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Role of Hippo Pathway-YAP/TAZ Signaling in Angiogenesis

Gandhi T. K. Boopathy, Wanjin Hong

Frontiers in Cell and Developmental Biology · 2019 · Review · CC BY

doi:10.3389/fcell.2019.00049

Abstract

Angiogenesis is a highly coordinated process of formation of new blood vessels from pre-existing blood vessels. The process of development of the proper vascular network is a complex process that is crucial for the vertebrate development. Several studies have defined essential roles of Hippo pathway-YAP/TAZ in organ size control, tissue regeneration, and self-renewal. Thus Hippo pathway is one of the central components in tissue homeostasis. There are mounting evidences on the eminence of Hippo pathway-YAP/TAZ in angiogenesis in multiple model organisms. Hippo pathway-YAP/TAZ is now demonstrated to regulate endothelial cell proliferation, migration and survival; subsequently regulating vascular sprouting, vascular barrier formation, and vascular remodeling. Major intracellular signaling programs that regulate angiogenesis concomitantly activate YAP/TAZ to regulate key events in angiogenesis. In this review, we provide a brief overview of the recent findings in the Hippo pathway and YAP/TAZ signaling in angiogenesis.

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.

Introduction

The Hippo signaling pathway is an evolutionarily conserved signaling pathway that is the latest addition to the family of signaling pathways known to be involved in control organ size and development. The Hippo pathway is an evolutionarily conserved serine/threonine kinase signaling cascade originally identified in fruit fly (Drosophila melanogaster). This discovery of a new signaling pathway is a key advance in the understanding of the signaling networks controlling metazoan physiology and development. A list of key Hippo pathway genes in fruit fly and the orthologs in humans are listed in Table 1. Hippo pathway negatively regulates the activity of transcriptional co-activators, Yes-associated protein 1 (YAP) and Transcriptional coactivator with PDZ-binding motif (TAZ); both YAP and TAZ are orthologs of Drosophila Yorkie [Yki]. YAP and TAZ are transcriptional coactivators, do not have DNA binding capacity. So, active YAP/TAZ translocate to nucleus and interact majorly with TEA domain family member (TEAD) transcription factors (TEAD1-4; orthologs of Drosophila Scalloped [Sd]). In nucleus, the YAP/TAZ-TEAD protein complex transcribes genes that control cell proliferation, apoptosis and cell fate.

Angiogenesis is an organized process of formation of new blood vessels from pre-existing vessels by involving a series of events that comprise endothelial cell sprouting, branching, formation of lumen, and remodeling into a functionally perfused vascular network. Angiogenesis is the fundamental to multiple biological processes such as development, wound healing, and reproduction. Dysregulation of angiogenesis is a key factor in the progression of a variety of diseases including diabetic retinopathy, age-related macular degeneration (AMD), rheumatoid arthritis and cancer. Recently, a wealth of studies has significantly expanded the role of Hippo pathway network in angiogenesis. The aim of this review is to outline the current findings in Hippo pathway-YAP/TAZ in angiogenesis.

Hippo-YAP/TAZ Pathway

In mammals, the core Hippo pathway is largely characterized by Serine/Threonine kinases; mammalian Sterile 20-related 1 and 2 kinases (MST1 and MST2; orthologs of Drosophila Hippo [Hpo]) and Large tumor suppressor 1 and 2 kinases (LATS1 and LATS2; orthologs of Drosophila Warts [Wts]) (Figure 1).

MST kinases are known to undergo auto-activation through auto-phosphorylation on the activation loop of the MST dimer, MST1 at Thr183 and MST2 at Thr180. The carboxyl terminus of MST kinases have a distinctive coiled-coil structure called SARAH domain [named after the three genes that contain the homologous structures – Salvador (Salvador 1/WW45), RASSF1-6 and Hippo (MST1/MST2)]. SARAH domain mediates homo- and heterodimerization of MST1/MST2. MST1/MST2 heterodimer forms a complex with SARAH domain containing protein, Salvador 1 (SAV1). Being 96% identical proteins, MOB kinase activator 1A and 1B (MOB1A and MOB1B) forms a complex with LATS1 and LATS2 kinases. MST1/MST2 kinases activate LATS1 and LATS2 kinases by phosphorylating at Thr1079 and Thr1041, respectively. Both MOB1A and MOB1B are phosphorylated by MST1/MST2 kinases at Thr35 and Thr12; these phosphorylation events promote the interaction of MOB1A/MOB1B to LATS1/LATS2. Also, phosphorylation at MOB1A/MOB1B promotes its affinity to LATS and this interaction leads to the auto-phosphorylation of LATS1/LATS2 at the activation loop (Ser909 at LATS1 and Ser872 at LATS2). Both, phosphorylation by MST1/MST2 kinases and the auto-phosphorylation on LATS are critically required for LATS1/LATS2 kinase activation.

Large tumor suppressor kinases belong to AGC group of kinases (named after the protein kinase A, G, and C families) that recognize the substrate consensus sequence HXRXXS/T. Key substrates of LATS kinases are transcription co-activators, YAP and TAZ. YAP is a key transcriptional regulator and the first protein identified with a WW domain (a motif comprising of two Tryptophan [W] residues) and TAZ is a YAP paralog (with 44% identity to YAP). YAP has five (Ser61, Ser109, Ser127, Ser164, and Ser381) and TAZ has four (Ser66, Ser89, Ser117, and Ser311) HXRXXS/T motifs phosphorylated by LATS1/LATS2 kinases. Phosphorylation of YAP and TAZ by LATS kinases either primes to their binding with 14-3-3 proteins leading to cytoplasmic sequestration of YAP/TAZ or ubiquitin-mediated protein degradation (; Figure 1).

When LATS1/LATS2 kinases are inactive, YAP/TAZ are not phosphorylated and translocate to nucleus. YAP/TAZ do not comprise DNA binding domain, but they bind to TEAD transcription factor family (TEAD1 – 4) to mediate target gene expression such as connective tissue growth factor (CTGF), cysteine-rich angiogenic inducer 61 (CYR61) and others to promote cell growth, proliferation, migration, and survival. Also, YAP/TAZ has been shown to interact with a variety of transcription factors, such as SMAD1, SMAD2/3, SMAD7, RUNT-related transcription factors (RUNX1 and RUNX2), T-box transcription factor 5 (TBX5), and p73. Also, YAP is shown to interact with the intracellular domain (ICD) of ErbB4 (one of the members of the epidermal growth factor receptors) in the nucleus to mediate modulate the expression of genes involved in proliferation, differentiation, and development.

Loss of any of the core components such as Merlin, MST1/MST2, Salvador-1, LATS1/2, MOB1A/MOB1B show an upregulation of YAP/TAZ-TEAD target gene transcription such as cell proliferation and tissue growth – justifying roles of these core members in the Hippo pathway.

