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Targeting Aberrant RAS/RAF/MEK/ERK Signaling for Cancer Therapy

Ufuk Degirmenci, Mei Wang, Jiancheng Hu

Cells · 2020 · Review · CC BY

doi:10.3390/cells9010198

Abstract

The RAS/RAF/MEK/ERK (MAPK) signaling cascade is essential for cell inter- and intra-cellular communication, which regulates fundamental cell functions such as growth, survival, and differentiation. The MAPK pathway also integrates signals from complex intracellular networks in performing cellular functions. Despite the initial discovery of the core elements of the MAPK pathways nearly four decades ago, additional findings continue to make a thorough understanding of the molecular mechanisms involved in the regulation of this pathway challenging. Considerable effort has been focused on the regulation of RAF, especially after the discovery of drug resistance and paradoxical activation upon inhibitor binding to the kinase. RAF activity is regulated by phosphorylation and conformation-dependent regulation, including auto-inhibition and dimerization. In this review, we summarize the recent major findings in the study of the RAS/RAF/MEK/ERK signaling cascade, particularly with respect to the impact on clinical cancer therapy.

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.

1. A Brief History of RAS/RAF/MEK/ERK Signaling Cascade

The period from 1964 to the 1980s was the era of oncogene discoveries; prominent viral oncogenes such as Ras (rat sarcoma) and Raf (rapidly accelerated fibrosarcoma) were identified during this time. Shortly after their discovery, these viral oncogenes were shown to be altered versions of normal cellular genes. Three cellular Ras genes encode the four members of the RAS family of small GTPases, KRAS4A, KRAS4B, HRAS, and NRAS, whose mutations drive one-third of human cancers. Instead of point mutations, V-RAF is an N-terminal truncated version of the cellular RAF gene (CRAF) that encodes a serine/threonine kinase. These milestone discoveries instigated our current understanding of the dominant cancer signaling pathway: RAS/RAF/MEK/ERK.

In 1984, it was first suggested that epidermal growth factor (EGF) stimulated activation of RAS, i.e., increased its GTP bound state, which linked RAS to the upstream receptor tyrosine kinase (RTK) signaling. The subsequent finding of RAS requirement for serum-stimulated DNA replication further solidified its role at the plasma membrane as a signal transducer. In the effort to unravel the function of RAF proteins, an early study showing that v-RAF could stimulate S-phase entry in the absence of RAS activity suggested that RAF functions as either downstream of RAS or in parallel to RAS to promote cell division. Studies of RAF in Drosophila and C. elegans confirmed its role in RTK signaling, which put RAF under RTKs and RAS. In separate studies, the cytoplasmic Ser/Thr kinases ERK1 and ERK2 were found to promote cell cycling; and ERK1/2 activity was shown to be enhanced by yet other cytosolic kinases, MEK1/2, that phosphorylate the conserved Thr/Tyr in the activation loop of ERK1/2. Further investigation of the kinase cascade revealed that CRAF is the upstream kinase that phosphorylates MEK1 at Ser222 and MEK2 at Ser218 that regulates the activity of MEK, and through which ERK, thus rank-ordering the MAPK signaling from RAS, RAF, MEK, and finally to ERK. The RAS GTPase is “switched on” to the GTP-bound active form by upstream regulators, such as RTKs, activated Ras can then physically interact with RAF and turn on the signaling cascade. These findings delineated how signals generated from membrane-bound receptors are conveyed through RAS GTPase and transmitted intracellularly through a kinase cascade, setting a milestone in understanding of cell communication and signaling (Figure 1).

For RAF research, the early spotlight on CRAF was shifted to BRAF after the discovery in 2002 that BRAF mutations (especially BRAFV600E) were dominant in cancer. Recent studies, however, have brought CRAF back to the center stage for its role in the complicated regulation of RAF kinases by the so called inhibitor-induced paradoxical activation of RAF seen in RAF and RAS mutant cancers. A main therapeutic challenge in treating RAS/RAF-driven cancers is to develop drugs that can inhibit this pathway without paradoxical activation.

There are several major reviews in the field that describe the importance of RAS and RAF signaling and their roles in cellular regulatory processes. In this paper, we refer to these reviews, at times, due to the abundance of original research articles. However, we do provide short summaries of crucial aspects of the field, with their primary references, where we feel it enhances the clarity of this review.

2. RAS GTPases and Their Activation

The mammalian RAS GTPases consist of three gene isoforms, HRAS, NRAS, and KRAS, and four protein isoforms (splicing isoforms of KRAS give rise to KRAS4A and KRAS4B proteins). Whilst the isoforms share most of their sequence, substantial differences appear in the C-terminal so-called hypervariable regions and in post-translational modifications. These differences in sequence and modification are considered to underlie the findings that RAS isoforms can function differentially in different biology and pathophysiology. From the standpoint of engaging MAPK signaling, KRAS is more efficient than HRAS for CRAF activation while the opposite is true for PI3K activation. Furthermore, both KRAS and HRAS have higher activity toward NFκB activation in contrast to NRAS. While being members of the most frequently mutated oncogene family in human cancer, RAS isoform mutants are clearly not equally prevalent in cancers. KRAS mutations are overwhelmingly represented in cancers as whole compared to the other two isoforms. There is also strong tissue predilection of the occurrence of RAS isoform mutations; while KRAS monopolizes pancreatic cancers, NRAS mutants dominate melanoma and AML. Furthermore, the RAS isoforms also have different favored mutations, which interplay with cancer types and tissue origins, adding complexity and intrigue. All these differences among RAS isoforms underscore the limitation of our understanding of RAS proteins and their downstream pathway engagements.

The cellular activities and functions of RAS proteins are regulated at different levels. As a GTPase, RAS activity is regulated by the GTP/GDP cycle. GTP-bound RAS proteins adopt the so-called active conformation that allows them to bind and activate downstream effectors, while the GDP-bound RAS proteins have altered conformations that impede such interactions. The process of dislodging bound GDP for GTP, thereby activating RAS, is facilitated by guanine exchange factor (GEF) proteins. The intrinsic GTPase activity, enhanced by RAS GTPase activating protein (GAP), hydrolyses the bound GTP into GDP and returns the protein to the inactive GDP-bound state, thus completing the GTP/GDP cycle. As an important signaling process, the GTP/GDP cycle is regulated by various stimuli, including the cell surface receptors, such as several RTKs. Genetic alterations that affect the regulation of RAS activation/inactivation cycle, particularly ones that result in the persistent activation of RAS, can lead to human pathologies—the so called RASopathies. For example, upregulation or gain-of-function mutations of RTKs stimulate the activity of the RasGEF, Sos, which in turn elevates the cellular level of GTP-bound Ras and oncogenic transformation. On the other hand, the loss-of-function mutations of RasGAPs, exemplified by NF1, also results in persistent RAS activation and proliferative diseases. The most common mutations leading to RAS activation are on RAS itself, which occur in one-third of human malignancies. There are two hot spots of RAS activating mutations: the mutations at glycines 12 and 13 (G12/13) that impair RAS association with RasGAPs and at glutamine 61 (Q61) that diminish the intrinsic GTPase activity of Ras.

The proper functions of RAS proteins are also subject to the regulation of their posttranslational modifications, which are essential for their trafficking, membrane localization, and interaction with regulators and effectors. RAS proteins belong to group of proteins that contain the C-terminal CAAX consensus sequence for the prenylation processing. The nascent RAS proteins in the cytosol are firstly modified by either protein farnesyltransferase or geranylgeranyltransferase on the cysteine residue of their CAAX box, after which they transiently associate with the endoplasmic reticulum (ER). On the ER, they are further processed by the endoprotease RCE1, followed by isoprenylcysteine carboxylmethyltransferase ICMT, which converts the carboxyl-terminus of RAS proteins from a hydrophilic region into a hydrophobic one, facilitating the insertion of Ras proteins into cellular membranes. Subsequently, RAS proteins can undergo isoform-specific modifications, such as phosphorylation for KRAS4B and palmitoylation for HRAS and NRAS, which facilitate transport and plasma membrane localization through distinct mechanisms.

Interestingly, the functions of RAS are subject to another layer of regulation—dimerization and nano-clustering on plasma membrane to trigger and transmit signaling downstream. Lipid rafts, subdomains of plasma membranes that have distinct chemical composition and properties, have been known since 1998 and were observed as lateral heterogeneity, and consequently non-random distribution, of proteins by proteolipid-based sorting. Earlier works in Ras nano-clustering showed that Ras proteins gather on lipid rafts differentially among isoforms. The current model is that all Ras isoforms in their GDP and GTP bound state give rise to distinct conformations and interact with distinct lipid compositions, cholesterol, PS, PA, PIP2, PIP3, PI3P, and PI4P, and that lipid composition contributes to the stability of the nanoclusters of Ras. RAS dimerization or nano-clustering is thought to be a key step in the generation of its ability to couple to RAF.

