/6 which results in the stabilization of beta-catenin. This latter effect is especially prominent in certain CIC, where GSK-3 inhibitors may prove clinically effective; however, they probably will have to be administered with beta-catenin or downstream TCF/LEF inhibitors. GSK-3 also interacts with the Raf/MEK/ERK, Hh, Notch, and other important regulatory pathways. It is intriguing to consider why inhibiting GSK-3 does not have dire consequences as so many pathways will be affected which will lead to activation/suppression of various signaling pathways. However, the GSK-3 inhibitor lithium has been used to treat patients for many years now without apparent increases in the cancer incidence. GSK-3 is a kinase with many biochemical, biological and neurological effects. Understanding of these effects may lead to improved therapies for certain diseases and conditions.

References 314

  1. 1.

    Embi N, Rylatt DB, Cohen P. Glycogen synthase kinase-3 from rabbit skeletal muscle. Separation from cyclic-AMP-dependent protein kinase and phosphorylase kinase. Eur J Biochem. 1980;107:519-527.

    Not in our library

  2. 2.

    Woodgett JR. Molecular cloning and expression of glycogen synthase kinase-3/factor A. EMBO J. 1990;9:2431-2438.

    Not in our library10.1002/j.1460-2075.1990.tb07419.x

  3. 3.

    Gao C, Holscher C, Liu Y, Li L. GSK3: a key target for the development of novel treatments for type 2 diabetes mellitus and Alzheimer disease. Reviews in the Neurosciences. 2012;23:1-11.

    Not in our library10.1515/rns.2011.061

  4. 4.

    Forlenza OV, de Paula VJ, Machado-Vieira R, Diniz BS, Gattaz WF. Does lithium prevent Alzheimer's disease? Drugs & Aging. 2012;29:335-342.

    Not in our library10.2165/11599180-000000000-00000

  5. 5.

    Amar S, Belmaker RH, Agam G. The possible involvement of glycogen synthase kinase-3 (GSK-3) in diabetes, cancer and central nervous system diseases. Current Pharmaceutical Design. 2011;17:2264-2277.

    Not in our library10.2174/138161211797052484

  6. 6.

    Juhaszova M, Zorov DB, Yaniv Y, Nuss HB, Wang S, Sollott SJ. Role of glycogen synthase kinase-3[beta] in cardioprotection. Circulation Research. 2009;104:1240-1252.

    Not in our library10.1161/circresaha.109.197996

  7. 7.

    Shimura T. Acquired radioresistance of cancer and the AKT/GSK3beta/cyclin D1 overexpression cycle. Journal of Radiation Research. 2011;52:539-544.

    Not in our library10.1269/jrr.11098

  8. 8.

    Fu Y, Hu D, Qiu J, Xie X, Ye F, Lu WG. Overexpression of glycogen synthase kinase-3 in ovarian carcinoma cells with acquired paclitaxel resistance. International Journal of Gynecological Cancer. 2011;21:439-444.

    Not in our library10.1097/igc.0b013e31820d7366

  9. 9.

    Kawazoe H, Bilim VN, Ugolkov AV, Yuuki K, Naito S, Nagaoka A, Kato T, Tomita Y. GSK-3 inhibition in vitro and in vivo enhances antitumor effect of sorafenib in renal cell carcinoma (RCC). Biochemical & Biophysical Research Communications. 2012;423:490-495.

    Not in our library10.1016/j.bbrc.2012.05.147

  10. 10.

    Thamilselvan V, Menon M, Thamilselvan S. Anticancer efficacy of deguelin in human prostate cancer cells targeting glycogen synthase kinase-3 beta/beta-catenin pathway. International Journal of Cancer. 2011;129:2916-2927.

    Not in our library10.1002/ijc.25949

  11. 11.

    Welham MJ, Kingham E, Sanchez-Ripoll Y, Kumpfmueller B, Storm M, Bone H. Controlling embryonic stem cell proliferation and pluripotency: the role of PI3K- and GSK-3-dependent signalling. Biochemical Society Transactions. 2011;39:674-678.

    Not in our library10.1042/bst0390674

  12. 12.

    Fung TK, Gandillet A, So CW. Selective treatment of mixed-lineage leukemia leukemic stem cells through targeting glycogen synthase kinase 3 and the canonical Wnt/[beta]-catenin pathway. Current Opinion in Hematology. 2012;19:280-286.

    Not in our library10.1097/moh.0b013e3283545615

  13. 13.

    Wray J, Kalkan T, Smith AG. The ground state of pluripotency. Biochemical Society Transactions. 2010;38:1027-1032.

    Not in our library10.1042/bst0381027

  14. 14.

    Hur EM, Zhou FQ. GSK3 signalling in neural development. Nature Reviews Neuroscience. 2010;11:539-551.

    Not in our library10.1038/nrn2870

  15. 15.

    Cheng H, Woodgett J, Maamari M, Force T. Targeting GSK-3 family members in the heart: a very sharp double-edged sword. Journal of Molecular & Cellular Cardiology. 2011;51:607-613.

    Not in our library10.1016/j.yjmcc.2010.11.020

  16. 16.

    Fu Y, Zheng S, An N, Athanasopoulos T, Popplewell L, Liang A, Li K, Hu C, Zhu Y. beta-catenin as a potential key target for tumor suppression. International Journal of Cancer. 2011;129:1541-1551.

    Not in our library10.1002/ijc.26102

  17. 17.

    Palomo V, Perez DI, Gil C, Martinez A. The potential role of glycogen synthase kinase 3 inhibitors as amyotrophic lateral sclerosis pharmacological therapy. Current Medicinal Chemistry. 2011;18:3028-3034.

    Not in our library10.2174/092986711796391697

  18. 18.

    Li YC, Gao WJ. GSK-3beta activity and hyperdopamine-dependent behaviors. Neurosci Biobehav Rev. 2011;35:645-654.

    Not in our library10.1016/j.neubiorev.2010.08.001

  19. 19.

    Wang H, Brown J, Martin M. Glycogen synthase kinase 3: a point of convergence for the host inflammatory response. Cytokine. 2011;53:130-140.

    Not in our library10.1016/j.cyto.2010.10.009

  20. 20.

    Trepiccione F, Christensen BM. Lithium-induced nephrogenic diabetes insipidus: new clinical and experimental findings. Journal of Nephrology. 2010;23(Suppl 16):S43-48.

    Not in our library

  21. 21.

    Klamer G, Song E, Ko KH, O'Brien TA, Dolnikov A. Using small molecule GSK3beta inhibitors to treat inflammation. Current Medicinal Chemistry. 2010;17:2873-2881.

    Not in our library10.2174/092986710792065090

  22. 22.

    Garcia I, Fall Y, Gomez G. QSAR, docking, and CoMFA studies of GSK3 inhibitors. Current Pharmaceutical Design. 2010;16:2666-2675.

    Not in our library10.2174/138161210792389225

  23. 23.

    Carter MD, Simms GA, Weaver DF. The development of new therapeutics for Alzheimer's disease. Clinical Pharmacology & Therapeutics. 2010;88:475-486.

    Not in our library10.1038/clpt.2010.165

  24. 24.

    Henriksen EJ. Dysregulation of glycogen synthase kinase-3 in skeletal muscle and the etiology of insulin resistance and type 2 diabetes. Current Diabetes Reviews. 2010;6:285-293.

    Not in our library10.2174/157339910793360888

  25. 25.

    Karam CS, Ballon JS, Bivens NM, Freyberg Z, Girgis RR, Lizardi-Ortiz JE, Markx S, Lieberman JA, Javitch JA. Signaling pathways in schizophrenia: emerging targets and therapeutic strategies. Trends in Pharmacological Sciences. 2010;31:381-390.

    Not in our library10.1016/j.tips.2010.05.004

  26. 26.

    Kim YM, Seo YH, Park CB, Yoon SH, Yoon G. Roles of GSK3 in metabolic shift toward abnormal anabolism in cell senescence. Annals of the New York Academy of Sciences. 2010;1201:65-71.

    Not in our library10.1111/j.1749-6632.2010.05617.x

  27. 27.

    Hoeflich KP, Luo J, Rubie EA, Tsao MS, Jin O, Woodgett JR. Requirement for glycogen synthase kinase-3beta in cell survival and NF-kappaB activation. Nature. 2000;406:86-90.

    Not in our library10.1038/35017574

  28. 28.

    Patel S, Woodgett. Glycogen synthase kinase-3 and cancer: good cop, bad cop? Cancer Cell. 2008;14:351-353.

    Not in our library10.1016/j.ccr.2008.10.013

  29. 29.

    Doble BW, Woodgett JR. GSK-3: tricks of the trade for a multi-tasking kinase. J Cell Sci. 2003;116:1175-1186.

    Not in our library10.1242/jcs.00384

  30. 30.
    What Are the bona fide GSK3 Substrates? · 2011
    No notice
  31. 31.

    MacAulay K, Doble BW, Patel S, Hansotia T, Sinclair EM, Drucker DJ, Nagy A, Woodgett JR. Glycogen synthase kinase 3alpha-specific regulation of murine hepatic glycogen metabolism. Cell Metab. 2007;6:329-337.

    Not in our library10.1016/j.cmet.2007.08.013

  32. 32.
    Abnormalities in brain structure and behavior in GSK-3alpha mutant mice · 2009
    No notice
  33. 33.

    Soutar MP, Kim WY, Williamson R, Peggie M, Hastie CJ, McLauchlan H, Snider WD, Gordon-Weeks PR, Sutherland C. J Evidence that glycogen synthase kinase-3 isoforms have distinct substrate preference in the brain. Neurochem. 2010;115:974-983.

    Not in our library10.1111/j.1471-4159.2010.06988.x

  34. 34.

    Banerji V, Frumm SM, Ross KN, Li LS, Schinzel AC, Hahn CK, Kakoza RM, Chow KT, Ross L, Alexe G, Tolliday N, Inguilizian H, Galinsky I, Stone RM, DeAngelo DJ, Roti G, Aster JC, Hahn WC, Kung AL, Stegmaier K. The intersection of genetic and chemical genomic screens identifies GSK-3alpha as a target in human acute myeloid leukemia. J Clin Invest. 2012;122:935-947.

    Not in our library10.1172/jci46465

  35. 35.
    Phosphorylation and inactivation of glycogen synthase kinase 3 by protein kinase A · 2000
    Not checked
  36. 36.

    Kim M, Datta A, Brakeman P, Yu W, Mostov KE. Polarity proteins PAR6 and aPKC regulate cell death through GSK-3beta in 3D epithelial morphogenesis. J Cell Sci. 2007;120:2309-2317.

    Not in our library10.1242/jcs.007443

  37. 37.

    Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature. 1995;378:785-789.

    Not in our library10.1038/378785a0

  38. 38.

    Stambolic V, Woodgett JR. Mitogen inactivation of glycogen synthase kinase-3 beta in intact cells via serine 9 phosphorylation. Biochem J. 1994;303:701-704.

    Not in our library10.1042/bj3030701

  39. 39.

    Sutherland C, Leighton IA, Cohen P. Inactivation of glycogen synthase kinase-3 beta by phosphorylation: new kinase connections in insulin and growth-factor signalling. Biochem J. 1993;296:15-19.

    Not in our library10.1042/bj2960015

  40. 40.

    Kockeritz L, Doble B, Patel S, Woodgett JR. Glycogen synthase kinase-3--an overview of an over-achieving protein kinase. Curr Drug Targets. 2006;7:1377-1388.

    Not in our library10.2174/1389450110607011377

  41. 41.

    Saito Y, Vandenheede JR, Cohen P. The mechanism by which epidermal growth factor inhibits glycogen synthase kinase 3 in A431cells. Biochem J. 1994;303:27-31.

    Not in our library10.1042/bj3030027

  42. 42.

    Brady MJ, Bourbonais FJ, Saltiel AR. The activation of glycogen synthase by insulin switches from kinase inhibition to phosphatase activation during adipogenesis in 3T3-L1 cells. J Biol Chem. 1998;273:14063-14066.

    Not in our library10.1074/jbc.273.23.14063

  43. 43.

    Frame S, Cohen P, Biondi RM. A common phosphate binding site explains the unique substrate specificity of GSK3 and its inactivation by phosphorylation. Mol Cell. 2001;7:1321-1327.

    Not in our library10.1016/s1097-2765(01)00253-2

  44. 44.