Regulation of the Hippo Signaling Pathway

The central mechanism to regulate the transcriptional co-activators – YAP/TAZ is by influencing the subcellular localization and the protein stability through phosphorylation by upstream kinases such as LATS1/LATS2 kinases. Numerous studies have shown that multitude of intracellular, extracellular, and non-cellular mechanisms can activate Hippo pathway and regulate YAP/TAZ activity (Figure 2). Following are the brief cellular events that regulate Hippo pathway and YAP/TAZ activity:

Hippo Pathway-YAP/TAZ Regulation by Cell Polarity and Cell Adhesion

Generally cells exhibit polarity. Polarity is a unique asymmetric organization of cellular components to carry out specified functions. Intercellular junctions such as adherens junctions (AJ), tight junctions (TJ), and gap junctions mediate communication and adhesion between adjoining epithelial and endothelial cells. Apical and basolateral cell polarity is established by AJs and TJs with the help of well-defined proteins in complexes called as polarity complexes. Crumbs (CRB1) is a transmembrane protein solely localized in the apical plasma membrane and is essential for substantiating the apical-basal polarity of a cell. Crumbs in association with FERM domain-containing protein 6 (FRMD6; Expanded Homolog), Kibra (WW domain containing protein) and Merlin (also called Neurofibromin 2 or Schwannomin) interacts and activates the Hippo pathway.

Angiomotin family of proteins consists of three proteins, angiomotin (AMOT), angiomotin-like 1 (AMOTL1), and angiomotin-like 2 (AMOTL2). They are characterized by coiled-coil domain, WW binding motif, actin binding domain, and PDZ-binding domain. Through these domains, AMOTs localize to TJs, acts as a scaffold protein bind to actin cytoskeleton, YAP/TAZ proteins and Rho-GTPases. AMOTs directly bind and negatively regulate the localization and the activity of YAP and TAZ both dependent and independent of Hippo pathway.

Cadherins are the key components of AJ that bind cells with each other. α-Catenin connect between cadherins and actin cytoskeleton in cells. α-Catenin forms a complex with 14-3-3 proteins and phosphorylated YAP and suppresses YAP activity by retaining YAP in the cytoplasm causing inactivation of YAP. Also, another component of AJ, Protein-tyrosine phosphatase type 14 (PTPN14) interacts with YAP through its PPXY motif and the WW domain of YAP. This interaction retains YAP to cytoplasmic front and causes inactivation of YAP. By interfering the function of AJs or TJs cause an activation of YAP/TAZ in multiple cells types.

Hippo Pathway-YAP/TAZ Regulation by Mechanical Cues

Mechanical forces such as stress, strain or distortion physiologically impacting cell density, stiffness of the extracellular environment and cell geometry are known to regulate the localization and activity of YAP/TAZ. The activity of YAP/TAZ in response to mechanical forces depends on the reorganization of actin cytoskeleton and the activity of Rho GTPases. Also, Spectrin – one of the cytoskeletal proteins play a key role in the maintenance of plasma membrane integrity. Spectrin by associating with actin filaments play an important role in the activity of YAP as the interruption of the spectrin cytoskeletal network is shown to activate YAP in fruit fly and humans. Also, recently, Roca-Cusachs and colleagues have shown that application of force directly to the nucleus is sufficient for the nuclear accumulation of YAP. Force transmission cause flattening of nucleus, stretches nuclear pore complexes (NPC), this causes mechanical resistance to molecular transport across NPC and resulting in nuclear import of YAP.

Hippo Pathway-YAP/TAZ Regulation by Cellular Signal Transduction

Several studies have shown that multiple extracellular ligands/growth factors and multiple signaling pathways regulate Hippo pathway. Earlier, ligands of G-protein-coupled receptors (GPCRs) such as lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) after association with GPCR, signals through G-proteins (Gα12/13) inhibits LATS1/LATS2 thereby activating YAP/TAZ.

Epidermal growth factor (EGF) through EGF-receptor (EGFR) inactivates Hippo pathway through phosphoinositide 3-kinase (PI3K) and phosphoinositide-dependent kinase (PDK1) independent of AKT signaling. Also, EGFR is known to activate YAP/TAZ through Ras-Raf-Mitogen-activated protein kinases (MAPK) signaling axis. Besides EGF, amphiregulin (AREG) is a growth factor that activates EGFR and in-turn activate YAP/TAZ. Interestingly, AREG is a transcriptional target of YAP/TAZ Focal adhesions (FAs) in cells are strongly associated with the extracellular matrix (ECM). Through specific ligands or through mechanical cues, integrins in FAs activate YAP/TAZ through Rho-GTPases. Integrins are also known to signal through Src family kinases to regulate YAP/TAZ. Mitogen-activated protein kinase kinase kinase kinases (MAP4K), MAP4K1/2/3/5 phosphorylate and activate Hippo pathway core component LATS1/LATS2 and inactivates YAP/TAZ. It appears that MST1/MST2 and MAP4Ks could have partially redundant roles in regulating LATS1/2 kinases. Src can phosphorylate activate YAP both by direct phosphorylation on the tyrosine residues (Y341, Y357, and Y394) and through inhibiting LATS1/LATS2 by phosphorylation. Interestingly, integrins also inactivate Hippo signaling to activate YAP/TAZ by inactivating Merlin through integrin-linked kinase (ILK).

Other kinases, such as thousand-and-one amino acids kinases (TAOK1/2/3) have been shown to directly phosphorylate and activate Hippo pathway core component MST1/MST2 kinases. In striatin-interacting phosphatase and kinase (STRIPAK) complex, the core of STRIPAK complex is the phosphatase protein phosphatase 2A (PP2A). PP2A is known to interact and dephosphorylate MST1/MST2 kinases causing the activation of YAP/TAZ.

Hippo Pathway in Angiogenesis

Studies have shown that YAP/TAZ expression was elevated in the retinal blood vasculature at an early stage of development (from postnatal day 5) and during differentiation of endothelial progenitor cells to matured endothelial cells in mice. Similar to the observation in multiple cell types, YAP is inactivated by phosphorylation and redistributed in a cell contact-dependent manner in human umbilical vein endothelial cells (HUVEC). In HUVECs, contact-inhibition is mainly due to vascular endothelial cadherin (VE-cadherin)-mediated cell junctional complex regulation. Knockdown of YAP in HUVECs and mice aortic rings showed a significant decrease in the total tubular network and endothelial sprouts, respectively. Similarly, endothelial cell-specific loss of YAP/TAZ in mice results in embryonic lethality – clearly indicating YAP/TAZ as a critical regulator for vascular sprouting, vascular barrier formation and angiogenesis.