3. RAF Isoforms

RAF proteins, pivotal components of Ras/RAF/MEK/ERK signaling cascade, include three isoforms: CRAF, BRAF, and ARAF. CRAF (also called Raf-1) is the first RAF protein identified in 1984, followed by ARAF in 1986 and BRAF in 1988. All RAF proteins share three conserved regions: CR1 (conserved region 1), which contains a RAS-binding domain (RBD) and a Cys-rich domain; CR2, which is characterized by Ser/Thr-rich sequence; and CR3, which is constituted of a putative kinase domain with an acidic N-terminus (NTA) and a regulatory C-terminus. Structures of RAF kinases revealed that the proteins could be divided into two functional regions as the regulatory domain (CR1 and CR2) and kinase domain (CR3). Although they have similar molecular structures, RAF proteins have quite different activity and play differential roles in cell function. BRAF, which is well-known in cancer, as it is a major target of genetic mutations in tumorigenesis, has the highest activity among three isoforms, likely by virtue of its constitutively-phosphorylated NTA motif. CRAF, which plays an indispensable role in RASopathies, has intermediate activity. Lastly, ARAF is rarely seen genetically altered and has the lowest kinase activity due, for the most part, to its non-canonical APE motif (Figure 2a).

As typical protein kinases, RAFs contain a kinase domain that comprises an N-lobe (amino-terminal lobe) and a larger C-lobe (Carboxyl-terminal lobe). The N-lobe that includes five antiparallel β-strands and a signal-integrated helix denoted as αC is connected by a flexible hinge to the C-lobe that mostly consists of α-helices and a key loop termed activation segment/activation loop. Although the kinase domains oscillate between closed and open conformations via inter-lobe motions, the active state is restricted to the closed conformation. The closed conformation is maintained by the alignment of two parallel hydrophobic cores (spines) of spatially conserved residues spanning N- and C-lobes. The regulatory spine (R-spine) is built upon the alignment of four residues in RAFs, F516 from β4 strand, L505 from αC, F595 from DFG, and H574 from HRD (BRAF residue numbers used here). The catalytic spine (C-spine) is formed to control kinase activation upon ATP loading. These hydrophobic spines limit the movement of αC helix and stabilize the active conformation of the kinase domain.

In inactive conformation of RAF, the “Asp-Phe-Gly (DFG)” motif at the N terminus of the activation loop is flipped “OUT” relative to its conformation in the active state “IN”. The “OUT” DFG blocks the ATP binding pocket and stabilizes an open inactive conformation. The αC helix adjacent to N-terminus of the dimer interface is also in an “OUT” position in the inactive kinase, where it binds to dimer interface residues (504–511 in BRAF) and further stabilizes the inactive conformation. In addition, F485 from the β3 strand, L597 on the activation loop, and V600 on helix AS-H1 form a hydrophobic network that provides further stabilization of inactive conformation. In the active state, αC assumes the “IN” conformation that helps the formation of a salt bridge between glutamine from αC and catalytic lysine from VAIK motif (E501-K483 for B-Raf, E393-K375 for C-Raf, and E354-K336 for A-Raf). The activation loop AS-H1 is disordered in the active conformation due to αC being pulled “IN”, which reciprocally enables dimerization. It is important to note that the hallmark of an active RAF kinase requires the assembly of the two hydrophobic spines in its core, which supersedes the more dynamic/oscillating elements such as the so-called “open” or “closed” states or formation of the conserved salt bridge.

4. RAF-Knockout Mouse Models

Gene-knockout mouse models of the three RAF proteins have yielded a vast amount of information on their functional differences. CRAF-knockout mice are embryonic lethal with poor development of the placenta, liver, and hematopoietic organs; BRAF-knockout mice die in utero at D12.5 with vascular and neuronal defects. In contrast, ARAF-knockout mice were born alive, but presented severe intestinal and neurological abnormalities.

Interestingly, mice that express a kinase-impaired CRAF with the loss of phosphorylation sites in NTA motif (YY340/341FF) exhibit a different phenotype from that caused by complete CRAF-deficiency. Several mechanisms have been suggested to explain potential kinase-independent functions of CRAF. Firstly, Rok-α is hyperactivated and mis-localized to the membrane in CRAF−/− cells, which blocks Fas death receptor internalization, leading to increased Fas on the plasma membrane and Fas-dependent apoptosis. Furthermore, CRAF NTA mutant mice show impaired wound healing and migration of keratinocytes. CRAF-deficient fibroblasts and keratinocytes exhibit rounded morphology and impaired migration, indicating the defective cytoskeleton. This phenotype could be rescued with Rok-α double knockout. Biochemical and functional evidence support a mechanism for these phenotypes of kinase-independent actions of CRAF being that the autoinhibitory Cysteine-rich domain of CRAF acts in trans to inhibit Rok-α. This involvement of CRAF in the regulation of apoptosis has been shown to be relevant in several human diseases. For example, Rok-α inhibition by CRAF is a prerequisite for Ras-induced cellular transformation, and it has been shown that CRAF plays a role in pathogen-mediated macrophage apoptosis and erythroid differentiation.

ERK signaling can inhibit apoptosis in various ways, including expression of caspase inhibitors, neutralization of Bcl-2 family proteins, and activation of NFκB. It is worth noting, however, that the anti-apoptotic role of CRAF does not depend on its ability to activate ERK. Additionally, targeting CRAF in KRAS G12V/Trp53 mutant lung tumors triggered massive apoptosis without blocking ERK phosphorylation, which may explain the acceptable levels of toxicity of this approach. In addition to its role in regulating Fas, mitochondrial CRAF has been shown to protect the cell from apoptosis; indeed, some growth factors have been reported to play roles in the translocation of CRAF to mitochondria where p21-activated kinase (Pak1) phosphorylates it on Ser338 in the NTA motif. There is also evidence suggesting that CRAF has a scaffold function for PKCθ to facilitate phosphorylation of BAD as a way of CRAF regulation. In addition, CRAF directly interacts with voltage-dependent anion channels and prevents the release of cytochrome C from mitochondria. Other targets of CRAF include two pro-apoptotic kinases, ASK1 and MST2, which also rely on a kinase-independent activity of CRAF. Deficiency of CRAF promotes apoptosis of cardiomyocyte, which can be rescued with ASK1 knockdown. Despite these reports, the definitive mechanism through which mitochondrial CRAF prevents apoptosis requires further investigation.

Similar to CRAF, ARAF also binds and sequesters MST2 independent of its kinase activity. ARAF interaction with MST2 is dependent on the presence of full-length splicing product controlled by hnRNP H. In primary tumors and cell lines, ARAF and MST2 co-localize to mitochondria and prevent apoptosis. In addition to MST2, ARAF was found to bind pyruvate kinase M2 (PKM2), which is an embryonic splice variant of PKM and responsible for aerobic glycolysis. In ARAF-transformed NIH3T3 cells, PKM2 is changed from dimeric to a highly active tetrameric conformation, linking ARAF to cancer metabolism.

Double knockout of RAF proteins generated more severe phenotype which suggested their additive effects. Studies indicated that RAF proteins could compensate for lack of one of the isoforms up to a certain point but all three are required for regulating the development of the organism. In addition to knockouts, constitutively-active BRAFV600E mutant mouse also showed a embryonically lethal phenotype.

5.1. Auto-Inhibited State of RAF

Once the RAS/RAF/MEK/ERK pathway was identified, research efforts focused on studying both negative and positive regulators of the signaling cascade. In non-dividing cells, RAF exists in an auto-inhibited state where its N-terminus docks on the kinase domain, inhibiting its catalytic activity. This is supported by the fact that overexpression of the N-terminal CR1 domain inhibits kinase activity in trans. The interaction between the two parts of CRAF was further validated by the study of the N-terminus mutations of CRAF in regulating its kinase activity. Moreover, RAF inhibitors that disrupt the auto-inhibited state trigger paradoxical activation, much to the disappointment of oncologists.