    Zhang N, Jiang Y, Zou J, Yu Q, Zhao W. Structural basis for the complete loss of GSK3beta catalytic activity due to R96 mutation investigated by molecular dynamics study. Proteins. 2009;75:671-681.

    Not in our library10.1002/prot.22279

  45. 45.

    Cole A, Frame S, Cohen P. Further evidence that the tyrosine phosphorylation of glycogen synthase kinase-3 (GSK3) in mammalian cells is an autophosphorylation event. Biochem J. 2004;377:249-255.

    Not in our library10.1042/bj20031259

  46. 46.

    Hughes K, Nikolakaki E, Plyte SE, Totty NF, Woodgett JR. Modulation of the glycogen synthase kinase-3 family by tyrosine phosphorylation. EMBO J. 1993;12:803-808.

    Not in our library10.1002/j.1460-2075.1993.tb05715.x

  47. 47.

    Bhat RV, Shanley J, Correll MP, Fieles WE, Keith RA, Scott CW, Lee CM. Regulation and localization of tyrosine216 phosphorylation of glycogen synthase kinase-3beta in cellular and animal models of neuronal degeneration. Proc Natl Acad Sci USA. 2000;97:11074-11079.

    Not in our library10.1073/pnas.190297597

  48. 48.

    Bijur GN, Jope RS. Proapoptotic stimuli induce nuclear accumulation of glycogen synthase kinase-3 beta. J Biol Chem. 2001;276:37436-37442.

    Not in our library10.1074/jbc.m105725200

  49. 49.

    Kang LJ, Lee HB, Bae HJ, Lee SG. Antidiabetic effect of propolis: reduction of expression of glucose-6-phosphatase through inhibition of Y279 and Y216 autophosphorylation of GSK-3α/β in HepG2 cells. Phytother Res. 2010;24:1554-1561.

    Not in our library10.1002/ptr.3147

  50. 50.

    Pajak B, Songin M, Strosznajder JB, Gajkowska B. Alzheimer's disease genetic mutation evokes ultrastructural alterations: correlation to an intracellular Abeta deposition and the level of GSK-3beta-P(Y216) phosphorylated form. Neurotoxicology. 2009;30:581-588.

    Not in our library10.1016/j.neuro.2009.05.008

  51. 51.

    Songin M, Strosznajder JB, Fitał M, Kuter K, Kolasiewicz W, Nowak P, Ossowska K. Glycogen synthase kinase 3β and its phosphorylated form (Y216) in the paraquat-induced model of parkinsonism. Neurotox Res. 2011;19:162-171.

    Not in our library10.1007/s12640-010-9153-7

  52. 52.

    Wang S, Toth ME, Bereczki E, Santha M, Guan ZZ, Winblad B, Pei JJ. Interplay between glycogen synthase kinase-3β and tau in the cerebellum of Hsp27 transgenic mouse. J Neurosci Res. 2011;89:1267-1275.

    Not in our library10.1002/jnr.22660

  53. 53.

    Hartigan JA, Xiong WC, Johnson GV. Glycogen synthase kinase 3beta is tyrosine phosphorylated by PYK2. Biochem Biophys Res Commun. 2001;284:485-489.

    Not in our library10.1006/bbrc.2001.4986

  54. 54.

    Sayas CL, Ariaens A, Ponsioen B, Moolenaar WH. GSK-3 is activated by the tyrosine kinase Pyk2 during LPA1-mediated neurite retraction. Mol Biol Cell. 2006;17:1834-1844.

    Not in our library10.1091/mbc.e05-07-0688

  55. 55.
    Deconstructing GSK‐3: The Fine Regulation of Its Activity · 2011
    No notice
  56. 56.

    Lesort M, Jope RS, Johnson GV. Insulin transiently increases tau phosphorylation: involvement of glycogen synthase kinase-3beta and Fyn tyrosine kinase. J Neurochem. 1999;72:576-584.

    Not in our library10.1046/j.1471-4159.1999.0720576.x

  57. 57.

    Thornton TM, Pedraza-Alva G, Deng B, Wood CD, Aronshtam A, Clements JL, Sabio G, Davis RJ, Matthews DE, Doble B, Rincon M. Phosphorylation by p38 MAPK as an alternative pathway for GSK3beta inactivation. Science. 2008;320:667-670.

    Not in our library10.1126/science.1156037

  58. 58.

    Bennecib M, Gong CX, Grundke-Iqbal I, Iqbal K. Role of protein phosphatase-2A and -1 in the regulation of GSK-3, cdk5 and cdc2 and the phosphorylation of tau in rat forebrain. FEBS Lett. 2000;485:87-93.

    Not in our library10.1016/s0014-5793(00)02203-1

  59. 59.

    Kim L, Harwood A, Kimmel AR. Receptor-dependent and tyrosine phosphatase-mediated inhibition of GSK3 regulates cell fate choice. Dev Cell. 2002;3:523-532.

    Not in our library10.1016/s1534-5807(02)00269-1

  60. 60.

    Tullai JW, Graham JR, Cooper GM. A GSK-3-mediated transcriptional network maintains repression of immediate early genes in quiescent cells. Cell Cycle. 2011;10:3072-3077.

    Not in our library10.4161/cc.10.18.17321

  61. 61.

    Shin S, Wolgamott L, Yu Y, Blenis J, Yoon SO. Glycogen synthase kinase (GSK)-3 promotes p70 ribosomal protein S6 kinase (p70S6K) activity and cell proliferation. Proc Natl Acad Sci USA. 2011;108:1204-1213.

    Not in our library10.1073/pnas.1110195108

  62. 62.

    Shin S, Wolgamott L, Yoon SO. Glycogen synthase kinase (GSK)-3 and mammalian target of rapamycin complex 1 (mTORC1) cooperate to regulate protein S6 kinase 1 (S6K1). Cell Cycle. 2012;11:1053-1054.

    Not in our library10.4161/cc.11.6.19784

  63. 63.

    McQueen J, van Dyk D, Young B, Loewen C, Measday V. The Mck1 GSK-3 kinase inhibits the activity of Clb2-Cdk1 post-nuclear division. Cell Cycle. 2012;11:3421-3432.

    Not in our library10.4161/cc.21731

  64. 64.

    Wang Z, Smith KS, Murphy M, Piloto O, Somervaille TC, Cleary ML. Glycogen synthase kinase 3 in MLL leukaemia maintenance and targeted therapy. Nature. 2008;455:1205-1209.

    Not in our library10.1038/nature07284

  65. 65.

    Rossig L, Badorff C, Holzmann Y, Zeiher AM, Dimmeler S. Glycogen synthase kinase-3 couples AKT-dependent signaling to the regulation of p21Cip1 degradation. J Biol Chem. 2002;277:9684-9689.

    Not in our library10.1074/jbc.m106157200

  66. 66.

    Diehl JA, Cheng M, Roussel MF, Sherr CJ. Glycogen synthase kinase- 3beta regulates cyclin D1 proteolysis and subcellular localization. Genes Dev. 1998;12:3499-3511.

    Not in our library10.1101/gad.12.22.3499

  67. 67.

    Welcker M, Singer J, Loeb KR, Grim J, Bloecher A, Gurien-West M, Clurman BE, Roberts JM. Multisite phosphorylation by Cdk2 and GSK3 controls cyclin E degradation. Mol Cell. 2003;12:381-392.

    Not in our library10.1016/s1097-2765(03)00287-9

  68. 68.

    Leis H, Segrelles C, Ruiz S, Santos M, Paramio JM. Expression, localization, and activity of glycogen synthase kinase 3beta during mouse skin tumorigenesis. Mol Carcinog. 2002;35:180-185.

    Not in our library10.1002/mc.10087

  69. 69.
    Glycogen synthase kinase 3 beta: can it be a target for oral cancer · 2010
    No notice
  70. 70.

    Yada M, Hatakeyama S, Kamura T, Nishiyama M, Tsunematsu R, Imaki H, Ishida N, Okumura F, Nakayama K, Nakayama KI. Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7. EMBO J. 2004;23:2116-2125.

    Not in our library10.1038/sj.emboj.7600217

  71. 71.

    Hoeflich KP, Luo J, Rubie EA, Tsao MS, Jin O, Woodgett JR. Requirement for glycogen synthase kinase-3beta in cell survival and NF-kappaB activation. Nature. 2000;406:86-90.

    Not in our library10.1038/35017574

  72. 72.

    Barre B, Perkins ND. Phosphorylation of the p52 NF-kappaB subunit. Cell Cycle. 2010;9:4774-4775.

    Not in our library10.4161/cc.9.24.14246

  73. 73.

    Haraguchi M, Okubo T, Miyashita Y, Miyamoto Y, Hayashi M, Crotti TN, McHugh KP, Ozawa M. Snail regulates cell-matrix adhesion by regulation of the expression of integrins and basement membrane proteins. J Biol Chem. 2008;283:23514-23523.

    Not in our library10.1074/jbc.m801125200

  74. 74.

    Yook JI, Li XY, Ota I, Hu C, Kim HS, Kim NH, Cha SY, Ryu JK, Choi YJ, Kim J, Fearon ER, Weiss SJ. A Wnt-Axin2-GSK3beta cascade regulates Snail1 activity in breast cancer cells. Nat Cell Biol. 2006;8:1398-1406.

    Not in our library10.1038/ncb1508

  75. 75.

    Foltz DR, Santiago MC, Berechid BE, Nye JS. Glycogen synthase kinase-3beta modulates notch signaling and stability. Curr Biol. 2002;12:1006-1011.

    Not in our library10.1016/s0960-9822(02)00888-6

  76. 76.

    Kashikar ND, Zhang W, Massion PP, Gonzalez AL, Datta PK. Role of STRAP in regulating GSK3beta function and Notch3 stabilization. Cell Cycle. 2011;10:1639-1654.

    Not in our library10.4161/cc.10.10.15630

  77. 77.

    G-Amlak M, Uddin S, Mahmud D, Damacela I, Lavelle D, Ahmed M, van Besien K, Wickrema A. Regulation of myeloma cell growth through Akt/Gsk3/forkhead signaling pathway. Biochem Biophys Res Commun. 2002;297:760-764.

    Not in our library10.1016/s0006-291x(02)02278-7

  78. 78.

    Ross SE, Erickson RL, Hemati N, MacDougald OA. Glycogen synthase kinase 3 is an insulin-regulated C/EBPalpha kinase. Mol Cell Biol. 1999;19:8433-8441.

    Not in our library10.1128/mcb.19.12.8433

  79. 79.

    de Groot RP, Auwerx J, Bourouis M, Sassone-Corsi P. Negative regulation of Jun/AP-1: conserved function of glycogen synthase kinase 3 and the Drosophila kinase shaggy. Oncogene. 1993;8:841-847.

    Not in our library

  80. 80.

    Buss H, Dorrie A, Schmitz ML, Frank R, Livingstone M, Resch K, Kracht M. Phosphorylation of serine 468 by GSK-3beta regulates basal p65 NF-kappaB activity. J Biol Chem. 2004;279:49571-49574.

    Not in our library10.1074/jbc.c400442200

  81. 81.

    Ma Y, Wang M, Li N, Wu R, Wang X. Bleomycin-induced nuclear factor kappaB activation in human bronchial epithelial cells involves the phosphorylation of glycogen synthase kinase 3beta. Toxicol Lett. 2009;187:194-200.

    Not in our library10.1016/j.toxlet.2009.02.023

  82. 82.

    Sanchez JF, Sniderhan LF, Williamson AL, Fan S, Chakraborty-Sett S, Maggirwar SB. Glycogen synthase kinase 3beta-mediated apoptosis of primary cortical astrocytes involves inhibition of nuclear factor kappaB signaling. Mol Cell Biol. 2003;23:4649-4662.

    Not in our library10.1128/mcb.23.13.4649-4662.2003

  83. 83.

    Qu L, Huang S, Baltzis D, Rivas-Estilla AM, Pluquet O, Hatzoglou M, Koumenis C, Taya Y, Yoshimura A, Koromilas AE. Endoplasmic reticulum stress induces p53 cytoplasmic localization and prevents p53-dependent apoptosis by a pathway involving glycogen synthase kinase-3beta. Genes Dev. 2004;18:261-277.

    Not in our library10.1101/gad.1165804

  84. 84.

    Charvet C, Maurer U. GSK-3 turns p53 deadly. Cell Cycle. 2011;10:3621-3622.