YAP/TAZ in VEGF Signaling

Vascularization is an important process during tissue development which is accurately mediated by vascular endothelial growth factor A (VEGF). VEGF is a primary factor for the initiation of sprouting angiogenesis and major regulator of blood vessel formation. VEGF induces angiogenesis by associating with VEGF receptors VEGFR1 and VEGFR2 through endothelial cell proliferation, survival and migration. During angiogenesis, VEGF-VEGFR2 signaling-axis critically requires YAP/TAZ activity to mediate angiogenesis. Activation of YAP/TAZ upon VEGF stimulation involves the activation Src family kinases and successive cytoskeletal remodeling in endothelial cells. Using bioluminescence-based biosensor of LATS kinase activity discovered that VEGF/VEGFR signaling pathway activates PI3K-AKT and MEK-ERK signaling axes that leads to the inhibition of MST kinases (MST1/MST2) and LATS kinases (LATS1/LATS2) and consecutive activation of YAP/TAZ. Clearly, YAP/TAZ are the key components of VEGF signaling in angiogenesis.

YAP/TAZ are also known to regulate VEGF signaling pathway. In HUVECs, siRNA based knockdown of YAP/TAZ or inhibition of YAP/TAZ by verteporfin effectively reduced VEGF-induced angiogenesis. Also, administration of verteporfin significantly reduced VEGF-induced blood vessel formation in Matrigel plugs using mouse endothelial cells, suggesting an important role of YAP/TAZ in VEGF-induced angiogenesis in vivo.

Also, activation of VEGF-VEGFR2-Src signaling axis also promotes YAP/TAZ based expression of several cytoskeletal reorganization genes such as Myosin 1C (MYO1C). MYO1C is one of nine isoforms of the myosin 1 gene in humans. The cell surface distribution of VEGFR2 is regulated by MYO1C in endothelial cells. During angiogenesis, as a positive feedback loop, YAP/TAZ could regulate VEGF induced signal transduction by regulating VEGFR2 localization to the cell surface through the regulation of MYO1C.

YAP/TAZ in Angiopoietin-2/Tie2 Signaling

Angiopoietins are a family of growth factors that include angiopoietins 1–4 (Ang1–4) and the receptors for angiopoietins are tyrosine kinases include Tie receptors (Tie1 and Tie2). Tie1 and Tie2 receptors are predominantly expressed in endothelial cells. Angiopoietins/Tie signaling axis has been suggested to play a critical role in sprouting angiogenesis and vascular remodeling. Ang2 is an autocrine factor highly secreted by endothelial cells at sites of active vascular remodeling and regulates angiogenesis in a pro-angiogenic or anti-angiogenic manner. In HUVECs and during post-natal development of the mouse retina, Ang2 is identified as a key target gene of YAP in endothelial cells; regulation of angiogenesis and vascular remodeling by YAP is shown to mediated by Ang2.

YAP/TAZ in Other Signaling Pathways/Events

The bona fide YAP/TAZ target genes are connective tissue growth factor (CTGF) and cysteine-rich angiogenic inducer 61 (CYR61). CYR61 and CTGF are CCN family (CYR61, CTGF, and NOV proteins) of extracellular matrix associated angiogenic regulators with 47% amino acid sequence identity. Both, CTGF and CYR61 bind to a variety of cell surface receptors in a context-dependent manner, including integrin receptors and exert endothelial cell function and angiogenesis. CYR61 and CTGF are the well-known ligands of integrins αVβ3, αIIbβ3, αvβ5, and α6β1. CTGF and CYR61 are shown to induce angiogenesis, at least in part, through the activation of integrin αVβ3 pathway and also involved in tumor angiogenesis.

YAP interacts with signal transducer and activator of transcription 3 (STAT3) in endothelial cells and this interaction maintains STAT3 in the nucleus and increases the transcription of ANG2 thereby promotes angiogenesis and vessel remodeling. Mochizuki and colleagues observed that YAP translocate into the nucleus after the onset of blood-flow and relocated to cytoplasm after the flow was interrupted in endothelial cells using transgenic zebrafish.

YAP/TAZ as Mechanical Sensors of Endothelium

Endothelial cells can sense mechanical forces, trigger cellular signaling and result in cell proliferation. Using human lung microvascular endothelial cells (HMVEC), Piccolo’s group have showed that cytoskeletal adaptation to the cell spread causes activation and nuclear accumulation of YAP/TAZ and when cells are maneuvered into a compact and round shape YAP/TAZ are inactivated and localized in the cytoplasm. Also, Gerhardt’s group have shown that the cellular stretch have increased the cell proliferation of HUVEC to fivefold which is dependent on YAP in response to mechanical stimulation at cell–cell junctions by VE-Cadherin. Interestingly, shear force caused by the blood-flow has also been shown to transport YAP/TAZ to nucleus in endothelial cells. Together, in endothelial cells, YAP/TAZ transduce mechanical signals exerted by the rigidity of the blood-flow, extracellular matrix and the cell geometry. However, the mechanical regulation of YAP/TAZ exists in a variety of cell types, regardless of their epithelial, mesenchymal, or endothelial nature, indicating a common mechanism of mechanical regulation of YAP/TAZ in all these cell types.

Hippo Pathway-YAP/TAZ in Retinal Angiogenesis

YAP and TAZ have been shown to play a key role in the development of retinal blood vessels. Targeted loss of YAP/TAZ in blood vessels, in early post-natal days, shows a substantially reduced vascular density and vessel outgrowth in retina. Also, the assembled blood vessels were enlarged (increased vessel diameter) and twisted in YAP/TAZ knockout. Interestingly, there was no vascular network observed in the deep vascular plexus, reduction of tight junction proteins (ZO1 and Claudin-5) and disordered vascular endothelial cadherin (VE-cadherin) were found in the retinas with the loss of YAP/TAZ. Also, YAP/TAZ is involved in the formation and maturation of the blood-retinal barrier (BRB) and blood-brain barrier (BBB) but not required for maintaining blood-barrier integrity during adulthood. YAP and TAZ are shown to be involved in junctional remodeling in endothelial cell and also, inhibited Notch and BMP signaling events in endothelial cells.