5.2. RAF Recruitment to Plasma Membrane by Activated RAS

RAS proteins are anchored on the plasma membrane through their prenylated C-terminal CAAX motif. Upon GTP-loading, RAS is able to recruit RAF to the plasma membrane via its RAS-binding domain (RBD), which consists of a ubiquitous fold shared by other RAS effectors such as PI3K p110 subunits and RAL guanine nucleotide dissociation stimulator (RALGDS). Single residue substitution in the RBD is sufficient to disrupt the association of RAF with RAS and abolish the activation of RAF. Outside of the RBD, the Cys-rich region has been shown to form zinc coordinated structures that interact with phospholipids and facilitate membrane translocation of several kinases, including CRAF. Furthermore, the Cys-rich region of RAF can also interact with the farnesyl group in RAS proteins. In addition, the N-terminus before RBD domain (also called as N’-segment) has been shown to regulate the binding selectivity of both RAF and Ras isoforms. Thus, RBD, Cys-rich region and N’-segment are involved in the plasma membrane recruitment of RAF proteins by active Ras. Despite the large amount of work and progress made in the understanding of RAS–RAF interaction, there are critical details missing on the major structural and functional interactions of these two proteins. For example, it is not clear how RAS triggers the de-phosphorylation of inhibitory Ser residues. In addition, the manner through which the auto-inhibitory intramolecular interactions of RAF proteins are relieved is also not yet clear, although Phosphatase 2A (PP2A) and PP1 have been shown to regulate this process.

5.3. Dimerization Is a Key Event in RAF Activation

Despite the differences in their ability to trigger downstream ERK signaling, all RAF isoforms are activated through dimer-driven transactivation. Under physiological condition, Ras-driven activation of RAF proteins occurs on the plasma membrane where activated RAS promotes RAF dimerization, a key event to trigger the kinase activity of RAF proteins. The notion of dimerization-driven transactivation of RAF proteins arises from an early observation that artificial oligomerization of CRAF triggers its kinase activity. The subsequent observation of RAS-induced heterodimerization of BRAF and CRAF under physiological conditions further supports the relevance of dimer formation. The finding that kinase-dead BRAF was able to activate ERK signaling through dimerizing with and activating CRAF not only provide further support for the role of RAF dimerization, but raised the awareness that both catalysis-dependent and -independent functions of RAF are functionally important. In addition to the BRAF–CRAF heterodimer, respective homodimers of the two isoforms, i.e., BRAF:BRAF and CRAF:CRAF, have also been detected, but were noted to have lower kinase activity. ARAF, however, has the lowest affinity for dimer formation due to its different structural features, most notably its non-canonical APE motif that does not stabilize the dimer interface as BRAF and CRAF are able to do. However, site-specific mutagenesis of this motif from AAE to APE enables ARAF to form dimers as strongly as CRAF. In summary, RAF family members can form physiologically relevant heterodimers and homodimers, resulting in their transactivation (Figure 2b).

The dimeric structure of RAF stabilizes the closed conformation of the kinase domain by limiting the oscillating motion of the two kinase lobes and promoting key conformational transitions. Conversely, the acquisition of the active conformation also facilitates RAF dimerization. Once RAF achieves active conformation, its dimer interface becomes further stabilized by the hydrophobic R-spine residue in the αC- helix (L505 for B-Raf, L397 for C-Raf, and L358 for A-Raf) located adjacent to the conserved RKTR motif, which is allosterically connected αC-helix and dimer interface. Upon the relocation of R509 to the center of the dimer interface, αC-helix interacts with the NTA motif of the trans RAF molecule and adopts the “IN” conformation

The dimerization of RAF proteins can be promoted by shortening their β3-αC loop; and in-frame deletions of β3-αC loop activate ARAF by enforcing homodimer formation, showing that ARAF can function as a “true” kinase to induce ERK phosphorylation, even though it is the weakest kinase in the family. The corresponding deletions in BRAF also ramp up its kinase activity through enhancing its homodimer formation. A surprising finding from these studies is that the kinase-dead BRAF mutant with an in-frame deletion of β3-αC loop (ΔNVTAP/V471F) can activate ERK signaling in the absence of active RAS due to its substantial dimer affinity.

The dimerization of RAF proteins can be also improved in other ways. The BRAF splicing variants lacked exon 4–7 exhibit a stronger dimer affinity and thereby a strong resistance to RAF inhibitors. In addition to alternative splicing products; gene fusions, translocations and deletions that remove the auto-inhibitory N-terminus allow RAFs to homodimerize with higher affinity. Furthermore, RAF inhibitors, especially the first-generation drugs, enhance RAF dimerization upon their binding, and thereby paradoxically activate the pathway, which is further discussed below. Understanding the complete mechanism of dimerization is still a work in progress, with questions remaining about the scaffolding proteins, activation direction, and the priming of the cells for RTK signaling by increasing RAS nanoclusters.

5.4. The Role of NTA Motif and Activation Loop Phosphorylation in RAF Activation

RAF proteins undergo multiple phosphorylation events during their activation cycle. Two major phosphorylation events, the NTA motif and the activation loop, play key roles. The NTA motif contains divergent loci for phosphorylation among RAFs, allowing them to have distinct regulations. In BRAF, the NTA motif contains SSDD, in which the D448 and D449 provide the initial negative charge before serine phosphorylation. In CRAF, this locus contains SSYY and requires phosphorylation of both serine and tyrosine residues. The constitutively phosphorylated SS and acidic DD in the NTA motif of BRAF can explain the higher activity of BRAF compared to ARAF and CRAF. Negative charges in this loci contribute to the relief of autoinhibition and are critical for dimerization-driven transactivation. In RAF homo/heterodimers, the phosphorylated NTA motif was suggested by molecular modeling to form multiple salt bridges that extend and stabilize the dimer interface between two protomers. It has been shown that the phosphorylation status of NTA motif dictates the direction of transactivation in RAF dimers; the protomer with phosphorylated NTA motif acts as an activator, while the other protomer with non-phosphorylated NTA motif does as a receiver in RAF dimers. A ‘receiver’ protomer can be switched into an ‘activator’ protomer upon phosphorylation in its NTA and thereby amplify the dimerization-driven transactivation of RAF proteins. Protein kinases that target the NTA motif play an important role not only in the activation of RAF proteins but also by controlling the receiver–activator switch. SRC family kinases are the main kinase family targeting YY in ARAF and CRAF. Although still controversial, p21-activated kinase (Pak) family members acting downstream of PI3K-CDC42 or RAC signaling cascades have been suggested to phosphorylate Ser338 in CRAF. Other kinases that potentially target the NTA motif of RAF proteins include the following: (1) Janus Kinase 2 (JAK2), which is able to phosphorylate CRAF to activate MEK1, (2) Casein Kinase 2 (CK2), which phosphorylates CRAF at Ser338 and BRAF at Ser446, and (3) Calcium/calmodulin-dependent protein kinase II (CaMKII), which can phosphorylate CRAF at S338.

The phosphorylation of activation loop is also important for the function of RAFs. The dimerization of RAF proteins facilitates their transition to an active conformation, which directly induces their activation loop auto-phosphorylation as a consequence. Like most protein kinases, the activation loop of RAFs contain two conserved phosphorylation sites relevant to their kinase function; for ARAF, these are Thr452 and Thr455; for BRAF, these are Thr599 and Ser602; and for CRAF, these are Thr491 and Ser494. Although studying the phosphorylation of the activation loop is difficult due to highly dynamic de-phosphorylation, the data from RAF co-activation assay suggest that cis auto-phosphorylation is the mechanism. A recent study of a mouse model with BRAF T599A/S602A mutation showed that the loss of activation loop phosphorylation could not duplicate the lethal phenotype of BRAF null mice. However, these mice had an aberrant development of the hematopoietic system and reduction of p-ERK level in the brain, among other characteristics, indicating the importance of proper activation loop phosphorylation of BRAF in development, function, and maintenance of cell populations.

6. Regulation of RAF by Accessory Molecules

Activation of RAF is also regulated by other proteins, including heat-shock protein 90(Hsp90), CDC37, kinase suppressor of Ras (KSR), and 14-3-3 proteins.

6.1. Hsp90/Cdc37 Chaperone Complex

The Hsp90/Cdc37 chaperone complex participates in proper protein folding that stabilizes protein kinases, including RAFs. The association of RAF proteins with hsp90/cdc37 complex is essential for their activity towards MEK. Further, the association of BRAF with hsp90/cdc37 complex facilitates the assembly of high molecular weight BRAF complex and promotes its kinase activity, probably by increasing dimer affinity. It is not surprising, therefore, that Hsp90 inhibitors can block the activity of RAF proteins and also induce their degradation, especially that of the constitutively active RAF mutants such as BRAF(V600E). Recently, Hsp90 inhibitors were shown to prevent development of resistance to RAF inhibitors on BRAF(V600E)-harboring cancers in clinical trials, even though the underlying mechanism were too complicated to pinpoint a single molecule.