    Not in our library10.4161/cc.10.21.17852

  85. 85.

    Kim NH, Kim HS, Li XY, Lee I, Choi HS, Kang SE, Cha SY, Ryu JK, Yoon D, Fearon ER, Rowe RG, Lee S, Maher CA, Weiss SJ, Yook JI. A p53/miRNA-34 axis regulates Snail1-dependent cancer cell epithelial-mesenchymal transition. J Cell Biol. 2011;195:417-433.

    Not in our library10.1083/jcb.201103097

  86. 86.

    Kim NH, Kim HS, Kim NG, Lee I, Choi HS, Li XY, Kang SE, Cha SY, Ryu JK, Na JM, Park C, Kim K, Lee S, Gumbiner BM, Yook JI, Weiss SJ. p53 and microRNA-34 are suppressors of canonical Wnt signaling. Sci Signal. 2011;4:ra71.

    Not in our library10.1126/scisignal.2001744

  87. 87.

    Bianchi M, De Lucchini S, Marin O, Turner DL, Hanks SK, Villa-Moruzzi E. Regulation of FAK Ser-722 phosphorylation and kinase activity by GSK3 and PP1 during cell spreading and migration. Biochem J. 2005;391:359-370.

    Not in our library10.1042/bj20050282

  88. 88.

    Batlle E, Sancho E, Francí C, Domínguez D, Monfar M, Baulida J, García De Herreros A. The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol. 2000;2:84-89.

    Not in our library10.1038/35000034

  89. 89.

    Bachelder RE, Yoon SO, Franci C, de Herreros AG, Mercurio AM. Glycogen synthase kinase-3 is an endogenous inhibitor of Snail transcription: implications for the epithelial-mesenchymal transition. J Cell Biol. 2005;168:29-33.

    Not in our library10.1083/jcb.200409067

  90. 90.

    Bauer K, Dowejko A, Bosserhoff AK, Reichert TE, Bauer RJ. P-cadherin induces an epithelial-like phenotype in oral squamous cell carcinoma by GSK-3beta-mediated Snail phosphorylation. Carcinogenesis. 2009;30:1781-1788.

    Not in our library10.1093/carcin/bgp175

  91. 91.
    Epithelial–Mesenchymal Transition (EMT) Induced by TNF-α Requires AKT/GSK-3β-Mediated Stabilization of Snail in Colorectal Cancer · 2013
    No notice
  92. 92.

    Zheng H, Li W, Wang Y, Liu Z, Cai Y, Xie T, Shi M, Wang Z, Jiang B. Glycogen synthase kinase-3beta regulates Snail and β-catenin expression during Fas-induced epithelial-mesenchymal transition in gastrointestinal cancer. Eur J Cancer. 2013;49:2734-2746.

    Not in our library10.1016/j.ejca.2013.03.014

  93. 93.

    Wen W, Ding J, Sun W, Fu J, Chen Y, Wu K, Ning B, Han T, Huang L, Chen C, Xie D, Li Z, Feng G, Wu M, Xie W, Wang H. Cyclin G1-mediated epithelial-mesenchymal transition via phosphoinositide 3-kinase/Akt signaling facilitates liver cancer progression. Hepatology. 2012;55:1787-1798.

    Not in our library10.1002/hep.25596

  94. 94.

    Liu H, Xu L, He H, Zhu Y, Liu J, Wang S, Chen L, Wu Q, Xu J, Gu J. Hepatitis B virus X protein promotes hepatoma cell invasion and metastasization by stabilizing Snail protein. Cancer Sci. 2012;103:2072-2081.

    Not in our library10.1111/cas.12017

  95. 95.

    Liu L, Dai Y, Chen J, Zeng T, Li Y, Chen L, Zhu YH, Li J, Li Y, Ma S, Xie D, Yuan YF, Guan XY. Maelstrom promotes hepatocellular carcinoma metastasis by inducing epithelial-mesenchymal transition by way of Akt/GSK-3β/Snail signaling. Hepatology. 2014;59:531-543.

    Not in our library10.1002/hep.26677

  96. 96.

    Belkhiri A, Dar AA, Zaika A, Kelley M, El-Rifai W. t-Darpp promotes cancer cell survival by up-regulation of Bcl2 through Akt-dependent mechanism. Cancer Res. 2008;68:395-403.

    Not in our library10.1158/0008-5472.can-07-1580

  97. 97.

    Ding Q, He X, Hsu JM, Xia W, Chen CT, Li LY, Lee DF, Liu JC, Zhong Q, Wang X, Hung MC. Degradation of Mcl-1 by beta-TrCP mediates glycogen synthase kinase 3-induced tumor suppression and chemosensitization. Molecular & Cellular Biology. 2007;27:4006-4017.

    Not in our library10.1128/mcb.00620-06

  98. 98.

    Morel C, Carlson SM, White FM, Davis RJ. Mcl-1 integrates the opposing actions of signaling pathways that mediate survival and apoptosis. Mol Cell Biol. 2009;29:3845-3852.

    Not in our library10.1128/mcb.00279-09

  99. 99.

    Inuzuka H, Fukushima H, Shaik S, Liu P, Lau AW, Wei W. Mcl-1 ubiquitination and destruction. Oncotarget. 2011;2:239-244.

    Not in our library10.18632/oncotarget.242

  100. 100.

    Nifoussi SK, Vrana JA, Domina AM, De Biasio A, Gui J, Gregory MA, Hann SR, Craig RW. Thr 163 phosphorylation causes Mcl-1 stabilization when degradation is independent of the adjacent GSK3-targeted phosphodegron, promoting drug resistance in cancer. PLoS One. 2012;7(10):e47060.

    Not in our library10.1371/journal.pone.0047060

  101. 101.

    Zhao Y, Altman BJ, Coloff JL, Herman CE, Jacobs SR, Wieman HL, Wofford JA, Dimascio LN, Ilkayeva O, Kelekar A, Reya T, Rathmell JC. Glycogen synthase kinase 3alpha and 3beta mediate a glucose-sensitive antiapoptotic signaling pathway to stabilize Mcl-1. Molecular & Cellular Biology. 2007;27:4328-4339.

    Not in our library10.1128/mcb.00153-07

  102. 102.

    Cheng YL, Huang WC, Chen CL, Tsai CC, Wang CY, Chiu WH, Chen YL Lin YS, Chang CF, Lin CF. Increased galectin-3 facilitates leukemia cell survival from apoptotic stimuli. Biochem Biophys Res Commun. 2011;412:334-340.

    Not in our library10.1016/j.bbrc.2011.07.099

  103. 103.

    Chou CH, Chou AK, Lin CC, Chen WJ, Wei CC, Yang MC, Hsu CM, Lung FW, Loh JK, Howng SL, Hong YR. GSK3beta regulates Bcl2L12 and Bcl2L12A anti-apoptosis signaling in glioblastoma and is inhibited by LiCl. Cell Cycle. 2012;11:532-542.

    Not in our library10.4161/cc.11.3.19051

  104. 104.

    Hsing CH, Chen YH, Chen CL, Huang WC, Lin MC, Tseng PC, Wang CY, Tsai CC, Choi PC, Lin CF. Anesthetic propofol causes glycogen synthase kinase-3[beta]-regulated lysosomal/mitochondrial apoptosis in macrophages. Anesthesiology. 2012;116:868-881.

    Not in our library10.1097/aln.0b013e31824af68a

  105. 105.

    Zhou F, Zhang L, van Laar T, van Dam H, Ten Dijke P. GSK3beta inactivation induces apoptosis of leukemia cells by repressing the function of c-Myb. Mol Biol Cell. 2011;22:3533-3540.

    Not in our library10.1091/mbc.e11-06-0483

  106. 106.

    Marchand B, Tremblay I, Cagnol S, Boucher MJ. Inhibition of glycogen synthase kinase-3 activity triggers an apoptotic response in pancreatic cancer cells through JNK-dependent mechanisms. Carcinogenesis. 2012;33:529-537.

    Not in our library10.1093/carcin/bgr309

  107. 107.

    Linseman DA, Butts BD, Precht TA, Phelps RA, Le SS, Laessig TA, Bouchard RJ, Florez-McClure ML, Heidenreich KA. Glycogen synthase kinase-3beta phosphorylates Bax and promotes its mitochondrial localization during neuronal apoptosis. Journal of Neuroscience. 2004;24:9993-10002.

    Not in our library10.1523/jneurosci.2057-04.2004

  108. 108.

    Tan J, Zhuang L, Leong HS, Iyer NG, Liu ET, Yu Q. Pharmacologic modulation of glycogen synthase kinase-3beta promotes p53-dependent apoptosis through a direct Bax-mediated mitochondrial pathway in colorectal cancer cells. Cancer Res. 2005;65:9012-9020.

    Not in our library10.1158/0008-5472.can-05-1226

  109. 109.

    Rocques N, Abou Zeid N, Sii-Felice K, Lecoin L, Felder-Schmittbuhl MP, Eychène A, Pouponnot C. GSK-3-mediated phosphorylation enhances Maf-transforming activity. Mol Cell. 2007;28:584-597.

    Not in our library10.1016/j.molcel.2007.11.009

  110. 110.

    Wang Y, van der Zee M, Fodde R, Blok LJ. Wnt/B-catenin and sex hormone signaling in endometrial homeostasis and cancer. Oncotarget. 2010;1:674-684.

    Not in our library10.18632/oncotarget.201

  111. 111.

    Chen X, Stoeck A, Lee SJ, Shih IeM, Wang MM, Wang TL. Jagged1 expression regulated by Notch3 and Wnt/beta-catenin signaling pathways in ovarian cancer. Oncotarget. 2010;1:210-218.

    Not in our library10.18632/oncotarget.127

  112. 112.
    Drug Discovery Approaches to Target Wnt Signaling in Cancer Stem Cells · 2010
    No notice
  113. 113.

    Pacheco-Pinedo EC, Morrisey EE. Wnt and Kras signaling-dark siblings in lung cancer. Oncotarget. 2011;2:569-574.

    Not in our library10.18632/oncotarget.305

  114. 114.

    Velpula KK, Dasari VR, Tsung AJ, Dinh DH, Rao JS. Cord blood stem cells revert glioma stem cell EMT by down regulating transcriptional activation of Sox2 and Twist1. Oncotarget. 2011;2:1028-1042.

    Not in our library10.18632/oncotarget.367

  115. 115.

    Jaitner S, Reiche JA, Schaffauer AJ, Hiendlmeyer E, Herbst H, Brabletz T, Kirchner T, Jung A. Human telomerase reverse transcriptase (hTERT) is a target gene of beta-catenin in human colorectal tumors. Cell Cycle. 2012;11:3331-3338.

    Not in our library10.4161/cc.21790

  116. 116.

    Singh AM, Bechard M, Smith K, Dalton S. Reconciling the different roles of Gsk3beta in “naive” and “primed” pluripotent stem cells. Cell Cycle. 2012;11:2991-2996.

    Not in our library10.4161/cc.21110

  117. 117.

    Conrad WH, Swift RD, Biechele TL, Kulikauskas RM, Moon RT, Chien AJ. Regulating the response to targeted MEK inhibition in melanoma: Enhancing apoptosis in NRAS- and BRAF-mutant melanoma cells with Wnt/beta-catenin activation. Cell Cycle. 2012;11:3724-3730.

    Not in our library10.4161/cc.21645

  118. 118.

    Cha YH, Kim NH, Park C, Lee I, Kim HS, Yook JI. MiRNA-34 intrinsically links p53 tumor suppressor and Wnt signaling. Cell Cycle. 2012;11:1273-1281.

    Not in our library10.4161/cc.19618

  119. 119.

    Genovese G, Ghosh P, Li H, Rettino A, Sioletic S, Cittadini A, Sgambato A. The tumor suppressor HINT1 regulates MITF and beta-catenin transcriptional activity in melanoma cells. Cell Cycle. 2012;11:2206-2215.

    Not in our library10.4161/cc.20765

  120. 120.

    Gall JM1, Wong V, Pimental DR, Havasi A, Wang Z, Pastorino JG, Bonegio RG, Schwartz JH, Borkan SC. Hexokinase regulates Bax-mediated mitochondrial membrane injury following ischemic stress. Kidney Int. 2011;79:1207-1216.

    Not in our library10.1038/ki.2010.532

  121. 121.