Angiogenic Regulation by Hippo Pathway-YAP/TAZ Signaling in Mice and Fish

The vasculature and the basic vascular plan of zebrafish embryos are quite similar to that of other mammalian models. Whole-body knockout of Yap in mice resulted in developmental arrest around embryonic day 8.5 due to vascular defects. Upon knockdown of YAP, using specific RNAs, in mouse retina resulted in significantly reduced vascular density. Endothelial specific loss of YAP in mice results in embryonic lethality because of impaired heart valve development caused by defect in endothelial-to-mesenchymal transition. Also, endothelial cell specific knockout of YAP/TAZ results in vascular defects during embryonic and postnatal development. These results clearly indicate that YAP is required for the early stages in the development of vasculature and placenta of mice. Interestingly, in zebrafish, inhibition or activation of YAP did not yield any significant abnormalities during angiogenesis. Loss of YAP/TAZ results in death of zebrafish due to severe developmental defects earlier than vascular development making it harder to study the role of YAP/TAZ in developmental vasculature in zebrafish. However, YAP is shown to be playing a key role in the maintenance of blood vessels in zebrafish.

Vascular Regression and Vessel Retraction

During angiogenesis, vascular networks undergo extensive vascular remodeling, such as vascular pruning and regression to form mature vasculature. Understanding molecular mechanisms of vessel regression has key therapeutic implications in diseases such as cancer and retinal diseases. Blood-flow has been shown to positively regulate endothelial YAP/TAZ, hence YAP/TAZ may sense the blood flow to regulate vascular shrinking for vascular regression. Inhibition of YAP/TAZ-TEAD transcriptional activity disrupts the vascular regression of caudal vein plexus in zebrafish. Complete loss of YAP showed vessel thinning and vessel retraction in dorsal longitudinal anastomotic vessel of zebrafish.

YAP/TAZ in Vascular Diseases

A gradual accumulation of deposits such as fat, cholesterol and cellular debris on the walls of arteries are a key characteristic of atherosclerosis, leading to stroke, or heart attack. In Endothelial cells, YAP/TAZ activity was high in disturbed shear stress (blood flow was disturbed mimicking atherogenic mechanical stress) than a uniform laminar shear stress (atheroprotective). In mice model for atherosclerotic- and human atherosclerotic-blood vessels, very high YAP/TAZ activity was observed, indicating mechanotransduction of YAP/TAZ is responsible for pathological effects of disturbed blood flow during atherosclerosis.

Pulmonary hypertension (PH) is a dangerous vascular disease represented by high blood pressure in the pulmonary arteries that can lead to heart failure. PH is characterized by vascular remodeling due to proliferation of smooth muscle cells and endothelial cells. After examination of pulmonary endothelial cells from lung tissues of PH patients, ECM stiffening has been shown to mechanoactivate YAP/TAZ, resulting in endothelial cell proliferation and migration, thereby YAP/TAZ advances the pathogenesis of PH. These studies clearly suggest that the inhibition of YAP/TAZ activity could be a treatment option for multiple diseases in the future.

Discussion

Research around the past decade has greatly lead to our understanding of the molecular mechanism, cellular and the physiological function of the Hippo signaling pathway. An array of studies have strongly conclusively proved the Hippo pathway as a key mechanism of regulation of organ size and tissue maintenance in metazoa. Angiogenesis is a key biological process of formation of blood vessels that is required for the transportation of required nutrients and oxygen to all parts of the body and brings back unwanted waste from the organs and tissues during health and disease states of an organism. At the organismal level, generation and maintenance of blood vessels during development and wound healing in physiological and pathological conditions is pivotal. Hence, the signaling events pertaining to endothelial cell proliferation, migration, and maintenance has been a major research focus. The inactivation of Hippo signaling pathway and/or activation of YAP/TAZ is vital for the functional consequences of multiple signaling pathways such as VEGF, angiopoietin, CYR61, etc., in angiogenesis. Multiple cell signaling pathways concomitantly activating YAP/TAZ in endothelial cells clearly imply that Hippo pathway-YAP/TAZ is the crucial signaling-nexus in vascular growth, migration, branching, and vascular network maintenance (Figure 3). However, exactly how the Hippo pathway-YAP/TAZ orchestrates such a vast degree of biological processes and the pertaining molecular mechanisms are currently not known. Elucidating the functional aspects of endothelial cell specific target genes of YAP/TAZ would be of utmost importance in understanding the role of Hippo pathway-YAP/TAZ in angiogenesis.

All the recently reported signaling events, MAP kinase signaling, Rho family of GTPases, etc., pertaining to the activation of YAP/TAZ in endothelial cells were reported in multiple other cell types and/or model organisms. However, one of the major questions is, is there any signaling event regulating the activity of YAP/TAZ specifically in endothelial cells? If there is any such event, it would be of great importance for therapeutic interference in diabetic retinopathy, AMD, rheumatoid arthritis and cancers.

It is quite interesting that YAP is essential for developmental angiogenesis in mice but not in zebrafish. However, it is possible that TAZ could take over the essential functions of YAP in the early development of zebrafish or YAP may be a regulating the expression of some essential genes in angiogenesis in mice but not in zebrafish. Further studies on the differences in the gene targets of YAP in mice and zebrafish endothelium could provide an answer.

The components of Hippo pathway and the transcriptional co-activators YAP/TAZ are promising therapeutic targets for multiple ailments. Currently, most commonly used anti-angiogenic agents in clinics are against VEGF. However, the clinical benefits with anti-VEGF therapies either develop resistance (primary or acquired resistance) or quite modest. Neutralizing antibodies against VEGF pathway target as well as YAP/TAZ target genes – CTGF and CYR61 would be a valuable addition to the repertoire of therapeutic antibodies targeting angiogenesis.

Endothelial cells are well known to sense mechanical forces and resulting in cellular responses pertaining to proliferation. In a key study, have showed that the cell geometry plays key role in the proliferation of endothelial cells. Also, shear force caused by the blood-flow has also been shown to activate YAP/TAZ in endothelial cells. Interestingly, this shear flow (disturbed flow due to atherosclerotic plaques) is sensed by the YAP/TAZ in the endothelial cells and are responsible for pathological effects of disturbed blood flow during atherosclerosis and PH. These studies point to a new paradigm inhibition of YAP/TAZ activity in treatment option for multiple diseases in the future.

Author Contributions

GB and WH researched the relevant literature and conceived and wrote the manuscript.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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    Chan S. W. Lim C. J. Guo K. Ng C. P. Lee I. Hunziker W. (2008 ). A role for TAZ in migration, invasion, and tumorigenesis of breast cancer cells. Cancer Res. 68 2592–2598.

    Not in our library10.1158/0008-5472.can-07-2696

  27. 27.

    Chappell J. C. Wiley D. M. Bautch V. L. (2011 ). Regulation of blood vessel sprouting. Semin. Cell Dev. Biol. 22 1005–1011.

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  28. 28.

    Chen C. C. Chen N. Lau L. F. (2001 ). The angiogenic factors Cyr61 and connective tissue growth factor induce adhesive signaling in primary human skin fibroblasts. J. Biol. Chem. 276 10443–10452.