6.2. KSR

Kinase suppressor of RAS (KSR) was initially identified through screening molecules essential for Ras function in Drosophila. It had been referred to as pseudo-kinase due to its low kinase activity. Subsequently, KSR was identified as a scaffold protein that not only brings close proximity between RAF and MEK1, but also allosterically activates RAF. It should be noted that KSR forms not only a side-to-side dimer with RAF proteins but also a face-to-face dimer with MEK, both of which are critical for its ability to transactivate RAF proteins.

6.3. Proteins 14-3-3

The 14-3-3 proteins were the first identified, and the most well-known, phosphoserine/phosphothreonine binding proteins, which can interact with a wide variety of proteins including transcriptions factors, cytoskeletal proteins, apoptosis factors and tumor suppressors. Binding to 14-3-3 can alter the proteins’ stability, localization, conformation, and association with other proteins. The functions of 14-3-3 has been reviewed extensively.

The 14-3-3 binds to phospho-serine/threonine residues in two conserved motifs of RAF proteins: RSXpS/TXP or RXXXpSXP. RAF proteins contain two 14-3-3 binding sites: S259 and S621 for CRAF; S365 and S729 for BRAF; and S214 and S582 for ARAF (Figure 2a). The 14-3-3 association with these two sites plays opposite roles in RAF activity. Activation of RAF by 14-3-3 occurs in the event of 14-3-3 binding two RAF molecules at the C-terminal phosphoserine, which promotes dimerization. Cryo-EM studies have shown that a dimeric 14-3-3 binds two phosphorylated serine residues on different RAF proteins, such as CRAF at Ser621 and BRAF at Ser 729, and thereby stabilizes the side-to-side heterodimer or homodimer. On the other hand, if a dimeric 14-3-3 binds to the N- and C-terminus of a single RAF, respectively, it can stabilize autoinhibitory conformation. The serine residues in conserved 14-3-3 binding motifs can be phosphorylated by Protein Kinase A (PKA), Akt, AMPK, or by LATS1 from the MST2-Hippo pathway. Regulation of phosphorylation events at two 14-3-3 binding sites can change the response drastically due to their opposite activity. The 14-3-3 binding site phosphorylation by different kinases may influence the therapeutic efficacy of cancer drugs. For example, in Ras-mutated cancer cells, the CRAF S621 is phosphorylated redundantly by AMPK and itself. Combination of RAF inhibitors with AMPK inhibitor could reduce the paradoxical activation. Recognition of the alternative kinases that could phosphorylate 14-3-3 binding sites and thereby alter RAF activity, could improve clinical success.

7. RAF Function as a Dimer

As mentioned above, the Arg at the center of RAF dimer interface is a key residue for RAF function, and its mutation to His blocks the dimerization-driven transactivation of RAF proteins. This mutation can also abolish the drug resistance of BRAF(V600E) splicing variants that lack a part of N-terminus and thereby have a higher dimer affinity than their prototype. Based on these observations, a monomer hypothesis in which RAF inhibitors bind and inhibit monomeric BRAF(V600E), but not dimeric variants, has been suggested to explain the drug resistance of BRAF mutants. However, this hypothesis has been challenged by other findings. Firstly, it was shown that BRAF(V600E) has an extended dimer interface in contrast to its wild-type counterpart and exists as dimer/oligomer when expressed in cells. Secondly, the Arg-to-His mutation did not fully diminish dimer formation of RAF proteins, and some RAF mutants with high dimer affinity such as BRAF(ΔNVTAP) and BRAF(ΔMLN) were still able to transactivate wild-type RAF in the presence of Arg-to-His mutation. Thirdly, the Arg-to-His mutation, together with APE motif alteration, completely dissociated BRAF(V600E) dimers and abolished their activity, which could be rescued by GST fusion-mediated re-dimerization. Lastly, RAF had been shown to phosphorylate MEK in a dimer-to-dimer manner in which an active RAF needs the other RAF partner to facilitate MEK phosphorylation (further discussed below). Therefore, the active monomer hypothesis is not supported at its current standing.

8. RAF–MEK Heterodimerization and MEK–MEK Homodimerization, Essential Events for Signaling

MEK was identified independently by multiple groups as a substrate of RAF in 1992, and their interaction was further supported by the yeast two-hybrid assay. Following these findings, MEK was shown to be phosphorylated by RAF on Ser218 and Ser222 in its activation loop. Recent studies have provided detailed mechanisms of RAF phosphorylation and activation of MEK. As a substrate, MEK needs to be recruited to RAF before activation. In quiescent cells, BRAF and MEK form a heterodimer in the cytosol, while CRAF and ARAF do not interact with MEK under this condition, presenting the question of how MEK is recruited to these RAFs. Crystallography studies have revealed that BRAF interacts with MEK1 in a face-to-face manner through two contact sites. The first contact site is αG helices, a structural component of kinase–substrate docking interaction. The second contact site is consisting of their activation loop which generates antiparallel β-sheet. Mutations on both contact sites that disrupt the BRAF/MEK interaction block both allosteric and catalytic activities of BRAF, suggesting that the RAF/MEK association plays an indispensable role in signal transmission from RAF to MEK.

Given the abilities of RAF proteins to form side-to-side dimers with themselves and face-to-face dimers with MEK, it is not surprising that RAF and MEK assemble a tetramer complex of MEK:RAF:RAF:MEK in the process of activation, which has been captured in crystal structures. Although how the RAF dimer phosphorylates MEK in this transient RAF/MEK tetramer is not completely understood, recent studies suggested that two MEK molecules need form a homodimer that is further phosphorylated by RAF dimer or itself, since monomeric MEK cannot be phosphorylated by RAF, and MEK homodimerization drives autophosphorylation. Moreover, phosphorylated MEK exerts its activity towards ERK as a dimer, suggesting that MEK/MEK homodimerization plays a critical role, as do RAF/RAF and RAF/MEK dimerizations, in the pathway activation.

9. Feedback Inhibition and Return to the Inactive State

Cessation of the activated ERK signal is a crucial part of controlled cell division; therefore, the triggered ERK pathway needs to return to the basal state with regulated feedback cues. As a part of immediate inhibitory phosphorylation; SOS1, the RAS-GEF, is phosphorylated by ERK, which inhibits interaction with Grb2 and creates 14-3-3 binding site for inhibitory binding. ERK also exerts negative feedback on RAF by phosphorylating multiple Ser/Thr sites on RAF. ERK phosphorylation of these Ser/Thr sites breaks the interaction of RAF with Ras, and also RAF-RAF dimerization. Additionally, some of these Ser/Thr sites can also be phosphorylated by c-Jun amino-terminal kinases (JNKs) as a protective mechanism under stress conditions. Further, the autophosphorylation of P-loop residues in RAF proteins serves as another feedback mechanism that impairs their kinase activity. For MEK, it can be phosphorylated at its N-terminus that intercepts its activity.

Shortly after inhibitory phosphorylation as described above, the components of Ras/RAF/MEK/ERK signaling cascade require dephosphorylation to return to the inactive state. It has been shown that PP5 participates in the dephosphorylation of pSer338 in the NTA motif of CRAF, while PP2A is involved in Ser/Thr site dephosphorylation in a PIN1 dependent manner. However, in the area of dephosphorylation, most underlying molecular mechanisms remain to be elucidated.

Outside of the signaling cascade and immediate inhibitory phosphorylation, Dual-specificity phosphatases (DUSP) and Sprouty proteins are involved in transcriptional inhibition of the ERK signaling. DUSP6 is upregulated by its transcription factor that activated by ERK1/2. Sprouty proteins are induced upon growth factor treatment, which can inhibit ERK signaling through different mechanisms. Spry1 and Spry2 are phosphorylated at their N-terminus upon RTK activation, which enables Spry to dock on Grb2. Furthermore, Spry4 inhibits ERK signaling by binding to CRAF.

10. Mutations in the Ras/RAF/MEK/ERK Signaling Cascade

The RAS signaling cascade has well-defined role in tumorigenesis. Point mutations across each of the members within the cascade have been identified as either driver of the tumor formation (RAS and RAF mutations) or indicator of poor prognosis (MEK and ERK mutations). Interestingly, driver mutations within the pathway are mutually exclusive. In this section, we describe the mutation hotspots for each member of the signaling cascade.

10.1. Ras Mutations

RAS mutations in all cancer types occur mostly in KRAS (85%), followed by NRAS (12%) and HRAS (3%). Interestingly, mutants of different RAS isoforms have tissue/cancer-type-dependent distributions. For example, NRAS is the most common in melanoma, while HRAS in adrenal glands and KRAS in pancreas. Moreover, KRAS G12D was shown to promote stronger colon cancer development than NRAS G12D in Apc-deficient mice, and HRAS G12V knock into the KRAS locus was not tumorigenic in the lungs of mice.