    Gizak A, Pirog M, Rakus D. Muscle FBPase binds to cardiomyocyte mitochondria under glycogen synthase kinase-3 inhibition or elevation of cellular Ca2+ level. FEBS Lett. 2012;586:13-19.

    Not in our library10.1016/j.febslet.2011.11.032

  122. 122.

    Luo J. Glycogen synthase kinase 3beta (GSK3beta) in tumorigenesis and cancer chemotherapy. Cancer Lett. 2009;273:194-200.

    Not in our library10.1016/j.canlet.2008.05.045

  123. 123.

    Shakoori A, Ougolkov A, Yu ZW, Zhang B, Modarressi MH, Billadeau DD, Mai M, Takahashi Y, Minamoto T. Deregulated GSK3beta activity in colorectal cancer: its association with tumor cell survival and proliferation. Biochem Biophys Res Commun. 2005;334:1365-1373.

    Not in our library10.1016/j.bbrc.2005.07.041

  124. 124.

    Ougolkov AV, Fernandez-Zapico ME, Savoy DN, Urrutia RA, Billadeau DD. Glycogen synthase kinase-3beta participates in nuclear factor kappaB-mediated gene transcription and cell survival in pancreatic cancer cells. Cancer Res. 2005;65:2076-2081.

    Not in our library10.1158/0008-5472.can-04-3642

  125. 125.

    Zhou W, Wang L, Gou SM, Wang TL, Zhang M, Liu T, Wang CY. shRNA silencing glycogen synthase kinase-3 beta inhibits tumor growth and angiogenesis in pancreatic cancer. Cancer Letters. 2012;316:178-186.

    Not in our library10.1016/j.canlet.2011.10.033

  126. 126.

    Farago M, Dominguez I, Landesman-Bollag E, Xu X, Rosner A, Cardiff RD, Seldin DC. Kinase-inactive glycogen synthase kinase 3beta promotes Wnt signaling and mammary tumorigenesis. Cancer Res. 2005;65:5792-5801.

    Not in our library10.1158/0008-5472.can-05-1021

  127. 127.

    Ma C, Wang J, Gao Y, Gao TW, Chen G, Bower KA, Odetallah M, Ding M, Ke Z, Luo J. The role of glycogen synthase kinase 3beta in the transformation of epidermal cells. Cancer Res. 2007;67:7756-7764.

    Not in our library10.1158/0008-5472.can-06-4665

  128. 128.

    Dong J, Peng J, Zhang H, Mondesire WH, Jian W, Mills GB, Hung MC, Meric-Bernstam F. Role of glycogen synthase kinase 3beta in rapamycin-mediated cell cycle regulation and chemosensitivity. Cancer Res. 2005;65:1961-1972.

    Not in our library10.1158/0008-5472.can-04-2501

  129. 129.

    Dal Col J, Dolcetti R. GSK-3beta inhibition: at the crossroad between Akt and mTOR constitutive activation to enhance cyclin D1 protein stability in mantle cell lymphoma. Cell Cycle. 2008;7:2813-2816.

    Not in our library10.4161/cc.7.18.6733

  130. 130.

    Wang Y, Lam JB, Lam KS, Liu J, Lam MC, Hoo RL, Wu D, Cooper GJ, Xu A. Adiponectin modulates the glycogen synthase kinase-3beta/betacatenin signaling pathway and attenuates mammary tumorigenesis of MDA-MB-231 cells in nude mice. Cancer Res. 2006;66:11462-11470.

    Not in our library10.1158/0008-5472.can-06-1969

  131. 131.

    Bartkova J, Lukas J, Müller H, Lützhøft D, Strauss M, Bartek J. Cyclin D1 protein expression and function in human breast cancer. Int J Cancer. 1994;57:353-361.

    Not in our library10.1002/ijc.2910570311

  132. 132.

    Gillett C, Fantl V, Smith R, Fisher C, Bartek J, Dickson C, Barnes D, Peters G. Amplification and overexpression of cyclin D1 in breast cancer detected by immunohistochemical staining. Cancer Res. 1994;54:1812-1817.

    Not in our library

  133. 133.

    Dickson C, Fantl V, Gillett C, Brookes S, Bartek J, Smith R, Fisher C, Barnes D, Peters G. Amplification of chromosome band 11q13 and a role for cyclin D1 in human breast cancer. Cancer Lett. 1995;90:43-50.

    Not in our library10.1016/0304-3835(94)03676-a

  134. 134.
    β-Catenin, a novel prognostic marker for breast cancer: Its roles in cyclin D1 expression and cancer progression · 2000
    Not checked
  135. 135.

    Hsu W, Shakya R, Costantini F. Impaired mammary gland and lymphoid development caused by inducible expression of Axin in transgenic mice. J Cell Biol. 2001;155:1055-1064.

    Not in our library10.1083/jcb.200107066

  136. 136.

    Landesman-Bollag E, Song DH, Romieu-Mourez R, Sussman DJ, Cardiff RD, Sonenshein GE, Seldin DC. Protein kinase CK2: signaling and tumorigenesis in the mammary gland. Mol Cell Biochem. 2001;227:153-165.

    Not in our library

  137. 137.

    Sokolosky M, Chappell WH, Stadelman K, Abrams SL, Davis NM, Steelman LS, McCubrey JA. Inhibition of GSK-3β activity can result in drug and hormonal resistance and alter sensitivity to targeted therapy in MCF-7 breast cancer cells. Cell Cycle. 2014.

    Not in our library10.4161/cc.27728

  138. 138.

    Bahram F, von der Lehr N, Cetinkaya C, Larsson LG. c-Myc hot spot mutations in lymphomas result in inefficient ubiquitination and decreased proteasome-mediated turnover. Blood. 2000;95:2104-2110.

    Not in our library

  139. 139.

    Oster SK, Ho CS, Soucie EL, Penn LZ. The myc oncogene: MarvelouslY Complex. Adv Cancer Res. 2002;84:81-154.

    Not in our library10.1016/s0065-230x(02)84004-0

  140. 140.

    Gregory MA, Qi Y, Hann SR. Phosphorylation by glycogen synthase kinase-3 controls c-myc proteolysis and subnuclear localization. J Biol Chem. 2003;278:51606-51612.

    Not in our library10.1074/jbc.m310722200

  141. 141.
    DNA-dependent protein kinase catalytic subunit modulates the stability of c-Myc oncoprotein · 2008
    Not checked
  142. 142.

    de Castro J, Gamallo C, Palacios J, Moreno-Bueno G, Rodriguez N, Feliu J, Gonzalez-Baron M. beta-catenin expression pattern in primary oesophageal squamous cell carcinoma. Relationship with clinicopathologic features and clinical outcome. Virchows Arch. 2000;437:599-604.

    Not in our library10.1007/s004280000266

  143. 143.

    Amit S, Hatzubai A, Birman Y, Andersen JS, Ben-Shushan E, Mann M, Ben-Neriah Y, Alkalay I. Axin-mediated CKI phosphorylation of beta-catenin at Ser 45: a molecular switch for the Wnt pathway. Genes Dev. 2002;16:1066-1076.

    Not in our library10.1101/gad.230302

  144. 144.

    Iwai S, Katagiri W, Kong C, Amekawa S, Nakazawa M, Yura Y. Mutations of the APC, beta-catenin, and axin 1 genes and cytoplasmic accumulation of beta-catenin in oral squamous cell carcinoma. J Cancer Res Clin Oncol. 2005;131:773-782.

    Not in our library10.1007/s00432-005-0027-y

  145. 145.

    Yeh KT, Chang JG, Lin TH, Wang YF, Chang JY, Shih MC, Lin CC. Correlation between protein expression and epigenetic and mutation changes of Wnt pathway-related genes in oral cancer. Int J Oncol. 2003;23:1001-1007.

    Not in our library

  146. 146.

    Sokolosky ML, Stadelman KM, Chappell WH, Abrams SL, Martelli AM, Stivala F, Libra M, Nicoletti F, Drobot LB, Franklin RA, Steelman LS, McCubrey JA. Involvement of Akt-1 and mTOR in sensitivity of breast cancer to targeted therapy. Oncotarget. 2011;2:538-550.

    Not in our library10.18632/oncotarget.302

  147. 147.

    Taylor JR, Lehmann BD, Chappell WH, Abrams SL, Steelman LS, McCubrey JA. Cooperative effects of Akt-1 and Raf-1 on the induction of cellular senescence in doxorubicin or tamoxifen treated breast cancer cells. Oncotarget. 2011;2:610-626.

    Not in our library10.18632/oncotarget.315

  148. 148.

    Hafsi S, Pezzino FM, Candido S, Ligresti G, Spandidos DA, Soua Z, McCubrey JA, Travali S, Libra M. Gene alterations in the PI3K/PTEN/AKT pathway as a mechanism of drug-resistance. Int J Oncol. 2012;40:639-644.

    Not in our library10.3892/ijo.2011.1312

  149. 149.

    Steelman LS, Navolanic P, Chappell WH, Abrams SL, Wong EW, Martelli AM, Cocco L, Stivala F, Libra M, Nicoletti F, Drobot LB, Franklin RA, McCubrey JA. Involvement of Akt and mTOR in chemotherapeutic- and hormonal-based drug resistance and response to radiation in breast cancer cells. Cell Cycle. 2011;10:3003-3015.

    Not in our library10.4161/cc.10.17.17119

  150. 150.

    Martelli AM, Evangelisti C, Chappell W, Abrams SL, Bäsecke J, Stivala F, Donia M, Fagone P, Nicoletti F, Libra M, Ruvolo V, Ruvolo P, Kempf CR, Steelman LS, McCubrey JA. Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway. Leukemia. 2011;25:1064-1079.

    Not in our library10.1038/leu.2011.46

  151. 151.
    Roles of the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways in controlling growth and sensitivity to therapy-implications for cancer and aging · 2011
    No notice
  152. 152.
    Phosphorylation of AKT: a Mutational Analysis · 2011
    No notice
  153. 153.

    Zawel L. P3Kalpha: a driver of tumor metastasis? Oncotarget. 2010;1:315-316.

    Not in our library10.18632/oncotarget.162

  154. 154.

    Schmidt-Kittler O, Zhu J, Yang J, Liu G, Hendricks W, Lengauer C, Gabelli SB, Kinzler KW, Vogelstein B, Huso DL, Zhou S. PI3Kalpha inhibitors that inhibit metastasis. Oncotarget. 2010;1:339-348.

    Not in our library10.18632/oncotarget.166

  155. 155.

    Garrett JT, Chakrabarty A, Arteaga CL. Will PI3K pathway inhibitors be effective as single agents in patients with cancer? Oncotarget. 2011;2:1314-1321.

    Not in our library10.18632/oncotarget.409

  156. 156.

    Sander S, Rajewsky K. Burkitt lymphomagenesis linked to MYC plus PI3K in germinal center B cells. Oncotarget. 2012;3:1066-1067.

    Not in our library10.18632/oncotarget.726

  157. 157.

    Alinari L, Christian B, Baiocchi RA. Novel targeted therapies for mantle cell lymphoma. Oncotarget. 2012;3:203-211.

    Not in our library10.18632/oncotarget.426

  158. 158.

    Antico Arciuch VG, Russo MA, Dima M, Kang KS, Dasrath F, Liao XH, Refetoff S, Montagna C, Di Cristofano A. Thyrocyte-specific inactivation of p53 and Pten results in anaplastic thyroid carcinomas faithfully recapitulating human tumors. Oncotarget. 2011;2:1109-1126.

    Not in our library10.18632/oncotarget.380

  159. 159.

    Weber GL, Parat MO, Binder ZA, Gallia GL, Riggins GJ. Abrogation of PIK3CA or PIK3R1 reduces proliferation, migration, and invasion in glioblastoma multiforme cells. Oncotarget. 2011;2:833-849.

    Not in our library10.18632/oncotarget.346

  160. 160.

    Dbouk HA, Backer JM. A beta version of life: p110beta takes center stage. Oncotarget. 2010;1:729-733.

    Not in our library10.18632/oncotarget.207

  161. 161.

    Burger JA, Hoellenriegel J. Phosphoinositide 3'-kinase delta: turning off BCR signaling in chronic lymphocytic leukemia. Oncotarget. 2011;2:737-738.

    Not in our library10.18632/oncotarget.341

  162. 162.