    Not in our library10.1074/jbc.m008087200

  29. 29.

    Choi H. J. Zhang H. Park H. Choi K. S. Lee H. W. Agrawal V. (2015 ). Yes-associated protein regulates endothelial cell contact-mediated expression of angiopoietin-2. Nat. Commun. 6:6943.

    Not in our library10.1038/ncomms7943

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    Chung A. S. Ferrara N. (2011 ). Developmental and pathological angiogenesis. Ann. Rev. Cell Dev. Biol. 27 563–584.

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  31. 31.

    Coultas L. Chawengsaksophak K. Rossant J. (2005 ). Endothelial cells and VEGF in vascular development. Nature 438 937–945.

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    Couzens A. L. Knight J. D. Kean M. J. Teo G. Weiss A. Dunham W. H. (2013 ). Protein interaction network of the mammalian Hippo pathway reveals mechanisms of kinase-phosphatase interactions. Sci. Signal. 6:rs15.

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    Crawford T. N. Alfaro D. V. III Kerrison J. B. Jablon E. P. (2009 ). Diabetic retinopathy and angiogenesis. Curr. Diabetes Rev. 5 8–13.

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    Daly C. Pasnikowski E. Burova E. Wong V. Aldrich T. H. Griffiths J. (2006 ). Angiopoietin-2 functions as an autocrine protective factor in stressed endothelial cells. Proc. Natl. Acad. Sci. U.S.A. 103 15491–15496.

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    Deng H. Wang W. Yu J. Zheng Y. Qing Y. Pan D. (2015 ). Spectrin regulates Hippo signaling by modulating cortical actomyosin activity. Elife 4:e06567.

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  36. 36.

    Deng Y. Pang A. Wang J. H. (2003 ). Regulation of mammalian STE20-like kinase 2 (MST2) by protein phosphorylation/dephosphorylation and proteolysis. J. Biol. Chem. 278 11760–11767.

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    Dong J. Feldmann G. Huang J. Wu S. Zhang N. Comerford S. A. (2007 ). Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell 130 1120–1133.

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  38. 38.

    Dupont S. Morsut L. Aragona M. Enzo E. Giulitti S. Cordenonsi M. (2011 ). Role of YAP/TAZ in mechanotransduction. Nature 474 179–183.

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  39. 39.

    Ebos J. M. Lee C. R. Kerbel R. S. (2009 ). Tumor and host-mediated pathways of resistance and disease progression in response to antiangiogenic therapy. Clin. Cancer Res. 15 5020–5025.

    Not in our library10.1158/1078-0432.ccr-09-0095

  40. 40.
    Integrin signalling regulates YAP/TAZ to control skin homeostasis · 2016
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    Elosegui-Artola A. Andreu I. Beedle A. E. M. Lezamiz A. Uroz M. Kosmalska A. J. (2017 ). Force triggers YAP nuclear entry by regulating transport across nuclear pores. Cell 171:e1314.

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    Fagiani E. Christofori G. (2013 ). Angiopoietins in angiogenesis. Cancer Lett. 328 18–26.

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    Fan R. Kim N. G. Gumbiner B. M. (2013 ). Regulation of Hippo pathway by mitogenic growth factors via phosphoinositide 3-kinase and phosphoinositide-dependent kinase-1. Proc. Natl. Acad. Sci. U.S.A. 110 2569–2574.

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  44. 44.

    Ferrigno O. Lallemand F. Verrecchia F. L’hoste S. Camonis J. Atfi A. (2002 ). Yes-associated protein (YAP65) interacts with Smad7 and potentiates its inhibitory activity against TGF-beta/Smad signaling. Oncogene 21 4879–4884.

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    The Spectrin cytoskeleton regulates the Hippo signalling pathway · 2015
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    Galan J. A. Avruch J. (2016 ). MST1/MST2 protein kinases: regulation and physiologic roles. Biochemistry 55 5507–5519.

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    Gillespie P. G. Cyr J. L. (2004 ). Myosin-1c, the hair cell’s adaptation motor. Annu. Rev. Physiol. 66 521–545.

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    Grzeszkiewicz T. M. Kirschling D. J. Chen N. Lau L. F. (2001 ). CYR61 stimulates human skin fibroblast migration through Integrin alpha vbeta 5 and enhances mitogenesis through integrin alpha vbeta 3, independent of its carboxyl-terminal domain. J. Biol. Chem. 276 21943–21950.

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  49. 49.

    Halder G. Johnson R. L. (2011 ). Hippo signaling: growth control and beyond. Development 138 9–22.

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  50. 50.

    Hamaratoglu F. Willecke M. Kango-Singh M. Nolo R. Hyun E. Tao C. (2006 ). The tumour-suppressor genes NF2/Merlin and expanded act through Hippo signalling to regulate cell proliferation and apoptosis. Nat. Cell Biol. 8 27–36.

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    Hanahan D. (1997 ). Signaling vascular morphogenesis and maintenance. Science 277 48–50.

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    Hao Y. Chun A. Cheung K. Rashidi B. Yang X. (2008 ). Tumor suppressor LATS1 is a negative regulator of oncogene YAP. J. Biol. Chem. 283 5496–5509.

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    Harvey K. F. Pfleger C. M. Hariharan I. K. (2003 ). The Drosophila Mst ortholog, hippo, restricts growth and cell proliferation and promotes apoptosis. Cell 114 457–467.

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    Haskins J. W. Nguyen D. X. Stern D. F. (2014 ). Neuregulin 1-activated ERBB4 interacts with YAP to induce Hippo pathway target genes and promote cell migration. Sci. Signal. 7:ra116.

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    He J. Bao Q. Zhang Y. Liu M. Lv H. Liu Y. (2018 ). Yes-associated protein promotes angiogenesis via signal transducer and activator of transcription 3 in endothelial cells. Circ. Res. 122 591–605.

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    Hergovich A. Schmitz D. Hemmings B. A. (2006a ). The human tumour suppressor LATS1 is activated by human MOB1 at the membrane. Biochem. Biophys. Res. Commun. 345 50–58.

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    Hergovich A. Stegert M. R. Schmitz D. Hemmings B. A. (2006b ). NDR kinases regulate essential cell processes from yeast to humans. Nat. Rev. Mol. Cell. Biol. 7 253–264.

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    Hu J. Sun S. Jiang Q. Wang W. Gui Y. Song H. (2013 ). Yes-associated protein (yap) is required for early embryonic development in zebrafish (danio rerio). Int. J. Biol. Sci. 9 267–278.

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    Jedsadayanmata A. Chen C. C. Kireeva M. L. Lau L. F. Lam S. C. (1999 ). Activation-dependent adhesion of human platelets to Cyr61 and Fisp12/mouse connective tissue growth factor is mediated through integrin alpha(IIb)beta(3). J. Biol. Chem. 274 24321–24327.