RAS proteins have two mutational hotspots, 12–13 and 61. Most mutations changing G12 or G13, likely to intercept GAP’s Arg finger loop accession to the RAS GTPase site and prevent it from promoting hydrolysis. As a consequence, G12 and G13 mutants trap RAS in a constitutively active state. Mutations at Q61 inhibits intrinsic GTP hydrolysis and GAP-mediated GTP hydrolysis (Figure 3). It is worth noting that, in addition to the isoform-dependent tissue distribution in RAS-driven cancers, the site of mutation hotspots also comes into play in the tissue/cancer-type distribution. For example, 90% of KRAS mutations in pancreatic ductal adenocarcinoma are at the position G12, while 90% of NRAS mutations in melanoma are at Q61. These patterns might indicate underlying fundamental signaling landscapes and RAS mutant interplay with these landscapes. Adding to the complexity of RAS mutations, the oncogenic stimuli also mold the site of mutation and the type of tumor development. For example, KRAS Q61R/L dominates the G12 mutation in urethane treated mice.

10.2. RAF Mutations

Although V-RAF was discovered as a first oncogenic Ser/Thr protein kinase, its cellular prototype CRAF is rarely mutated in cancers. The function of RAF as a prominent cancer driver was not established until the discovery of BRAF(V600E) in 2002. In cancer genomes, BRAF is a major target of oncogenic mutations and a single-point mutation, and V600E represents >90% of events, while mutations in CRAF, ARAF, and KSRs are much less and have been detected in decreasing order of frequency (Figure 4).

Cancer-related mutations of RAF are enriched in special domains of the proteins and can be categorized into multiple groups based on how they trigger the pathway. The first group (or Class I) of RAF mutations activate RAF by mimicking phosphorylation of the activation loop. The second group (or Class II) of RAF mutations turn on RAF activity by relieving the auto-inhibitory status. The third group (or Class III) of RAF mutations have no, or impaired, kinase activity and agonist the pathway through transactivating their wild-type counterparts.

Class I RAF mutations include V600E/D mutations in activation loop of BRAF and constitute the largest group in the RAF mutation spectrum. The V600E/D mutation stabilizes the active conformation of BRAF by forming a salt bridge with K507, thereby dramatically triggering the kinase activity of BRAF independent of Ras. Class II RAF mutations are mainly located at the activation loop (K601 and L597), or Gly-rich loop (P-loop, G464 and G469), and disrupt the inhibitory interaction of activation loop with Gly-rich loop and thus destabilize the auto-inhibitory status. This type of mutant has intermediate kinase activity and increased dimer affinity, and it triggers ERK signaling with or without active RAS. Class III RAF mutations are mostly found in the Gly-rich loop (G466 and G469E), the DFG motif (D594 and G596), the catalytic loop (N581), or the C-spine (V471F). These mutants have greatly reduced kinase activity compared with wild-type RAF and drive the activation of ERK signaling by transactivating the wild-type RAF with their enhanced dimerization affinity. Unlike the Class I and Class II mutants, the Class III mutants require active Ras to trigger signaling cascade.

In addition to the highly prevalent mutations above, there are also some minor populations of RAF mutations in cancer genomes. N-terminal truncations of CR1 and CR2 domains, or kinase domain fusions with other proteins that relieve the N-terminal inhibition, have been identified in RAF genes. These N-terminal truncations or kinase domain fusions allow RAF to dimerize and activate ERK signaling in a RAS-independent manner. Under physiological conditions, RAF dimerization occurs on the plasma membrane. The mutations in the Cysteine-rich domain and Ras-binding domain (RBD) of RAF can promote its plasma membrane recruitment, and thereby dimerization, to trigger ERK signaling. In addition, mutations that abolish the inhibitory 14-3-3 association with the N-terminus of RAF (S259 in CRAF and S365 in BRAF) were also found in a small group of cancers.

10.3. MEK and ERK Mutations

In contrast to Ras and RAF mutations, MEK mutations are much less common in cancer genomes. These mutations do not co-occur with Ras or RAF mutations, indicating that they function as cancer drivers. MEK mutations are classified into two groups according to their activation mechanism. The first group of MEK mutations turns on the kinase activity of MEK by disrupting the inhibitory intramolecular interaction mediated by the regulatory helix A, while the second group does so through enhancing MEK homodimerization. These two types of MEK mutants also exhibit differential sensitivities to MEK inhibitors in clinic or under clinic trials. Like RAF, the elevated dimer affinity may also result in the resistance to inhibitors. Finally, ERK mutations are very rare in cancer genomes. However, a mutational hotspot has been identified on the site of D321/E322, which blocks the Dusp6-mediated dephosphorylation of ERK and thereby extends the half-life of active ERK.

11.1. Is RAS Druggable?

Oncogenic Ras mutants have been considered “undruggable” over the decades due to their high affinity with GTP and the lack of proper binding pocket for small molecule inhibitor binding. Recently, the Shokat group at UCSF showed that KRAS G12C could be targeted by using a covalent small molecule that docks in the switch II pocket and cross-links with Cys12. This discovery spurred the race to develop KRAS-G12C-targeting drugs for clinical use. AMG510 and MRTX1257 were the first ones to be developed as drugs to target KRAS G12C mutant for non-small cell lung cancer. The results from phase I trials were promising and showed a 50% response rate for patients with KRAS G12C mutations. However, these drugs still require further investigation; besides validating efficacy, the impact of co-mutations and the development of drug resistance also need to be evaluated. Unfortunately, KRAS G12C is only represented in a small fraction of RAS mutant cancers, and the challenge remains to drug the other RAS mutants.

Among alternatives to target mutant RAS isoforms, inhibiting their functionally relevant post-translational modification represents a promising approach. The protein prenylation processing pathway attracted significant attention in the early targeted therapeutic field. Initial effort was largely focused on protein farnesyltransferase, for good reason. First, it was discovered as the canonical prenylation enzyme for all RAS isoforms under normal cellular conditions. Second, it has been under careful genetic, biochemical, structural and functional studies. However, as the first targeted therapy development, inadequate understanding of the alternative prenylation pathway of K- and N-RAS by geranylgeranyl transferase and corresponding inadequate stratification method led to the dismal clinical results for farnesyltransferase inhibitors. In recent years, new trials have been initiated that are designed to target the HRAS driven cancers, as H-RAS is not subject to alternate prenylation. It will be interesting to see the level of efficacy from these trials; early data has shown promise (https://www.aacr.org/Newsroom/Pages/News-Release-Detail.aspx?ItemID=1350).

The earlier dismal trial results for farnesyltransferase inhibitors also sparked the interest in protein geranylgeranyl transferase (GGTase I), which prenylates K- and NRAS when farnesyltransferase is inhibited. Targeting GGTase I, alone or in combination with FTIs, became an active area of investigation following the FTI trials. Indeed, there are major efforts in developing GGTase I inhibitors for the treatment of certain cancers. However, the toxicity of combination therapy of GGTase I and FTase may have limited the pace of such development. Among the three steps of prenylation modifications, the last step of carboxymethylation by isoprenylcysteine carboxylmethyltransferase (ICMT) has also attracted much attention. Genetic suppression of ICMT in both cell and mouse models showed that ICMT inhibition led to the inhibition of tumorigenesis in multiple cancer model systems. Proof-of-concept ICMT inhibitors have largely replicated the efficacy of genetic cancer models. It will be quite interesting to follow the progress and evolvement of the development.

For some RAS mutants, targeting their key effectors could be an effective alternative method. The small molecule inhibitor Rigosertib has been used to block the interactions of active Ras with the Ras-binding domain of effectors, and it has shown efficacy to target Ras-mutated cancers in phase III clinic trials. Sulindac and MCP110, two other Ras-effector interaction inhibitors, were also shown to inhibit RAS driven tumorigenesis.

Like other oncogenes, Ras mutants need a set of cellular factors to facilitate their oncogenicity. These synthetic lethal factors/networks could be targeted for cancer therapy. Two recent studies showed that targeting RAF/MEK/ERK signaling together with autophagy signaling led to synthetic lethality and achieved a promising efficacy on Ras-driven cancers, suggesting that synthetic lethal factors/networks may be highly valuable for developing new drugs/methods against Ras-mutated cancers. Indeed, prior evidence of manipulating autophagy by inhibiting ICMT has shown encouraging results, which supports that ICMT can be used to regulate RAS-driven signaling. For the effort of identifying the targets downstream of ERK signaling in modulating autophagy, several screens have been carried out with whole genome shRNA knockdown libraries, which yielded few druggable factors. The strong biology, however, appeals to future reliable screening approaches such as Cas9-CRISPR-mediated knockout. Nevertheless, exploring all synthetic lethal factors/networks of Ras should provide better understanding how oncogenic Ras induces cancers and also accelerate the development of drugs against Ras-mutated cancers.