    Adams JR, Schachter NF, Liu JC, Zacksenhaus E, Egan SE. Elevated PI3K signaling drives multiple breast cancer subtypes. Oncotarget. 2011;2:435-447.

    Not in our library10.18632/oncotarget.285

  163. 163.

    Agoulnik IU, Hodgson MC, Bowden WA, Ittmann MM. INPP4B: the new kid on the PI3K block. Oncotarget. 2011;2:321-328.

    Not in our library10.18632/oncotarget.260

  164. 164.

    Martelli AM, Chiarini F, Evangelisti C, Cappellini A, Buontempo F, Bressanin D, Fini M, McCubrey JA. Dual Inhibitors of phosphatidylinositol 3-kinase and mammalian target of rapamycin: a novel therapeutic strategy for acute leukemia treatment? Oncotarget. 2012;3:371-394.

    Not in our library10.18632/oncotarget.477

  165. 165.

    Martelli AM, Chiarini F, Evangelisti C, Ognibene A, Bressanin D, Billi AM, Manzoli L, Cappellini A, McCubrey JA. Targeting the liver Kinase B1/AMP-dependent kinase pathway as a therapeutic strategy for hematological malignancies. Expert Opinion Therapeutic Targets. 2012;16:729-742.

    Not in our library10.1517/14728222.2012.694869

  166. 166.

    Peterson TR, Laplante M, Thoreen CC, Sancak Y, Kang SA, Kuehl WM, Gray NS, Sabatini DM. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell. 2009;137:873-886.

    Not in our library10.1016/j.cell.2009.03.046

  167. 167.

    Chiarini F, Lonetti A, Teti G, Orsini E, Bressanin D, Cappellini A, Ricci F, Tazzari PL, Ognibene A, Falconi M, Pagliaro P, Iacobucci I, Martinelli G, Amadori S, McCubrey JA, Martelli AM. A combination of temsirolimus, an allosteric mTOR inhibitor, with clofarabine as a new therapeutic option for patients withacute myeloid leukemia. Oncotarget. 2012;3:1615-1628.

    Not in our library10.18632/oncotarget.762

  168. 168.

    Bressanin D, Evangelisti C, Ricci F, Tabellini G, Chiarini F, Tazzari PL, Melchionda F, Buontempo F, Pagliaro P, Pession A, McCubrey JA, Martelli AM. Harnessing the PI3K/Akt/mTOR pathway in T-cell acute lymphoblastic leukemia: eliminating activity by targeting at different levels. Oncotarget. 2012;3:811-823.

    Not in our library10.18632/oncotarget.579

  169. 169.

    McCubrey JA, Steelman LS, Bertrand FE, Davis NM, Abrams SL, Montalto G, D'Assoro AB, Libra M, Nicoletti F, Maestro R, Basecke J, Cocco L, Cervello M, Martelli AM. Multifaceted roles of GSK-3 and Wnt/β-catenin in hematopoiesis and leukemogenesis: opportunities for therapeutic intervention. Leukemia. 2014;28:15-33.

    Not in our library10.1038/leu.2013.184

  170. 170.

    Grimaldi C, Chiarini F, Tabellini G, Ricci F, Tazzari PL, Battistelli M, Falcieri E, Bortul R, Melchionda F, Iacobucci I, Pagliaro P, Martinelli G, Pession A, Barata JT, McCubrey JA, Martelli AM. AMP-dependent kinase/mammalian target of rapamycin complex 1 signaling in T-cell acute lymphoblastic leukemia: therapeutic implications. Leukemia. 2012;26:91-100.

    Not in our library10.1038/leu.2011.269

  171. 171.

    Martelli AM, Chiarini F, Evangelisti C, Ognibene A, Bressanin D, Billi AM, Manzoli L, Cappellini A, McCubrey JA. Targeting the liver kinase B1/AMP-activated protein kinase pathway as a therapeutic strategy for hematological malignancies. Expert Opin Ther Targets. 2012;16:729-742.

    Not in our library10.1517/14728222.2012.694869

  172. 172.

    Habib SL. Mechanism of activation of AMPK and upregulation of OGG1 by rapamycin in cancer cells. Oncotarget. 2011;2:958-959.

    Not in our library10.18632/oncotarget.381

  173. 173.

    Jansen M, Ten Klooster JP, Offerhaus GJ, Clevers H. LKB1 and AMPK family signaling: the intimate link between cell polarity and energy metabolism. Physiol Rev. 2009;89:777-798.

    Not in our library10.1152/physrev.00026.2008

  174. 174.

    van der Velden YU, Haramis AP. Insights from model organisms on the functions of the tumor suppressor protein LKB1: zebrafish chips in. Aging. 2011;3:363-367.

    Not in our library10.18632/aging.100319

  175. 175.

    Godlewski J, Bronisz A, Nowicki MO, Chiocca EA, Lawler S. microRNA-451: A conditional switch controlling glioma cell proliferation and migration. Cell Cycle. 2010;9:2742-2748.

    Not in our library

  176. 176.

    Liu B, Fan Z, Edgerton SM, Yang X, Lind SE, Thor AD. Potent anti-proliferative effects of metformin on trastuzumab-resistant breast cancer cells via inhibition of erbB2/IGF-1 receptor interactions. Cell Cycle. 2011;10:2959-2966.

    Not in our library10.4161/cc.10.17.16359

  177. 177.

    Vazquez-Martin A, Oliveras-Ferraros C, Cufi S, Martin-Castillo B, Menendez JA. Metformin activates an ataxia telangiectasia mutated (ATM)/Chk2-regulated DNA damage-like response. Cell Cycle. 2011;10:1499-1501.

    Not in our library10.4161/cc.10.9.15423

  178. 178.

    Mashhedi H, Blouin MJ, Zakikhani M, David S, Zhao Y, Bazile M, Birman E, Algire C, Aliaga A, Bedell BJ, Pollak M. Metformin abolishes increased tumor (18)F-2-fluoro-2-deoxy-D-glucose uptake associated with a high energy diet. Cell Cycle. 2011;10:2770-2778.

    Not in our library10.4161/cc.10.16.16219

  179. 179.

    Oliveras-Ferraros C, Cufi S, Vazquez-Martin A, Torres-Garcia VZ, Del Barco S, Martin-Castillo B, Menendez JA. Micro(mi)RNA expression profile of breast cancer epithelial cells treated with the anti-diabetic drug metformin: induction of the tumor suppressor miRNA let-7a and suppression of the TGFbeta-induced oncomiR miRNA-181a. Cell Cycle. 2011;10:1144-1451.

    Not in our library10.4161/cc.10.7.15210

  180. 180.

    Chappell WH, Abrams SL, Franklin RA, Lahair MM, Montalto G, Cervello M, Martelli AM, Nicoletti F, Candido S, Libra M, Polesel J, Talamini R, Milella M, Tafuri A, Steelman LS, McCubrey JA. Ectopic NGAL expression can alter sensitivity of breast cancer cells to EGFR, Bcl-2, CaM-K inhibitors and the plant natural product berberine. Cell Cycle. 2012;11:4447-4461.

    Not in our library10.4161/cc.22786

  181. 181.

    Krymskaya VP, Goncharova EA. PI3K/mTORC1 activation in hamartoma syndromes: therapeutic prospects. Cell Cycle. 2009;8:403-413.

    Not in our library10.4161/cc.8.3.7555

  182. 182.

    Sato T, Nakashima A, Guo L, Tamanoi F. Specific activation of mTORC1 by Rheb G-protein in vitro involves enhanced recruitment of its substrate protein. J Biol Chem. 2009;284:12783-12791.

    Not in our library10.1074/jbc.m809207200

  183. 183.
    Mutations and Deregulation of Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR Cascades Which Alter Therapy Response. · 2012
    No notice
  184. 184.
    Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR Cascade Inhibitors: How Mutations Can Result in Therapy Resistance and How to Overcome Resistance · 2012
    No notice
  185. 185.
    Targeted therapy for hepatocellular carcinoma: novel agents on the horizon · 2012
    No notice
  186. 186.

    Carracedo A, Ma L, Teruya-Feldstein J, Rojo F, Salmena L, Alimonti A, Egia A, Sasaki AT, Thomas G, Kozma SC, Papa A, Nardella C, Cantley LC, Baselga J, Pandolfi PP. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest. 2008;118:3065-3074.

    Not in our library10.1172/jci34739

  187. 187.

    Tamburini J, Green AS, Chapuis N, Bardet V, Lacombe C, Mayeux P, Bouscary D. Targeting translation in acute myeloid leukemia: a new paradigm for therapy? Cell Cycle. 2009;8:3893-3899.

    Not in our library10.4161/cc.8.23.10091

  188. 188.

    Wang H, Brown J, Gu Z, Garcia CA, Liang R, Alard P, Beurel E, Jope RS, Greenway T, Martin M. Convergence of the mammalian target of rapamycin complex 1- and glycogen synthase kinase 3-β-signaling pathways regulates the innate inflammatory response. J Immunol. 2011;186:5217-5226.

    Not in our library10.4049/jimmunol.1002513

  189. 189.

    Inoki K, Ouyang H, Zhu T, Lindvall C, Wang Y, Zhang X, Yang Q, Bennett C, Harada Y, Stankunas K, Wang CY, He X, MacDougald OA, You M, Williams BO, Guan KL. TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell. 2006;126:955-968.

    Not in our library10.1016/j.cell.2006.06.055

  190. 190.

    Koo J, Yue P, Gal AA, Khuri FR, Sun SY. Maintaining glycogen synthase kinase-3 activity is critical for mTOR kinase inhibitors to inhibit cancer cell growth. Cancer Res. 2014.

    Not in our library10.1158/0008-5472.can-13-2946

  191. 191.

    Huang J, Zhang Y, Bersenev A, O'Brien WT, Tong W, Emerson SG, Klein PS. Pivotal role for glycogen synthase kinase-3 in hematopoietic stem cell homeostasis in mice. J Clin Invest. 2009;119:3519-3529.

    Not in our library10.1172/jci40572

  192. 192.

    Yilmaz OH, Valdez R, Theisen BK, Guo W, Ferguson DO, Wu H, Morrison SJ. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature. 2006;441:475-482.

    Not in our library10.1038/nature04703

  193. 193.

    Chen C, Liu Y, Liu R, Ikenoue T, Guan KL, Liu Y, Zheng P. TSC-mTOR maintains quiescence and function of hematopoietic stem cells by repressing mitochondrial biogenesis and reactive oxygen species. J Exp Med. 2008;205:2397-2408.

    Not in our library10.1084/jem.20081297

  194. 194.

    Lee JY, Nakada D, Yilmaz OH, Tothova Z, Joseph NM, Lim MS, Gilliland DG, Morrison SJ. mTOR activation induces tumor suppressors that inhibit leukemogenesis and deplete hematopoietic stem cells after Pten deletion. Cell Stem Cell. 2010;7:593-605.

    Not in our library10.1016/j.stem.2010.09.015

  195. 195.

    Adams GB, Scadden DT. The hematopoietic stem cell in its place. Nat Immunol. 2006;7:333-337.

    Not in our library10.1038/ni1331

  196. 196.

    Gan B, Hu J, Jiang S, Liu Y, Sahin E, Zhuang L, Fletcher-Sananikone E, Colla S, Wang YA, Chin L, Depinho RA. Lkb1 regulates quiescence and metabolic homeostasis of haematopoietic stem cells. Nature. 2010;468:701-704.

    Not in our library10.1038/nature09595

  197. 197.

    Gurumurthy S, Xie SZ, Alagesan B, Kim J, Yusuf RZ, Saez B, Tzatsos A, Ozsolak F, Milos P, Ferrari F, Park PJ, Shirihai OS, Scadden DT, Bardeesy N. The Lkb1 metabolic sensor maintains haematopoietic stem cell survival. Nature. 2010;468:659-663.

    Not in our library10.1038/nature09572

  198. 198.

    Gan B, DePinho RA. mTORC1 signaling governs hematopoietic stem cell quiescence. Cell Cycle. 2009;8:1003-1006.

    Not in our library10.4161/cc.8.7.8045

  199. 199.

    Chen C, Liu Y, Liu Y, Zheng P. mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Sci Signal. 2009;2:ra75.

    Not in our library10.1126/scisignal.2000559

  200. 200.

    Huang J, Nguyen-McCarty M, Hexner EO, Danet-Desnoyers G, Klein PS. Maintenance of hematopoietic stem cells through regulation of Wnt and mTOR pathways. Nat Med. 2012;18:1778-1785.