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    Kim J. Kim Y. H. Park D. Y. Bae H. Lee D. H. Kim K. H. (2017 ). YAP/TAZ regulates sprouting angiogenesis and vascular barrier maturation. J. Clin. Investig. 127 3441–3461.

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    Kim N. G. Gumbiner B. M. (2015 ). Adhesion to fibronectin regulates Hippo signaling via the FAK-Src-PI3K pathway. J. Cell Biol. 210 503–515.

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    Kim N. G. Koh E. Chen X. Gumbiner B. M. (2011 ). E-cadherin mediates contact inhibition of proliferation through Hippo signaling-pathway components. Proc. Natl. Acad. Sci. U.S.A. 108 11930–11935.

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    Kireeva M. L. Lam S. C. Lau L. F. (1998 ). Adhesion of human umbilical vein endothelial cells to the immediate-early gene product Cyr61 is mediated through integrin alphavbeta3. J. Biol. Chem. 273 3090–3096.

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    Korn C. Augustin H. G. (2015 ). Mechanisms of vessel pruning and regression. Dev. Cell 34 5–17.

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    Lai J. K. Stainier D. Y. (2017 ). Pushing yap into the nucleus with shear force. Dev. Cell 40 517–518.

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    Lau L. F. Lam S. C. (1999 ). The CCN family of angiogenic regulators: the integrin connection. Exp. Cell Res. 248 44–57.

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    Lawson N. D. Weinstein B. M. (2002 ). Arteries and veins: making a difference with zebrafish. Nat. Rev. Genet. 3 674–682.

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    Lee K. P. Lee J. H. Kim T. S. Kim T. H. Park H. D. Byun J. S. (2010 ). The Hippo-Salvador pathway restrains hepatic oval cell proliferation, liver size, and liver tumorigenesis. Proc. Natl. Acad. Sci. U.S.A. 107 8248–8253.

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    Lei Q. Y. Zhang H. Zhao B. Zha Z. Y. Bai F. Pei X. H. (2008 ). TAZ promotes cell proliferation and epithelial-mesenchymal transition and is inhibited by the hippo pathway. Mol. Cell. Biol. 28 2426–2436.

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    Li P. Silvis M. R. Honaker Y. Lien W. H. Arron S. T. Vasioukhin V. (2016 ). alphaE-catenin inhibits a Src-YAP1 oncogenic module that couples tyrosine kinases and the effector of Hippo signaling pathway. Genes Dev. 30 798–811.

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    Ling C. Zheng Y. Yin F. Yu J. Huang J. Hong Y. (2010 ). The apical transmembrane protein Crumbs functions as a tumor suppressor that regulates Hippo signaling by binding to Expanded. Proc. Natl. Acad. Sci. U.S.A. 107 10532–10537.

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    Liu W. F. Nelson C. M. Tan J. L. Chen C. S. (2007 ). Cadherins, RhoA, and Rac1 are differentially required for stretch-mediated proliferation in endothelial versus smooth muscle cells. Circ. Res. 101 e44–e52.

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    Liu X. Yang N. Figel S. A. Wilson K. E. Morrison C. D. Gelman I. H. (2013 ). PTPN14 interacts with and negatively regulates the oncogenic function of YAP. Oncogene 32 1266–1273.

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    Machnicka B. Czogalla A. Hryniewicz-Jankowska A. Boguslawska D. M. Grochowalska R. Heger E. (2014 ). Spectrins: a structural platform for stabilization and activation of membrane channels, receptors and transporters. Biochim. Biophys. Acta 1838 620–634.

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    Mah A. S. Elia A. E. Devgan G. Ptacek J. Schutkowski M. Snyder M. (2005 ). Substrate specificity analysis of protein kinase complex Dbf2-Mob1 by peptide library and proteome array screening. BMC Biochem. 6:22.

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    Maisonpierre P. C. Suri C. Jones P. F. Bartunkova S. Wiegand S. J. Radziejewski C. (1997 ). Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 277 55–60.

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    Martin-Belmonte F. Perez-Moreno M. (2011 ). Epithelial cell polarity, stem cells and cancer. Nat. Rev. Cancer 12 23–38.

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    Meadows K. L. Hurwitz H. I. (2012 ). Anti-VEGF therapies in the clinic. Cold Spring. Harb. Perspect. Med. 2:a006577.

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    Meng Z. Moroishi T. Guan K. L. (2016 ). Mechanisms of Hippo pathway regulation. Genes Dev. 30 1–17.

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  80. 80.
    MAP4K family kinases act in parallel to MST1/2 to activate LATS1/2 in the Hippo pathway · 2015
    No notice
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    Morin-Kensicki E. M. Boone B. N. Howell M. Stonebraker J. R. Teed J. Alb J. G. (2006 ). Defects in yolk sac vasculogenesis, chorioallantoic fusion, and embryonic axis elongation in mice with targeted disruption of Yap65. Mol. Cell. Biol. 26 77–87.

    Not in our library10.1128/mcb.26.1.77-87.2006

  82. 82.

    Murakami M. Nakagawa M. Olson E. N. Nakagawa O. (2005 ). A WW domain protein TAZ is a critical coactivator for TBX5, a transcription factor implicated in Holt-Oram syndrome. Proc. Natl. Acad. Sci. U.S.A. 102 18034–18039.

    Not in our library10.1073/pnas.0509109102

  83. 83.
    Yap/Taz transcriptional activity is essential for vascular regression via Ctgf expression and actin polymerization. · 2017
    Not checked
  84. 84.

    Nakajima H. Yamamoto K. Agarwala S. Terai K. Fukui H. Fukuhara S. (2017 ). Flow-dependent endothelial YAP regulation contributes to vessel maintenance. Dev. Cell 40:e526.

    Not in our library10.1016/j.devcel.2017.02.019

  85. 85.
    YAP and TAZ regulate adherens junction dynamics and endothelial cell distribution during vascular development · 2018
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    Nishida N. Yano H. Nishida T. Kamura T. Kojiro M. (2006 ). Angiogenesis in cancer. Vasc. Health Risk Manage. 2 213–219.

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    Nishio M. Hamada K. Kawahara K. Sasaki M. Noguchi F. Chiba S. (2012 ). Cancer susceptibility and embryonic lethality in Mob1a/1b double-mutant mice. J. Clin. Investig. 122 4505–4518.

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  88. 88.

    Paleolog E. M. (2002 ). Angiogenesis in rheumatoid arthritis. Arthritis Res. 4(Suppl. 3) S81–S90.