11.2. RAF/MEK/ERK Inhibitors and Resistance

Among the members of the Ras/RAF/MEK/ERK signaling cascades, RAF is a key direct effector of oncogenic Ras mutants and also a prominent target of oncogenic mutations. As the first kinase in this pathway, RAF has been thought as an ideal target for drug development against cancers. The first-generation RAF inhibitors, Vemurafenib, Dabrafenib, and Encorafenib, were developed and applied to treatment of BRAF(V600E)-harboring cancers as single agents or together with MEK inhibitors. These drugs achieved a promising efficacy at the initial therapeutic phase, although this efficacy was abrogated by quick-rising drug resistance. Mechanistic studies have shown that cancer cells reactivate this pathway upon drug treatment through two different ways: (1) upregulating the cellular level of active Ras, which leads to paradoxical activation of ERK signaling; and (2) alternative splicing of BRAF(V600E) to generate variants with truncated N-terminus, which enhances BRAF(V600E) homodimerization and decreases drug affinity. Interestingly, these drug-resistance cancer cells become addicted to RAF inhibitors, and drug withdrawal delays the growth of resistant cancers (Figure 5). This phenomenon can be explained by the concept of a “sweet-spot” for hyperactive Ras/RAF/MEK/ERK-signaling-driven cancer progression (Figure 5a). Specifically, cancer cells need optimal ERK signaling for growth, and ERK signaling that is too high will induce cell death or senescence and hence be toxic to cancer cells. Drug-resistant cancer cells have much higher ERK signaling than drug-sensitive cancer cells. Drug treatment decreases the ERK signaling in drug-resistance cancer cells to a level suitable for growth, while a drug withdrawal or “drug holiday” will inhibit their growth (Figure 5b,c).

The paradoxical effect of the first-generation RAF inhibitors not only abrogated their efficacy but also induced secondary malignancies, a major side-effect of RAF inhibitors. To overcome the drug resistance of the first-generation RAF inhibitors, second-generation of RAF inhibitors were developed and underwent clinical trials; such inhibitors include pan-RAF inhibitors (such as LY3009120, TAK632, TAK580, CCT3833, BGB283, BAL3833, LXH254, and RAF265), and paradox breakers (such as PLX8349). The pan-RAF inhibitors can inhibit both protomers in RAF dimers with similar affinity, while the paradox breakers induce an αC helix-out conformation upon loading and thereby prevent dimerization-driven transactivation.

To block hyperactive Ras/RAF/MEK/ERK signaling in cancers, MEK and ERK have also been used as targets for drug designs. Two MEK inhibitors (trametinib and cobimetinib) have been developed and approved for treating BRAF(V600E)-harboring cancers as single agents or together with RAF inhibitors, while ERK inhibitors are still undergoing clinical trials. In contrast to RAF inhibitors, these inhibitors have no paradoxical effect, but they do have a lower therapeutic index since they strongly inhibit this signaling pathway in normal cells. This also implies that targeting downstream MEK/ERK may not be a good choice to treat Ras- or RAF-mutated cancers.

The development of RAF/MEK/ERK inhibitors has significantly improved targeted cancer therapy, and it has also accelerated our understanding of molecular mechanisms that tune the output of Ras signaling, which in turn facilitates the development of next-generation inhibitors. Studies on these inhibitors have revealed a dominant role of component interactions that include RAF/RAF, RAF/MEK, and MEK/MEK dimerizations in regulating Ras signaling. Since the structures of these complexes have been resolved, the development of allosteric inhibitors that break these interactions would be an attractive area of research in the coming years. In contrast to the first- and second-generation RAF inhibitors, these allosteric inhibitors should have many more advantages, such as no paradoxical effect and less off-target effects.

12. Closing Remarks

The second-generation RAF inhibitors, which are expected to show longer-lasting effects on cancer growth, are now entering the clinical market. Despite the enthusiasm, it is still not well understood how well cancers will respond to these drugs in the long term. The studies on inhibitor-RAF interactions and the wild-type RAF response to the new inhibitors could help minimizing the off-target effects in patients. Determining the crystal structure and direct interaction between inhibitors/effectors would provide better insights into their mode of action in the pathways. This information not only could create potentially avenues for improved inhibition with better the drug specificity and efficacy; it could also reveal and validate novel allosteric targets within the pathway. Understanding the interactions between RAS/RAF/MEK mutants and their wild-type counterparts could result in the discovery of novel allosteric target sites to block the formation of dimers and tetramers between mutant and wild-type proteins. Besides the focus on RAS-downstream-signaling-partner studies, it is also interesting to follow the progress in the effort of targeting RAS functions, either directly or via modulating the functional post-translational prenylation pathway enzymes. With these comprehensive research efforts, we hope to have more specific and potent drugs targeting RAS/RAF/MEK/ERK signaling, to aid in the management of human cancers.

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    Not in our library10.1074/jbc.c000079200

  57. 57.

    Winter-Vann A.M., Kamen B.A., Bergo M.O., Young S.G., Melnyk S., James S.J., Casey P.J. Targeting Ras signaling through inhibition of carboxyl methylation: An unexpected property of methotrexate. Proc. Natl. Acad. Sci. USA. 2003;100:6529-6534.

    Not in our library10.1073/pnas.1135239100

  58. 58.

    Inouye K., Mizutani S., Koide H., Kaziro Y. Formation of the Ras Dimer Is Essential for Raf-1 Activation. J. Biol. Chem. 2000;275:3737-3740.

    Not in our library10.1074/jbc.275.6.3737

  59. 59.

    Varma R., Mayor S. GPI-anchored proteins are organized in submicron domains at the cell surface. Nature. 1998;394:798-801.

    Not in our library10.1038/29563

  60. 60.

    Prior I.A., Muncke C., Parton R.G., Hancock J.F. Direct visualization of Ras proteins in spatially distinct cell surface microdomains. J. Cell Biol. 2003;160:165-170.

    Not in our library10.1083/jcb.200209091

  61. 61.

    Plowman S.J., Muncke C., Parton R.G., Hancock J.F. H-ras, K-ras, and inner plasma membrane raft proteins operate in nanoclusters with differential dependence on the actin cytoskeleton. Proc. Natl. Acad. Sci. USA. 2005;102:15500-15505.

    Not in our library10.1073/pnas.0504114102

  62. 62.

    Zhou Y., Hancock J.F. Ras nanoclusters: Versatile lipid-based signaling platforms. Biochim. Biophys. Acta Mol. Cell Res. 2015;1853:841-849.

    Not in our library10.1016/j.bbamcr.2014.09.008

  63. 63.

    Tian T., Harding A., Inder K., Plowman S., Parton R.G., Hancock J.F. Plasma membrane nanoswitches generate high-fidelity Ras signal transduction. Nat. Cell Biol. 2007;9:905-914.

    Not in our library10.1038/ncb1615

  64. 64.

    Huleihel M., Goldsborough M., Cleveland J., Gunnell M., Bonner T., Rapp U.R. Characterization of murine A-raf, a new oncogene related to the v-raf oncogene. Mol. Cell. Biol. 1986;6:2655-2662.

    Not in our library10.1128/mcb.6.7.2655

  65. 65.

    Beck T.W., Huleihel M., Gunnell M., Bonner T.I., Rapp U.R. The complete coding sequence of the human A-raf-1 oncogene and transforming activity of a human A-raf carrying retrovirus. Nucl. Acids Res. 1987;15:595-609.

    Not in our library10.1093/nar/15.2.595

  66. 66.

    Ikawa S., Fukui M., Ueyama Y., Tamaoki N., Yamamoto T., Toyoshima K. B-raf, a new member of the raf family, is activated by DNA rearrangement. Mol. Cell. Biol. 1988;8:2651-2654.

    Not in our library10.1128/mcb.8.6.2651

  67. 67.

    Daum G., Eisenmann-Tappe I., Fries H.-W., Troppmair J., Rapp U.R. The ins and outs of Raf kinases. Trends Biochem. Sci. 1994;19:474-480.

    Not in our library10.1016/0968-0004(94)90133-3

  68. 68.

    Wellbrock C., Karasarides M., Marais R. The RAF proteins take centre stage. Nat. Rev. Mol. Cell Biol. 2004;5:875-885.

    Not in our library10.1038/nrm1498

  69. 69.

    Nassar N., Horn G., Herrmann C.A., Scherer A., McCormick F., Wittinghofer A. The 2.2 Å crystal structure of the Ras-binding domain of the serine/threonine kinase c-Raf1 in complex with RaplA and a GTP analogue. Nature. 1995;375:554-560.