    Not in our library10.1038/nm.2984

  201. 201.

    Ito K, Carracedo A, Weiss D, Arai F, Ala U, Avigan DE, Schafer ZT, Evans RM, Suda T, Lee CH, Pandolfi PP. A PML–PPAR-delta pathway for fatty acid oxidation regulates hematopoietic stem cell maintenance. Nat Med. 2012;18:1350-1358.

    Not in our library10.1038/nm.2882

  202. 202.

    Burns KA, Vanden Heuvel JP. Modulation of PPAR activity via phosphorylation. Biochim Biophys Acta. 2007;1771:952-960.

    Not in our library10.1016/j.bbalip.2007.04.018

  203. 203.

    Clapham JC, Arch JR. Thermogenic and metabolic antiobesity drugs: rationale and opportunities. Diabetes Obes Metab. 2007;9:259-275.

    Not in our library10.1111/j.1463-1326.2006.00608.x

  204. 204.

    Narkar VA, Downes M, Yu RT, Embler E, Wang YX, Banayo E, Mihaylova MM, Nelson MC, Zou Y, Juguilon H, Kang H, Shaw RJ, Evans RM. AMPK and PPARdelta agonists are exercise mimetics. Cell. 2008;134:405-415.

    Not in our library10.1016/j.cell.2008.06.051

  205. 205.

    Ito K, Bernardi R, Morotti A, Matsuoka S, Saglio G, Ikeda Y, Rosenblatt J, Avigan DE, Teruya-Feldstein J, Pandolfi PP. PML targeting eradicates quiescent leukaemia-initiating cells. Nature. 2008;453:1072-1078.

    Not in our library10.1038/nature07016

  206. 206.

    Bernardi R, Guernah I, Jin D, Grisendi S, Alimonti A, Teruya-Feldstein J, Cordon-Cardo C, Simon MC, Rafii S, Pandolfi PP. PML inhibits HIF-1alpha translation and neoangiogenesis through repression of mTOR. Nature. 2006;442:779-785.

    Not in our library10.1038/nature05029

  207. 207.

    Bernardi R, Papa A, Egia A, Coltella N, Teruya-Feldstein J, Signoretti S, Pandolfi PP. Pml represses tumour progression through inhibition of mTOR. EMBO Mol Med. 2011;3:249-257.

    Not in our library10.1002/emmm.201100130

  208. 208.

    Sato N, Meijer L, Skaltsounis L, Greengard P, Brivanlou AH. Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nat Med. 2004;10:55-63.

    Not in our library10.1038/nm979

  209. 209.

    Doble BW, Patel S, Wood GA, Kockeritz LK, Woodgett JR. Functional redundancy of GSK-3alpha and GSK-3beta in Wnt/beta-catenin signaling shown by using an allelic series of embryonic stem cell lines. Dev Cell. 2007;12:957-971.

    Not in our library10.1016/j.devcel.2007.04.001

  210. 210.

    Gattinoni L, Klebanoff CA, Restifo NP. Pharmacologic induction of CD8+ T cell memory: better living through chemistry. Sci Transl Med. 2009;1:11ps12.

    Not in our library10.1126/scitranslmed.3000302

  211. 211.

    Gattinoni L, Lugli E, Ji Y, Pos Z, Paulos CM, Quigley MF, Almeida JR, Gostick E, Yu Z, Carpenito C, Wang E, Douek DC, Price DA, June CH, Marincola FM, Roederer M, et al. A human memory T cell subset with stem cell-like properties. Nat Med. 2011;17:1290-1297.

    Not in our library10.1038/nm.2446

  212. 212.

    Gattinoni L, Klebanoff CA, Restifo NP. Paths to stemness: building the ultimate antitumour T cell. Nat Rev Cancer. 2012;12:671-684.

    Not in our library10.1038/nrc3322

  213. 213.

    Clevers H, Nusse R. Wnt/β-catenin signaling and disease. Cell. 2012;149:1192-1205.

    Not in our library10.1016/j.cell.2012.05.012

  214. 214.

    Anastas JN, Moon RT. WNT signalling pathways as therapeutic targets in cancer. Nat Rev Cancer. 2013;13:11-26.

    Not in our library10.1038/nrc3419

  215. 215.

    Wang J, Sinha T, Wynshaw-Boris A. Wnt signaling in mammalian development: lessons from mouse genetics. Cold Spring Harb Perspect Biol. 2012;4(5).

    Not in our library10.1101/cshperspect.a007963

  216. 216.

    van Noort M, Meeldijk J, van der Zee R, Destree O, Clevers H. Wnt signaling controls the phosphorylation status of beta-catenin. J Biol Chem. 2002;277:17901-17905.

    Not in our library10.1074/jbc.m111635200

  217. 217.

    Hagen T, Vidal-Puig A. Characterisation of the phosphorylation of beta-catenin at the GSK-3 priming site Ser45. Biochem Biophys Res Commun. 2002;294:324-328.

    Not in our library10.1016/s0006-291x(02)00485-0

  218. 218.

    Hagen T, di Daniel E, Culbert AA, Reith AD. Expression and characterization of GSK-3 mutants and their effect on beta-catenin phosphorylation in intact cells. J Biol Chem. 2002;277:23330-23335.

    Not in our library10.1074/jbc.m201364200

  219. 219.

    Liu C, Li Y, Semenov M, Han C, Baeg GH, Tan Y, Zhang Z, Lin X, He X. Control of beta-. catenin phosphorylation/degradation by a dual-kinase mechanism. Cell. 2002;108:837-847.

    Not in our library10.1016/s0092-8674(02)00685-2

  220. 220.

    Sakanaka C. Phosphorylation and regulation of beta-catenin by casein kinase I epsilon. J Biochem. 2002;132:697-703.

    Not in our library10.1093/oxfordjournals.jbchem.a003276

  221. 221.

    Yanagawa S, Matsuda Y, Lee JS, Matsubayashi H, Sese S, Kadowaki T, Ishimoto A. Casein kinase I phosphorylates the Armadillo protein and induces its degradation in Drosophila. EMBO J. 2002;21:1733-1742.

    Not in our library10.1093/emboj/21.7.1733

  222. 222.

    Ikeda S, Kishida S, Yamamoto H, Murai H, Koyama S, Kikuchi A. Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3beta and beta-catenin and promotes GSK-3beta-dependent phosphorylation of beta-catenin. EMBO J. 1998;17:1371-1384.

    Not in our library10.1093/emboj/17.5.1371

  223. 223.

    Jho E, Lomvardas S, Costantini F. A GSK3beta phosphorylation site in axin modulates interaction with beta-catenin and Tcf-mediated gene expression. Biochem Biophys Res Commun. 1999;266:28-35.

    Not in our library10.1006/bbrc.1999.1760

  224. 224.

    Yamamoto H, Kishida S, Kishida M, Ikeda S, Takada S, Kikuchi A. Phosphorylation of axin, a Wnt signal negative regulator, by glycogen synthase kinase-3beta regulates its stability. J Biol Chem. 1999;274:10681-10684.

    Not in our library10.1074/jbc.274.16.10681

  225. 225.

    Rubinfeld B, Albert I, Porfiri E, Fiol C, Munemitsu S, Polakis. Binding of GSK3beta to the APC-beta-catenin complex and regulation of complex assembly. Science. 1996;272:1023-1026.

    Not in our library10.1126/science.272.5264.1023

  226. 226.

    Schwarz-Romond T, Asbrand C, Bakkers J, Kuhl M, Schaeffer HJ, Huelsken J, Behrens J, Hammerschmidt M, Birchmeier W. The ankyrin repeat protein Diversin recruits Casein kinase I epsilon to the beta-catenin degradation complex and acts in both canonical Wnt and Wnt/JNK signaling. Genes Dev. 2002;16:2073-2084.

    Not in our library10.1101/gad.230402

  227. 227.

    Bax B, Carter PS, Lewis C, Guy AR, Bridges A, Tanner R, Pettman G, Mannix C, Culbert AA, Brown MJ, Smith DG, Reith AD. The structure of phosphorylated GSK-3beta complexed with a peptide, FRATtide, that inhibits beta-catenin phosphorylation. Structure. 2001;9:1143-1152.

    Not in our library10.1016/s0969-2126(01)00679-7

  228. 228.

    Ferkey DM, Kimelman D. Glycogen synthase kinase-3 beta mutagenesis identifies a common binding domain for GBP and Axin. J Biol Chem. 2002;277:16147-16152.

    Not in our library10.1074/jbc.m112363200

  229. 229.

    Franca-Koh J, Yeo M, Fraser E, Young N, Dale TC. The regulation of glycogen synthase kinase-3 nuclear export by Frat/GBP. J Biol Chem. 2002;277:43844-43848.

    Not in our library10.1074/jbc.m207265200

  230. 230.

    Ding VW, Chen RH, McCormick F. Differential regulation of glycogen synthase kinase 3beta by insulin and Wnt signaling. J Biol Chem. 2000;275:32475-32481.

    Not in our library10.1074/jbc.m005342200

  231. 231.

    Yuan H, Mao J, Li L, Wu D. Suppression of glycogen synthase kinase activity is not sufficient for leukemia enhancer factor-1 activation. J Biol Chem. 1999;274:30419-30423.

    Not in our library10.1074/jbc.274.43.30419

  232. 232.

    Zeng X, Tamai K, Doble B, Li S, Huang H, Habas R, Okamura H, Woodgett J, He X. A dual-kinase mechanism for Wnt co-receptor phosphorylation and activation. Nature. 2005;438:873-877.

    Not in our library10.1038/nature04185

  233. 233.

    Zeng X, Huang H, Tamai K, Zhang X, Harada Y, Yokota C, Almeida K, Wang J, Doble B, Woodgett J, Wynshaw-Boris A, Hsieh JC, He X. Initiation of Wnt signaling: control of Wnt coreceptor Lrp6 phosphorylation/activation via frizzled, dishevelled and axin functions. Development. 2008;135:367-375.

    Not in our library10.1242/dev.013540

  234. 234.

    MacDonald BT, Tamai K, He X. Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell. 2009;17:9-26.

    Not in our library10.1016/j.devcel.2009.06.016

  235. 235.

    Davidson G, Wu W, Shen J, Bilic J, Fenger U, Stannek P, Glinka A, Niehrs C. Casein kinase 1 gamma couples Wnt receptor activation to cytoplasmic signal transduction. Nature. 2005;438:867-872.

    Not in our library10.1038/nature04170

  236. 236.

    Wu D, Pan W. GSK3: a multifaceted kinase in Wnt signaling. Trends Biochem Sci. 2010;35:161-168.

    Not in our library10.1016/j.tibs.2009.10.002

  237. 237.

    Major MB, Camp ND, Berndt JD, Yi X, Goldenberg SJ, Hubbert C, Biechele TL, Gingras AC, Zheng N, Maccoss MJ, Angers S, Moon RT. Wilms tumor suppressor WTX negatively regulates WNT/beta-catenin signaling. Science. 2007;316:1043-1046.

    Not in our library10.1126/science/1141515

  238. 238.

    Valvezan AJ, Zhang F, Diehl JA, Klein PS. Adenomatous polyposis coli (APC) regulates multiple signaling pathways by enhancing glycogen synthase kinase-3 (GSK-3) activity. J Biol Chem. 2012;287:3823-3832.

    Not in our library10.1074/jbc.m111.323337

  239. 239.

    Desbois-Mouthon C, Blivet-Van Eggelpoël MJ, Beurel E, Boissan M, Delélo R, Cadoret A, Capeau J. Dysregulation of glycogen synthase kinase-3beta signaling in hepatocellular carcinoma cells. Hepatology. 2002;36(6):1528-36.

    Not in our library10.1053/jhep.2002.37192

  240. 240.

    Huang KT, Huang YH, Li P, He B, Chen ZK, Yu X, Chen JO, Zhang QY, Shi HQ, Shan YF. The correlation between TSC2 and GSK3β levels, and outcomes of patients with hepatocellular carcinoma treated by hepatectomy. Hepatol Res. 2013.

    Not in our library10.1111/hepr.12256

  241. 241.

    Huang KT, Huang YH, Li P, He B, Chen ZK, Yu X, Chen JO, Zhang QY, Shi HQ, Shan YF. The correlation between TSC2 and GSK3β levels, and outcomes of patients with hepatocellular carcinoma treated by hepatectomy. Hepatol Res. 2013.