    Not in our library10.1186/ar575

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    Pan D. (2010 ). The hippo signaling pathway in development and cancer. Dev. Cell 19 491–505.

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  90. 90.

    Park H. W. Guan K. L. (2013 ). Regulation of the Hippo pathway and implications for anticancer drug development. Trends Pharmacol. Sci. 34 581–589.

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  91. 91.

    Piccolo S. Dupont S. Cordenonsi M. (2014 ). The biology of YAP/TAZ: hippo signaling and beyond. Physiol. Rev. 94 1287–1312.

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    Pobbati A. V. Chan S. W. Lee I. Song H. Hong W. (2012 ). Structural and functional similarity between the Vgll1-TEAD and the YAP-TEAD complexes. Structure 20 1135–1140.

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  93. 93.

    Poon C. L. Lin J. I. Zhang X. Harvey K. F. (2011 ). The sterile 20-like kinase Tao-1 controls tissue growth by regulating the salvador-warts-hippo pathway. Dev. Cell 21 896–906.

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  94. 94.

    Potente M. Gerhardt H. Carmeliet P. (2011 ). Basic and therapeutic aspects of angiogenesis. Cell 146 873–887.

    Not in our library10.1016/j.cell.2011.08.039

  95. 95.

    Praskova M. Khoklatchev A. Ortiz-Vega S. Avruch J. (2004 ). Regulation of the MST1 kinase by autophosphorylation, by the growth inhibitory proteins, RASSF1 and NORE1, and by Ras. Biochem. J. 381 453–462.

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    Praskova M. Xia F. Avruch J. (2008 ). MOBKL1A/MOBKL1B phosphorylation by MST1 and MST2 inhibits cell proliferation. Curr. Biol. 18 311–321.

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  97. 97.

    Reddy B. V. Irvine K. D. (2013 ). Regulation of hippo signaling by EGFR-MAPK signaling through Ajuba family proteins. Dev. Cell 24 459–471.

    Not in our library10.1016/j.devcel.2013.01.020

  98. 98.
    Yap- and Cdc42-Dependent Nephrogenesis and Morphogenesis during Mouse Kidney Development · 2013
    No notice
  99. 99.

    Robinson B. S. Huang J. Hong Y. Moberg K. H. (2010 ). Crumbs regulates salvador/warts/hippo signaling in Drosophila via the FERM-domain protein Expanded. Curr. Biol. 20 582–590.

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  100. 100.

    Roman B. L. Weinstein B. M. (2000 ). Building the vertebrate vasculature: research is going swimmingly. BioEssays 22 882–893.

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  101. 101.

    Rosenbluh J. Nijhawan D. Cox A. G. Li X. Neal J. T. Schafer E. J. (2012 ). beta-Catenin-driven cancers require a YAP1 transcriptional complex for survival and tumorigenesis. Cell 151 1457–1473.

    Not in our library10.1016/j.cell.2012.11.026

  102. 102.

    Ross R. (1999 ). Atherosclerosis–an inflammatory disease. N. Engl. J. Med. 340 115–126.

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  103. 103.

    Scheel H. Hofmann K. (2003 ). A novel interaction motif, SARAH, connects three classes of tumor suppressor. Curr. Biol. 13 R899–R900.

    Not in our library10.1016/j.cub.2003.11.007

  104. 104.

    Schlegelmilch K. Mohseni M. Kirak O. Pruszak J. Rodriguez J. R. Zhou D. (2011 ). Yap1 acts downstream of alpha-catenin to control epidermal proliferation. Cell 144 782–795.

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  105. 105.

    Serrano I. Mcdonald P. C. Lock F. Muller W. J. Dedhar S. (2013 ). Inactivation of the Hippo tumour suppressor pathway by integrin-linked kinase. Nat. Commun. 4:2976.

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    Si Y. Ji X. Cao X. Dai X. Xu L. Zhao H. (2017 ). Src Inhibits the Hippo Tumor Suppressor Pathway through Tyrosine Phosphorylation of Lats1. Cancer Res. 77 4868–4880.

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  107. 107.

    Strano S. Munarriz E. Rossi M. Castagnoli L. Shaul Y. Sacchi A. (2001 ). Physical interaction with Yes-associated protein enhances p73 transcriptional activity. J. Biol. Chem. 276 15164–15173.

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  108. 108.

    Sudol M. (1994 ). Yes-associated protein (YAP65) is a proline-rich phosphoprotein that binds to the SH3 domain of the Yes proto-oncogene product. Oncogene 9 2145–2152.

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  109. 109.

    Sudol M. Bork P. Einbond A. Kastury K. Druck T. Negrini M. (1995 ). Characterization of the mammalian YAP (Yes-associated protein) gene and its role in defining a novel protein module, the WW domain. J. Biol. Chem. 270 14733–14741.

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    Tang Y. Rowe R. G. Botvinick E. L. Kurup A. Putnam A. J. Seiki M. (2013 ). MT1-MMP-dependent control of skeletal stem cell commitment via a beta1-integrin/YAP/TAZ signaling axis. Dev. Cell 25 402–416.

    Not in our library10.1016/j.devcel.2013.04.011

  111. 111.

    Tepass U. Theres C. Knust E. (1990 ). crumbs encodes an EGF-like protein expressed on apical membranes of Drosophila epithelial cells and required for organization of epithelia. Cell 61 787–799.

    Not in our library10.1016/0092-8674(90)90189-l

  112. 112.

    Tiwari A. Jung J. J. Inamdar S. M. Nihalani D. Choudhury A. (2013 ). The myosin motor Myo1c is required for VEGFR2 delivery to the cell surface and for angiogenic signaling. Am. J. Physiol. Heart Circ. Physiol. 304 H687–H696.

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    Varelas X. (2014 ). The Hippo pathway effectors TAZ and YAP in development, homeostasis and disease. Development 141 1614–1626.

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    Varelas X. Sakuma R. Samavarchi-Tehrani P. Peerani R. Rao B. M. Dembowy J. (2008 ). TAZ controls Smad nucleocytoplasmic shuttling and regulates human embryonic stem-cell self-renewal. Nat. Cell Biol. 10 837–848.

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    Varelas X. Samavarchi-Tehrani P. Narimatsu M. Weiss A. Cockburn K. Larsen B. G. (2010 ). The crumbs complex couples cell density sensing to Hippo-dependent control of the TGF-beta-SMAD pathway. Dev. Cell 19 831–844.

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  116. 116.

    Varzavand A. Hacker W. Ma D. Gibson-Corley K. Hawayek M. Tayh O. J. (2016 ). alpha3beta1 integrin suppresses prostate cancer metastasis via regulation of the hippo pathway. Cancer Res. 76 6577–6587.

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  117. 117.