    Not in our library10.1038/375554a0

  70. 70.

    Scheffler J.E., Waugh D.S., Bekesi E., Kiefer S.E., LoSardo J.E., Neri A., Prinzo K.M., Tsao K.L., Wegrzynski B., Emerson S.D., et al. Characterization of a 78-residue fragment of c-Raf-1 that comprises a minimal binding domain for the interaction with Ras-GTP. J. Biol. Chem. 1994;269:22340-22346.

    Not in our library

  71. 71.

    Chuang E., Barnard D., Hettich L., Zhang X.F., Avruch J., Marshall M.S. Critical binding and regulatory interactions between Ras and Raf occur through a small, stable N-terminal domain of Raf and specific Ras effector residues. Mol. Cell. Biol. 1994;14:5318-5325.

    Not in our library10.1128/mcb.14.8.5318

  72. 72.

    Emerson S.D., Waugh D.S., Scheffler J.E., Tsao K.-L., Prinzo K.M., Fry D.C. Chemical Shift Assignments and Folding Topology of the RAS-Binding Domain of Human RAF-1 As Determined by Heteronuclear Three-Dimensional NMR Spectroscopy. Biochemistry. 1994;33:7745-7752.

    Not in our library10.1021/bi00191a001

  73. 73.

    Mott H.R., Carpenter J.W., Zhong S., Ghosh S., Bell R.M., Campbell S.L. The solution structure of the Raf-1 cysteine-rich domain: A novel ras and phospholipid binding site. Proc. Natl. Acad. Sci. USA. 1996;93:8312-8317.

    Not in our library10.1073/pnas.93.16.8312

  74. 74.

    Diaz B., Barnard D., Filson A., MacDonald S., King A., Marshall M. Phosphorylation of Raf-1 serine 338-serine 339 is an essential regulatory event for Ras-dependent activation and biological signaling. Mol. Cell. Biol. 1997;17:4509-4516.

    Not in our library10.1128/mcb.17.8.4509

  75. 75.

    Mason C.S., Springer C.J., Cooper R.G., Superti-Furga G., Marshall C.J., Marais R. Serine and tyrosine phosphorylations cooperate in Raf-1, but not B-Raf activation. EMBO J. 1999;18:2137-2148.

    Not in our library10.1093/emboj/18.8.2137

  76. 76.

    Dhillon A.S., Yip Y.Y., Grindlay G.J., Pakay J.L., Dangers M., Hillmann M., Clark W., Pitt A., Mischak H., Kolch W. The C-terminus of Raf-1 acts as a 14-3-3-dependent activation switch. Cell. Signal. 2009;21:1645-1651.

    Not in our library10.1016/j.cellsig.2009.07.001

  77. 77.

    Kondo Y., Ognjenović J., Banerjee S., Karandur D., Merk A., Kulhanek K., Wong K., Roose J.P., Subramaniam S., Kuriyan J. Cryo-EM structure of a dimeric B-Raf:14-3-3 complex reveals asymmetry in the active sites of B-Raf kinases. Science. 2019;366:109-115.

    Not in our library10.1126/science.aay0543

  78. 78.

    Muslin A.J., Tanner J.W., Allen P.M., Shaw A.S. Interaction of 14-3-3 with Signaling Proteins Is Mediated by the Recognition of Phosphoserine. Cell. 1996;84:889-897.

    Not in our library10.1016/s0092-8674(00)81067-3

  79. 79.

    Morrison D.K., Heidecker G., Rapp U.R., Copeland T.D., Morrisonst D.K., Heideckerq G., Rappq U.R., Copeland T.D. Identification of the major phosphorylation sites of the Raf-1 kinase. J. Biol. Chem. 1993;268:17309-17316.

    Not in our library

  80. 80.

    Hu J., Stites E.C., Yu H., Germino E.A., Meharena H.S., Stork P.J.S., Kornev A.P., Taylor S.S., Shaw A.S. Allosteric Activation of Functionally Asymmetric RAF Kinase Dimers. Cell. 2013;154:1036-1046.

    Not in our library10.1016/j.cell.2013.07.046

  81. 81.

    Blasco R.B., Francoz S., Santamaría D., Cañamero M., Dubus P., Charron J., Baccarini M., Barbacid M. c-Raf, but Not B-Raf, Is Essential for Development of K-Ras Oncogene-Driven Non-Small Cell Lung Carcinoma. Cancer Cell. 2011;19:652-663.

    Not in our library10.1016/j.ccr.2011.04.002

  82. 82.

    Karreth F.A., Frese K.K., DeNicola G.M., Baccarini M., Tuveson D.A. C-Raf is required for the initiation of lung cancer by K-Ras(G12D). Cancer Discov. 2011;1:128-136.

    Not in our library10.1158/2159-8290.cd-10-0044

  83. 83.

    Lito P., Saborowski A., Yue J., Solomon M., Joseph E., Gadal S., Saborowski M., Kastenhuber E., Fellmann C., Ohara K., et al. Disruption of CRAF-Mediated MEK Activation Is Required for Effective MEK Inhibition in KRAS Mutant Tumors. Cancer Cell. 2014;25:697-710.

    Not in our library10.1016/j.ccr.2014.03.011

  84. 84.

    Yuan J., Ng W.H., Lam P.Y.P.P., Wang Y., Xia H., Yap J., Guan S.P., Lee A.S.G.G., Wang M., Baccarini M., et al. The dimer-dependent catalytic activity of RAF family kinases is revealed through characterizing their oncogenic mutants. Oncogene. 2018;37:5719-5734.

    Not in our library10.1038/s41388-018-0365-2

  85. 85.

    Yap J., Yuan J., Tee Z.H., Huang X., Ng W.H., Hu J. Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods. JoVE. 2019;149:e59795.

    Not in our library10.3791/59795

  86. 86.

    Haling J.R., Sudhamsu J., Yen I., Sideris S., Sandoval W., Phung W., Bravo B.J., Giannetti A.M., Peck A., Masselot A., et al. Structure of the BRAF-MEK Complex Reveals a Kinase Activity Independent Role for BRAF in MAPK Signaling. Cancer Cell. 2014;26:402-413.

    Not in our library10.1016/j.ccr.2014.07.007

  87. 87.

    Kornev A.P., Haste N.M., Taylor S.S., Ten Eyck L.F. Surface comparison of active and inactive protein kinases identifies a conserved activation mechanism. Proc. Natl. Acad. Sci. USA. 2006;103:17783-17788.

    Not in our library10.1073/pnas.0607656103

  88. 88.

    Taylor S.S., Kornev A.P. Protein kinases: Evolution of dynamic regulatory proteins. Trends Biochem. Sci. 2011;36:65-77.

    Not in our library10.1016/j.tibs.2010.09.006

  89. 89.

    Taylor S.S., Shaw A., Hu J., Meharena H.S., Kornev A. Pseudokinases from a structural perspective. Biochem. Soc. Trans. 2013;41:981-986.

    Not in our library10.1042/bst20130120

  90. 90.

    Shaw A.S., Kornev A.P., Hu J., Ahuja L.G., Taylor S.S. Kinases and Pseudokinases: Lessons from RAF. Mol. Cell. Biol. 2014;34:1538-1546.

    Not in our library10.1128/mcb.00057-14

  91. 91.

    Hu J., Ahuja L.G., Meharena H.S., Kannan N., Kornev A.P., Taylor S.S., Shaw A.S. Kinase Regulation by Hydrophobic Spine Assembly in Cancer. Mol. Cell. Biol. 2015;35:264-276.

    Not in our library10.1128/mcb.00943-14

  92. 92.

    Kim J., Ahuja L.G., Chao F., Xia Y., Mcclendon C.L., Kornev A.P., Taylor S.S., Veglia G. A dynamic hydrophobic core orchestrates allostery in protein kinases. Sci. Adv. 2017;3:e1600663.

    Not in our library10.1126/sciadv.1600663

  93. 93.

    Vijayan R.S.K., He P., Modi V., Duong-Ly K.C., Ma H., Peterson J.R., Dunbrack R.L., Levy R.M. Conformational analysis of the DFG-out kinase motif and biochemical profiling of structurally validated type II inhibitors. J. Med. Chem. 2015;58:466-479.

    Not in our library10.1021/jm501603h

  94. 94.

    Treiber D.K., Shah N.P. Ins and Outs of Kinase DFG Motifs. Chem. Biol. 2013;20:745-746.

    Not in our library10.1016/j.chembiol.2013.06.001

  95. 95.