    Not in our library10.1111/hepr.12256

  242. 242.

    Desbois-Mouthon C, Blivet-Van Eggelpoël MJ, Beurel E, Boissan M, Delélo R, Cadoret A, Capeau J. Dysregulation of glycogen synthase kinase-3beta signaling in hepatocellular carcinoma cells. Hepatology. 2002;36:1528-1536.

    Not in our library10.1053/jhep.2002.37192

  243. 243.

    Ding Q, Xia W, Liu JC, Yang JY, Lee DF, Xia J, Bartholomeusz G, Li Y, Pan Y, Li Z, Bargou RC, Qin J, Lai CC, Tsai FJ, Tsai CH, Hung MC. Erk associates with and primes GSK-3beta for its inactivation resulting in upregulation of beta-catenin. Mol Cell. 2005;19(2):159-70.

    Not in our library10.1016/j.molcel.2005.06.009

  244. 244.

    Cai X1, Li M, Vrana J, Schaller MD. Glycogen synthase kinase 3-beta and extracellular signal-regulated kinase-dependent phosphorylation of paxillin regulates cytoskeletal rearrangement. Mol Cell Biol. 2006;26:2857-2868.

    Not in our library10.1128/mcb.26.7.2857-2868.2006

  245. 245.

    Liu J, Ding X, Tang J, Cao Y, Hu P, Zhou F, Shan X, Cai X, Chen Q, Ling N, Zhang B, Bi Y, Chen K, Ren H, Huang A, He TC, Tang N. Enhancement of canonical Wnt/β-catenin signaling activity by HCV core protein promotes cell growth of hepatocellular carcinoma cells. PLoS One. 2011;6(11):e27496.

    Not in our library10.1371/journal.pone.0027496

  246. 246.

    Chen J, Chan AW, To KF, Chen W, Zhang Z, Ren J, Song C, Cheung YS, Lai PB, Cheng SH, Ng MH, Huang A, Ko BC. SIRT2 overexpression in hepatocellular carcinoma mediates epithelial to mesenchymal transition by protein kinase B/glycogen synthase kinase-3β/β-catenin signaling. Hepatology. 2013;57(6):2287-98.

    Not in our library10.1002/hep.26278

  247. 247.
    The sirtuins, oxidative stress and aging: an emerging link · 2013
    No notice
  248. 248.

    Shakoori A, Mai W, Miyashita K, Yasumoto K, Takahashi Y, Ooi A, Kawakami K, Minamoto T. Inhibition of GSK-3beta activity attenuates proliferation of human colon cancer cells in rodents. Cancer Sci. 2007;98:1388-1393.

    Not in our library10.1111/j.1349-7006.2007.00545.x

  249. 249.

    Kunnimalaiyaan M, Vaccaro AM, Ndiaye MA, Chen H. Inactivation of glycogen synthase kinase-3β, a downstream target of the raf-1 pathway, is associated with growth suppression in medullary thyroid cancer cells. Mol Cancer Ther. 2007;6:1151-8.

    Not in our library10.1158/1535-7163.mct-06-0665

  250. 250.

    Smalley KS, Contractor R, Haass NK, Kulp AN, Atilla-Gokcumen GE, Williams DS, Bregman H, Flaherty KT, Soengas MS, Meggers E, Herlyn M. An organometallic protein kinase inhibitor pharmacologically activates p53 and induces apoptosis in human melanoma cells. Cancer Res. 2007;67:209-217.

    Not in our library10.1158/0008-5472.can-06-1538

  251. 251.

    Miyashita K, Kawakami K, Nakada M, Mai W, Shakoori A, Fujisawa H, Hayashi Y, Hamada J, Minamoto T. Potential therapeutic effect of glycogen synthase kinase 3beta inhibition against human glioblastoma. Clin Cancer Res. 2009;15:887-897.

    Not in our library10.1158/1078-0432.ccr-08-0760

  252. 252.

    Pyko IV, Nakada M, Sabit H, Teng L, Furuyama N, Hayashi Y, Kawakami K, Minamoto T, Fedulau AS, Hamada J. Glycogen synthase kinase 3β inhibition sensitizes human glioblastoma cells to temozolomide by affecting O6-methylguanine DNA methyltransferase promoter methylation via c-Myc signaling. Carcinogenesis. 2013;34:2206-2217.

    Not in our library10.1093/carcin/bgt182

  253. 253.

    Kitano A, Shimasaki T, Chikano Y, Nakada M, Hirose M, Higashi T, Ishigaki Y, Endo Y, Takino T, Sato H, Sai Y, Miyamoto K, Motoo Y, Kawakami K, Minamoto T. Aberrant glycogen synthase kinase 3β is involved in pancreatic cancer cell invasion and resistance to therapy. PLoS One. 2013;8(2):e55289.

    Not in our library10.1371/journal.pone.0055289

  254. 254.

    Mai W, Kawakami K, Shakoori A, Kyo S, Miyashita K, Yokoi K, Jin M, Shimasaki T, Motoo Y, Minamoto T. Deregulated GSK3beta sustains gastrointestinal cancer cells survival by modulating human telomerase reverse transcriptase and telomerase. Clin Cancer Res. 2009;15:6810-6819.

    Not in our library10.1158/1078-0432.ccr-09-0973

  255. 255.

    Beurel E, Blivet-Van Eggelpoël MJ, Kornprobst M, Moritz S, Delelo R, Paye F, Housset C, Desbois-Mouthon C. Glycogen synthase kinase-3 inhibitors augment TRAIL-induced apoptotic death in human hepatoma cells. Biochem Pharmacol. 2009;77:54-65.

    Not in our library10.1016/j.bcp.2008.09.026

  256. 256.

    Mai W, Kawakami K, Shakoori A, Kyo S, Miyashita K, Yokoi K, Jin M, Shimasaki T, Motoo Y, Minamoto T. Deregulated GSK3beta sustains gastrointestinal cancer cells survival by modulating human telomerase reverse transcriptase and telomerase. Clin Cancer Res. 2009;15:6810-6819.

    Not in our library10.1158/1078-0432.ccr-09-0973

  257. 257.

    Beurel E, Blivet-Van Eggelpoël MJ, Kornprobst M, Moritz S, Delelo R, Paye F, Housset C, Desbois-Mouthon C. Glycogen synthase kinase-3 inhibitors augment TRAIL-induced apoptotic death in human hepatoma cells. Biochem Pharmacol. 2009;77:54-65.

    Not in our library10.1016/j.bcp.2008.09.026

  258. 258.

    Fuentealba LC, Eivers E, Ikeda A, Hurtado C, Kuroda H, Pera EM, De Robertis EM. Integrating patterning signals: Wnt/GSK3 regulates the duration of the BMP/Smad1 signal. Cell. 2007;131:980-993.

    Not in our library10.1016/j.cell.2007.09.027

  259. 259.

    Ng JM, Curran T. The Hedgehog's tale: developing strategies for targeting cancer. Nat Rev Cancer. 2011;11:493-501.

    Not in our library10.1038/nrc3079

  260. 260.

    Metcalfe C, de Sauvage FJ. Hedgehog fights back: mechanisms of acquired resistance against smoothened antagonists. Cancer Res. 2011;71:5057-5061.

    Not in our library10.1158/0008-5472.can-11-0923

  261. 261.

    Takenaka K, Kise Y, Miki H. GSK3beta positively regulates Hedgehog signaling through Sufu in mammalian cells. Biochem Biophys Res Commun. 2007;353:501-508.

    Not in our library10.1016/j.bbrc.2006.12.058

  262. 262.

    Kogerman P, Grimm T, Kogerman L, Krause D, Undén AB, Sandstedt B, Toftgård R, Zaphiropoulos PG. Mammalian suppressor-of-fused modulates nuclear-cytoplasmic shuttling of Gli-1. Nat Cell Biol. 1999;1:312-319.

    Not in our library10.1038/13031

  263. 263.

    Kise Y, Morinaka A, Teglund S, Miki H. Sufu recruits GSK3beta for efficient processing of Gli3. Biochem Biophys Res Commun. 2009;387:569-574.

    Not in our library10.1016/j.bbrc.2009.07.087

  264. 264.

    Bray SJ. Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol. 2006;7:678-689.

    Not in our library10.1038/nrm2009

  265. 265.

    Schroeter EH, Kisslinger JA, Kopan R. Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain. Nature. 1998;393:382-386.

    Not in our library10.1038/30756

  266. 266.

    De Strooper B, Annaert W, Cupers P, Saftig P, Craessaerts K, Mumm JS, Schroeter EH, Schrijvers V, Wolfe MS, Ray WJ, Goate A, Kopan R. A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature. 1999;398:518-522.

    Not in our library10.1038/19083

  267. 267.

    Struhl G, Adachi A. Nuclear access and action of notch in vivo. Cell. 1998;93:649-660.

    Not in our library10.1016/s0092-8674(00)81193-9

  268. 268.

    Ohtsuka T, Ishibashi M, Gradwohl G, Nakanishi S, Guillemot F, Kageyama R. Hes1 and Hes5 as notch effectors in mammalian neuronal differentiation. EMBO J. 1999;18:2196-2207.

    Not in our library10.1093/emboj/18.8.2196

  269. 269.

    Jouve C, Palmeirim I, Henrique D, Beckers J, Gossler A, Ish-Horowicz D, Pourquié O. Notch signalling is required for cyclic expression of the hairy-like gene HES1 in the presomitic mesoderm. Development. 2000;127:1421-1429.

    Not in our library10.1242/dev.127.7.1421

  270. 270.

    Song J, Park S, Kim M, Shin I. Down-regulation of Notch-dependent transcription by Akt in vitro. FEBS Lett. 2008;582:1693-1699.

    Not in our library10.1016/j.febslet.2008.04.024

  271. 271.

    Han X, Ju JH, Shin I. Glycogen synthase kinase 3-beta phosphorylates novel S/T-P-S/T domains in Notch1 intracellular domain and induces its nuclear localization. Biochem Biophys Res Commun. 2012;423:282-288.

    Not in our library10.1016/j.bbrc.2012.05.111

  272. 272.

    Jin YH, Kim H, Oh M, Ki H, Kim K. Regulation of Notch1/NICD and Hes1 expressions by GSK-3alpha/beta. Mol Cells. 2009;27:15-19.

    Not in our library10.1007/s10059-009-0001-7

  273. 273.

    Jin YH, Kim H, Ki H, Yang I, Yang N, Lee KY, Kim N, Park HS, Kim K. Beta-catenin modulates the level and transcriptional activity of Notch1/NICD through its direct interaction. Biochim Biophys Acta. 2009;1793:290-299.

    Not in our library10.1016/j.bbamcr.2008.10.002

  274. 274.

    Espinosa L, Inglés-Esteve J, Aguilera C, Bigas A. Phosphorylation by glycogen synthase kinase-3 beta down-regulates Notch activity, a link for Notch and Wnt pathways. J Biol Chem. 2003;278:32227-32235.

    Not in our library10.1074/jbc.m304001200

  275. 275.

    Stambolic V, Ruel L, Woodgett JR. Lithium inhibits glycogen synthase kinase-3 activity and mimics wingless signalling in intact cells. Curr Biol. 1996;6:1664-1668.

    Not in our library10.1016/s0960-9822(02)70790-2

  276. 276.

    Howland RH. Lithium: underappreciated and underused? J Psychosoc Nurs Ment Health Serv. 2007;45:13-17.

    Not in our library10.3928/02793695-20070801-04

  277. 277.

    Ricci P, Bandini G, Franchi P, Motta MR, Visani G, Calamandrei G. Haematological effects of lithium carbonate: a study in 56 psychiatric patients. Haematologica. 1981;66:627-633.

    Not in our library

  278. 278.

    Boggs DR, Joyce RA. The hematopoietic effects of lithium. Semin Hematol. 1983;20:129-138.

    Not in our library

  279. 279.

    Joyce RA. Sequential effects of lithium on haematopoiesis. Br J Haematol. 1984;56:307-321.

    Not in our library10.1111/j.1365-2141.1984.tb03958.x

  280. 280.

    Ballin A, Lehman D, Sirota P, Litvinjuk U, Meytes D. Increased number of peripheral blood CD34+ cells in lithium-treated patients. Br J Haematol. 1998;100:219-221.