    Veyssier-Belot C. Cacoub P. (1999 ). Role of endothelial and smooth muscle cells in the physiopathology and treatment management of pulmonary hypertension. Cardiovasc. Res. 44 274–282.

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    Wang K. C. Yeh Y. T. Nguyen P. Limqueco E. Lopez J. Thorossian S. (2016 ). Flow-dependent YAP/TAZ activities regulate endothelial phenotypes and atherosclerosis. Proc. Natl. Acad. Sci. U.S.A. 113 11525–11530.

    Not in our library10.1073/pnas.1613121113

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    Wang L. Luo J. Y. Li B. Tian X. Y. Chen L. J. Huang Y. (2016 ). Integrin-YAP/TAZ-JNK cascade mediates atheroprotective effect of unidirectional shear flow. Nature 540 579–582.

    Not in our library10.1038/nature20602

  120. 120.

    Wang W. Huang J. Chen J. (2011 ). Angiomotin-like proteins associate with and negatively regulate YAP1. J. Biol. Chem. 286 4364–4370.

    Not in our library10.1074/jbc.c110.205401

  121. 121.

    Wang W. Huang J. Wang X. Yuan J. Li X. Feng L. (2012 ). PTPN14 is required for the density-dependent control of YAP1. Genes Dev. 26 1959–1971.

    Not in our library10.1101/gad.192955.112

  122. 122.

    Wang X. Freire Valls A. Schermann G. Shen Y. Moya I. M. Castro L. (2017 ). YAP/TAZ orchestrate VEGF signaling during developmental angiogenesis. Dev. Cell 42:e467.

    Not in our library10.1016/j.devcel.2017.08.002

  123. 123.

    Wong K. K. Li W. An Y. Duan Y. Li Z. Kang Y. (2015 ). beta-spectrin regulates the hippo signaling pathway and modulates the basal actin network. J. Biol. Chem. 290 6397–6407.

    Not in our library10.1074/jbc.m114.629493

  124. 124.

    Wu S. Huang J. Dong J. Pan D. (2003 ). hippo encodes a Ste-20 family protein kinase that restricts cell proliferation and promotes apoptosis in conjunction with salvador and warts. Cell 114 445–456.

    Not in our library10.1016/s0092-8674(03)00549-x

  125. 125.

    Yagi R. Chen L. F. Shigesada K. Murakami Y. Ito Y. (1999 ). A WW domain-containing yes-associated protein (YAP) is a novel transcriptional co-activator. EMBO J. 18 2551–2562.

    Not in our library10.1093/emboj/18.9.2551

  126. 126.

    Yang S. Zhao J. Sun X. (2016 ). Resistance to anti-VEGF therapy in neovascular age-related macular degeneration: a comprehensive review. Drug Des. Dev. Ther. 10 1857–1867.

    Not in our library10.2147/dddt.s97653

  127. 127.

    Yu F. X. Zhao B. Panupinthu N. Jewell J. L. Lian I. Wang L. H. (2012 ). Regulation of the Hippo-YAP pathway by G-protein-coupled receptor signaling. Cell 150 780–791.

    Not in our library10.1016/j.cell.2012.06.037

  128. 128.

    Yu J. Zheng Y. Dong J. Klusza S. Deng W. M. Pan D. (2010 ). Kibra functions as a tumor suppressor protein that regulates Hippo signaling in conjunction with Merlin and Expanded. Dev. Cell 18 288–299.

    Not in our library10.1016/j.devcel.2009.12.012

  129. 129.

    Zhang H. Von Gise A. Liu Q. Hu T. Tian X. He L. (2014 ). Yap1 is required for endothelial to mesenchymal transition of the atrioventricular cushion. J. Biol. Chem. 289 18681–18692.

    Not in our library10.1074/jbc.m114.554584

  130. 130.

    Zhang J. Ji J. Y. Yu M. Overholtzer M. Smolen G. A. Wang R. (2009 ). YAP-dependent induction of amphiregulin identifies a non-cell-autonomous component of the Hippo pathway. Nat. Cell Biol. 11 1444–1450.

    Not in our library10.1038/ncb1993

  131. 131.

    Zhang N. Bai H. David K. K. Dong J. Zheng Y. Cai J. (2010 ). The Merlin/NF2 tumor suppressor functions through the YAP oncoprotein to regulate tissue homeostasis in mammals. Dev. Cell 19 27–38.

    Not in our library10.1016/j.devcel.2010.06.015

  132. 132.

    Zhao B. Li L. Lu Q. Wang L. H. Liu C. Y. Lei Q. (2011 ). Angiomotin is a novel Hippo pathway component that inhibits YAP oncoprotein. Genes Dev. 25 51–63.

    Not in our library10.1101/gad.2000111

  133. 133.

    Zhao B. Li L. Tumaneng K. Wang C. Y. Guan K. L. (2010 ). A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF(beta-TRCP). Genes Dev. 24 72–85.

    Not in our library10.1101/gad.1843810

  134. 134.

    Zhao B. Li L. Wang L. Wang C. Y. Yu J. Guan K. L. (2012 ). Cell detachment activates the Hippo pathway via cytoskeleton reorganization to induce anoikis. Genes Dev. 26 54–68.

    Not in our library10.1101/gad.173435.111

  135. 135.

    Zhao B. Wei X. Li W. Udan R. S. Yang Q. Kim J. (2007 ). Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Dev. 21 2747–2761.

    Not in our library10.1101/gad.1602907

  136. 136.

    Zhao B. Ye X. Yu J. Li L. Li W. Li S. (2008 ). TEAD mediates YAP-dependent gene induction and growth control. Genes Dev. 22 1962–1971.

    Not in our library10.1101/gad.1664408

  137. 137.

    Zheng Y. Liu B. Wang L. Lei H. Pulgar Prieto K. D. Pan D. (2017 ). Homeostatic control of Hpo/MST kinase activity through autophosphorylation-dependent recruitment of the STRIPAK PP2A phosphatase complex. Cell Rep. 21 3612–3623.

    Not in our library10.1016/j.celrep.2017.11.076

  138. 138.

    Zheng Y. Wang W. Liu B. Deng H. Uster E. Pan D. (2015 ). Identification of happyhour/MAP4K as alternative Hpo/Mst-like kinases in the hippo kinase cascade. Dev. Cell 34 642–655.

    Not in our library10.1016/j.devcel.2015.08.014

  139. 139.

    Zhou D. Conrad C. Xia F. Park J. S. Payer B. Yin Y. (2009 ). Mst1 and Mst2 maintain hepatocyte quiescence and suppress hepatocellular carcinoma development through inactivation of the Yap1 oncogene. Cancer Cell 16 425–438.

    Not in our library10.1016/j.ccr.2009.09.026

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