    Not in our library10.1046/j.1365-2141.1998.00537.x

  281. 281.

    Klein PS, Melton DA. A molecular mechanism for the effect of lithium on development. Proc Natl Acad Sci USA. 1996;93:8455-8459.

    Not in our library10.1073/pnas.93.16.8455

  282. 282.

    Hedgepeth CM, Conrad LJ, Zhang J, Huang HC, Lee VM, Klein PS. Activation of the Wnt signaling pathway: a molecular mechanism for lithium action. Dev Biol. 1997;185:82-91.

    Not in our library10.1006/dbio.1997.8552

  283. 283.

    Phiel CJ, Klein PS. Molecular targets of lithium action. Annu Rev Pharmacol Toxicol. 2001;41:789-813.

    Not in our library10.1146/annurev.pharmtox.41.1.789

  284. 284.

    Ougolkov AV, Billadeau DD. Inhibition of glycogen synthase kinase-3. Methods Mol Biol. 2008;468:67-75.

    Not in our library10.1007/978-1-59745-249-6_5

  285. 285.

    Ougolkov AV, Bone ND, Fernandez-Zapico ME, Kay NE, Billadeau DD. Inhibition of glycogen synthase kinase-3 activity leads to epigenetic silencing of nuclear factor kappaB target genes and induction of apoptosis in chronic lymphocytic leukemia B cells. Blood. 2007;110:735-742.

    Not in our library10.1182/blood-2006-12-060947

  286. 286.

    Cao Q, Lu X, Feng YJ. Glycogen synthase kinase-3beta positively regulates the proliferation of human ovarian cancer cells. Cell Res. 2006;16:671-677.

    Not in our library10.1038/sj.cr.7310078

  287. 287.

    Shakoori A, Mai W, Miyashita K, Yasumoto K, Takahashi Y, Ooi A, Kawakami K, Minamoto T. Inhibition of GSK-3 beta activity attenuates proliferation of human colon cancer cells in rodents. Cancer Sci. 2007;98:1388-1393.

    Not in our library10.1111/j.1349-7006.2007.00545.x

  288. 288.

    Miyashita K, Kawakami K, Nakada M, Mai W, Shakoori A, Fujisawa H, Hayashi Y, Hamada J, Minamoto T. Potential therapeutic effect of glycogen synthase kinase 3beta inhibition against human glioblastoma. Clin Cancer Res. 2009;15:887-897.

    Not in our library10.1158/1078-0432.ccr-08-0760

  289. 289.

    Mirlashari MR, Randen I, Kjeldsen-Kragh J. Glycogen synthase kinase-3 (GSK-3) inhibition induces apoptosis in leukemic cells through mitochondria-dependent pathway. Leuk Res. 2012;36:499-508.

    Not in our library10.1016/j.leukres.2011.11.013

  290. 290.

    Huang HS, Liu ZM, Cheng YL. Involvement of glycogen synthase kinase-3β in arsenic trioxide-induced p21 expression. Toxicol Sci. 2011;121:101-109.

    Not in our library10.1093/toxsci/kfr023

  291. 291.

    Alao JP, Stavropoulou AV, Lam EW, Coombes RC. Role of glycogen synthase kinase 3 beta (GSK3beta) in mediating the cytotoxic effects of the histone deacetylase inhibitor trichostatin A (TSA) in MCF-7 breast cancer cells. Mol Cancer. 2006;5:40.

    Not in our library10.1186/1476-4598-5-40

  292. 292.

    Urbanska K, Trojanek J, Del Valle L, Eldeen MB, Hofmann F, Garcia-Echeverria C, Khalili K, Reiss K. Inhibition of IGF-I receptor in anchorage-independence attenuates GSK-3beta constitutive phosphorylation and compromises growth and survival of medulloblastoma cell lines. Oncogene. 2007;26:2308-2317.

    Not in our library10.1038/sj.onc.1210018

  293. 293.

    Dravid G, Ye Z, Hammond H, Chen G, Pyle A, Donovan P, Yu X, Cheng L. Defining the role of Wnt/beta-catenin signaling in the survival, proliferation, and self-renewal of human embryonic stem cells. Stem Cells. 2005;23:1489-1501.

    Not in our library10.1634/stemcells.2005-0034

  294. 294.

    Bakre MM, Hoi A, Mong JC, Koh YY, Wong KY, Stanton LW. Generation of multipotential mesendodermal progenitors from mouse embryonic stem cells via sustained Wnt pathway activation. J Biol Chem. 2007;282:31703-31712.

    Not in our library10.1074/jbc.m704287200

  295. 295.

    Doble BW, Woodgett JR. Exploring Pluripotency with Chemical Genetics. Cell Stem Cell. 2009;4:98-100.

    Not in our library10.1016/j.stem.2009.01.005

  296. 296.

    Riobo NA, Lu K, Ai X, Haines GM, Emerson CP. Phosphoinositide 3-kinase and Akt are essential for Sonic hedgehog signaling. Proc Nat Acad Sci USA. 2006;103:4505-4510.

    Not in our library10.1073/pnas.0504337103

  297. 297.

    Bone HK, Damiano T, Bartlett S, Perry A, Letchford J, Sanchez Ripoli Y, Nelson AS, Welham MJ. Involvement of GSK-3 in regulation of murine embryonic stem cell self-renewal revealed by a series of bisindolylmaleimides. Chem Biol. 2009;16:15-27.

    Not in our library10.1016/j.chembiol.2008.11.003

  298. 298.

    Miyashita K, Nakada M, Shakoori A, Ishigaki Y, Shimasaki T, Motoo Y, Kawakami K, Minamoto T. An emerging strategy for cancer treatment targeting aberrant glycogen synthase kinase 3 beta. Anticancer Agents Med Chem. 2009;9:1114-1122.

    Not in our library10.2174/187152009789734982

  299. 299.

    Panka DJ, Cho DC, Atkins MB, Mire JW. GSK-3beta inhibition enhances sorafenib-induced apoptosis in melanoma cell lines. Journal of Biological Chemistry. 2008;283:726-732.

    Not in our library10.1074/jbc.m705343200

  300. 300.

    Moore GJ, Cortese BM, Glitz DA, Zajac-Benitez C, Quiroz JA, Uhde TW, Drevets WC, Manji HK. A longitudinal study of the effects of lithium treatment on prefrontal and subgenual prefrontal gray matter volume in treatment-responsive bipolar disorder patients. J Clin Psychiatry. 2009;70:699-705.

    Not in our library10.4088/jcp.07m03745

  301. 301.

    Ban JO, Oh JH, Son SM, Won D, Song HS, Han SB, Moon DC, Kang KW, Song MJ, Hong JT. Troglitazone, a PPAR agonist, inhibits human prostate cancer cell growth through inactivation of NFκB via suppression of GSK-3β expression. Cancer Biol Ther. 2011;12:288-96.

    Not in our library10.4161/cbt.12.4.15961

  302. 302.

    Georgievska B1, Sandin J, Doherty J, Mörtberg A, Neelissen J, Andersson A, Gruber S, Nilsson Y, Schött P, Arvidsson PI, Hellberg S, Osswald G, Berg S, Fälting J, Bhat RV. AZD1080, a novel GSK3 inhibitor, rescues synaptic plasticity deficits in rodent brain and exhibits peripheral target engagement in humans. J Neurochem. 2013;125:446-456.

    Not in our library10.1111/jnc.12203

  303. 303.

    Marsell R1, Sisask G, Nilsson Y, Sundgren-Andersson AK, Andersson U, Larsson S, Nilsson O, Ljunggren O, Jonsson KB. GSK-3 inhibition by an orally active small molecule increases bone mass in rats. Bone. 2012;50:619-627.

    Not in our library10.1016/j.bone.2011.11.007

  304. 304.

    Meijer L, Skaltsounis AL, Magiatis P, Polychronopoulos P, Knockaert M, Leost M, Ryan XP, Vonica CA, Brivanlou A, Dajani R, Crovace C, Tarricone C, Musacchio A, Roe SM, Pearl L, Greengard P. GSK-3-selective inhibitors derived from Tyrian purple indirubins. Chem Biol. 2003;10:1255-1266.

    Not in our library10.1016/j.chembiol.2003.11.010

  305. 305.

    Bennett CN, Longo KA, Wright WS, Suva LJ, Lane TF, Hankenson KD, MacDougald OA. Regulation of osteoblastogenesis and bone mass by Wnt10b. Proc Natl Acad Sci U S A. 2005;102:3324-3329.

    Not in our library10.1073/pnas.0408742102

  306. 306.

    Ring DB, Johnson KW, Henriksen EJ, Nuss JM, Goff D, Kinnick TR, Ma ST, Reeder JW, Samuels I, Slabiak T, Wagman AS, Hammond ME, Harrison SD. Selective glycogen synthase kinase 3 inhibitors potentiate insulin activation of glucose transport and utilization in vitro and in vivo. Diabetes. 2003;52:588-595.

    Not in our library10.2337/diabetes.52.3.588

  307. 307.

    Zamek-Gliszczynski MJ1, Abraham TL, Alberts JJ, Kulanthaivel P, Jackson KA, Chow KH, McCann DJ, Hu H, Anderson S, Furr NA, Barbuch RJ, Cassidy KC. Pharmacokinetics, metabolism, and excretion of the glycogen synthase kinase-3 inhibitor LY2090314 in rats, dogs, and humans: a case study in rapid clearance by extensive metabolism with low circulating metabolite exposure. Drug Metab Dispos. 2013;41:714-726.

    Not in our library10.1124/dmd.112.048488

  308. 308.

    Kubic JD, Mascarenhas JB, Iizuka T, Wolfgeher D, Lang D. GSK-3 promotes cell survival, growth, and PAX3 levels in human melanoma cells. Mol Cancer Res. 2012;10:1065-1076.

    Not in our library10.1158/1541-7786.mcr-11-0387

  309. 309.

    Piazza F, Manni S, Tubi LQ, Montini B, Pavan L, Colpo A, Gnoato M, Cabrelle A, Adami F, Zambello R, Trentin L, Gurrieri C, Semenzato G. Glycogen Synthase Kinase-3 regulates multiple myeloma cell growth and bortezomib-induced cell death. BMC Cancer. 2010;10:526.

    Not in our library10.1186/1471-2407-10-526

  310. 310.

    Dickey A, Schleicher S, Leahy K, Hu R, Hallahan D, Thotala DK. GSK-3β inhibition promotes cell death, apoptosis, and in vivo tumor growth delay in neuroblastoma Neuro-2A cell line. J Neurooncol. 2011;104(1):145-53.

    Not in our library10.1007/s11060-010-0491-3

  311. 311.

    Beurel E, Blivet-Van Eggelpoël MJ, Kornprobst M, Moritz S, Delelo R, Paye F, Housset C, Desbois-Mouthon C. Glycogen synthase kinase-3 inhibitors augment TRAIL-induced apoptotic death in human hepatoma cells. Biochem Pharmacol. 2009;77(1):54-65.

    Not in our library10.1016/j.bcp.2008.09.026

  312. 312.

    Aguilar-Morante D, Morales-Garcia JA, Sanz-SanCristobal M, Garcia-Cabezas MA, Santos A, Perez-Castillo A. Inhibition of glioblastoma growth by the thiadiazolidinone compound TDZD-8. PLoS One. 2010;5(11):e13879.

    Not in our library10.1371/journal.pone.0013879

  313. 313.

    Zeng FY, Dong H, Cui J, Liu L, Chen T. Glycogen synthase kinase 3 regulates PAX3-FKHR-mediated cell proliferation in human alveolar rhabdomyosarcoma cells. Biochem Biophys Res Commun. 2010;391:1049-1055.

    Not in our library10.1016/j.bbrc.2009.12.017

  314. 314.

    del Ser T, Steinwachs KC, Gertz HJ, Andrés MV, Gómez-Carrillo B, Medina M, Vericat JA, Redondo P, Fleet D, León T. Treatment of Alzheimer's disease with the GSK-3 inhibitor tideglusib: a pilot study. J Alzheimers Dis. 2013;33:205-215.

    Not in our library10.3233/jad-2012-120805

Cited by papers we hold 12

Reads

Read by people on this page

None yet.

Checked or read by AI through naulon

None yet.

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.

Are you an author?

Is this your paper?

Claim it to add your note and be paid when agents cite it. Free.