    Thevakumaran N., Lavoie H., Critton D.A., Tebben A., Marinier A., Sicheri F., Therrien M. Crystal structure of a BRAF kinase domain monomer explains basis for allosteric regulation. Nat. Struct. Mol. Biol. 2015;22:37-43.

    Not in our library10.1038/nsmb.2924

  96. 96.

    Terrell E.M., Morrison D.K. Ras-Mediated Activation of the Raf Family Kinases. Cold Spring Harb. Perspect. Med. 2019;9:a033746.

    Not in our library10.1101/cshperspect.a033746

  97. 97.

    Wojnowski L., Stancato L.F., Zimmer A.M., Hahn H., Beck T.W., Larner A.C., Rapp U.R., Zimmer A. Craf-1 protein kinase is essential for mouse development. Mech. Dev. 1998;76:141-149.

    Not in our library10.1016/s0925-4773(98)00111-7

  98. 98.

    Mikula M., Schreiber M., Husak Z., Kucerova L., Rüth J., Wieser R., Zatloukal K., Beug H., Wagner E.F., Baccarini M. Embryonic lethality and fetal liver apoptosis in mice lacking the c-raf-1 gene. EMBO J. 2001;20:1952-1962.

    Not in our library10.1093/emboj/20.8.1952

  99. 99.

    Wojnowski L., Zimmer A.M., Beck T.W., Hahn H., Bernal R., Rapp U.R., Zimmer A. Endothelial apoptosis in Braf-deficient mice. Nat. Genet. 1997;16:293-297.

    Not in our library10.1038/ng0797-293

  100. 100.

    Wiese S., Pei G., Karch C., Troppmair J., Holtmann B., Rapp U.R., Sendtner M. Specific function of B-Raf in mediating survival of embryonic motoneurons and sensory neurons. Nat. Neurosci. 2001;4:137-142.

    Not in our library10.1038/83960

  101. 101.

    Pritchard C.A., Bolin L., Slattery R., Murray R., McMahon M. Post-natal lethality and neurological and gastrointestinal defects in mice with targeted disruption of the A-Raf protein kinase gene. Curr. Biol. 1996;6:614-617.

    Not in our library10.1016/s0960-9822(02)00548-1

  102. 102.

    Hüser M., Luckett J., Chiloeches A., Mercer K., Iwobi M., Giblett S., Sun X.M., Brown J., Marais R., Pritchard C., et al. MEK kinase activity is not necessary for Raf-1 function. EMBO J. 2001;20:1940-1951.

    Not in our library10.1093/emboj/20.8.1940

  103. 103.

    Piazzolla D., Meissl K., Kucerova L., Rubiolo C., Baccarini M. Raf-1 sets the threshold of Fas sensitivity by modulating Rok-alpha signaling. J. Cell Biol. 2005;171:1013-1022.

    Not in our library10.1083/jcb.200504137

  104. 104.

    Ehrenreiter K., Piazzolla D., Velamoor V., Sobczak I., Small J.V., Takeda J., Leung T., Baccarini M. Raf-1 regulates Rho signaling and cell migration. J. Cell Biol. 2005;168:955-964.

    Not in our library10.1083/jcb.200409162

  105. 105.

    Niault T., Sobczak I., Meissl K., Weitsman G., Piazzolla D., Maurer G., Kern F., Ehrenreiter K., Hamerl M., Moarefi I., et al. From autoinhibition to inhibition in trans: The Raf-1 regulatory domain inhibits Rok-alpha kinase activity. J. Cell Biol. 2009;187:335-342.

    Not in our library10.1083/jcb.200906178

  106. 106.

    Ehrenreiter K., Kern F., Velamoor V., Meissl K., Galabova-Kovacs G., Sibilia M., Baccarini M. Raf-1 Addiction in Ras-Induced Skin Carcinogenesis. Cancer Cell. 2009;16:149-160.

    Not in our library10.1016/j.ccr.2009.06.008

  107. 107.

    Sanclemente M., Francoz S., Esteban-Burgos L., Bousquet-Mur E., Djurec M., Lopez-Casas P.P., Hidalgo M., Guerra C., Drosten M., Musteanu M., et al. c-RAF Ablation Induces Regression of Advanced Kras/Trp53 Mutant Lung Adenocarcinomas by a Mechanism Independent of MAPK Signaling. Cancer Cell. 2018;33:217-228.e4.

    Not in our library10.1016/j.ccell.2017.12.014

  108. 108.

    Rubiolo C., Piazzolla D., Meissl K., Beug H., Huber J.C., Kolbus A., Baccarini M. A balance between Raf-1 and Fas expression sets the pace of erythroid differentiation. Blood. 2006;108:152-159.

    Not in our library10.1182/blood-2005-09-3866

  109. 109.

    Kolbus A., Pilat S., Husak Z., Deiner E.M., Stengl G., Beug H., Baccarini M. Raf-1 Antagonizes Erythroid Differentiation by Restraining Caspase Activation. J. Exp. Med. 2002;196:1347-1353.

    Not in our library10.1084/jem.20020562

  110. 110.

    Wang H.-G., Rapp U.R., Reed J.C. Bcl-2 Targets the Protein Kinase Raf-1 to Mitochondria. Cell. 1996;87:629-638.

    Not in our library10.1016/s0092-8674(00)81383-5

  111. 111.

    Panka D.J., Atkins M.B., Mier J.W. Targeting the Mitogen-Activated Protein Kinase Pathway in the Treatment of Malignant Melanoma. Clin. Cancer Res. 2006;12:2371s-2375s.

    Not in our library10.1158/1078-0432.ccr-05-2539

  112. 112.
    Raf induces NF-κB by membrane shuttle kinase MEKK1, a signaling pathway critical for transformation · 2000
    Not checked
  113. 113.

    Troppmair J., Hartkamp J., Rapp U.R. Activation of NF-κB by oncogenic Raf in HEK 293 cells occurs through autocrine recruitment of the stress kinase cascade. Oncogene. 1998;17:685-690.

    Not in our library10.1038/sj.onc.1201981

  114. 114.

    Norris J.L., Baldwin A.S. Oncogenic Ras Enhances NF-κB Transcriptional Activity through Raf-dependent and Raf-independent Mitogen-activated Protein Kinase Signaling Pathways. J. Biol. Chem. 1999;274:13841-13846.

    Not in our library10.1074/jbc.274.20.13841

  115. 115.

    Majewski M., Nieborowska-Skorska M., Salomoni P., Slupianek A., Reiss K., Trotta R., Calabretta B., Skorski T. Activation of Mitochondrial Raf-1 Is Involved in the Antiapoptotic Effects of Akt. Cancer Res. 1999;59:2815-2819.

    Not in our library

  116. 116.

    Wu X., Carr H.S., Dan I., Ruvolo P.P., Frost J.A. p21 activated kinase 5 activates Raf-1 and targets it to mitochondria. J. Cell. Biochem. 2008;105:167-175.

    Not in our library10.1002/jcb.21809

  117. 117.

    Jin S., Zhuo Y., Guo W., Field J. p21-activated Kinase 1 (Pak1)-dependent Phosphorylation of Raf-1 Regulates Its Mitochondrial Localization, Phosphorylation of BAD, and Bcl-2 Association. J. Biol. Chem. 2005;280:24698-24705.

    Not in our library10.1074/jbc.m413374200

  118. 118.

    Hindley A., Kolch W. Raf-1 and B-Raf promote protein kinase C theta interaction with BAD. Cell. Signal. 2007;19:547-555.

    Not in our library10.1016/j.cellsig.2006.08.004

  119. 119.

    Le Mellay V., Troppmair J., Benz R., Rapp U.R. Negative regulation of mitochondrial VDAC channels by C-Raf kinase. BMC Cell Biol. 2002;3:14.

    Not in our library10.1186/1471-2121-3-14

  120. 120.

    Chen J., Fujii K., Zhang L., Roberts T., Fu H. Raf-1 promotes cell survival by antagonizing apoptosis signal-regulating kinase 1 through a MEK-ERK independent mechanism. Proc. Natl. Acad. Sci. USA. 2001;98:7783-7788.

    Not in our library10.1073/pnas.141224398

  121. 121.

    Alavi A.S., Acevedo L., Min W., Cheresh D.A. Chemoresistance of Endothelial Cells Induced by Basic Fibroblast Growth Factor Depends on Raf-1–Mediated Inhibition of the Proapoptotic Kinase, ASK1. Cancer Res. 2007;67:2766-2772.

    Not in our library10.1158/0008-5472.can-06-3648

  122. 122.

    Tobiume K., Matsuzawa A., Takahashi T., Nishitoh H., Morita K., Takeda K., Minowa O., Miyazono K., Noda T., Ichijo H. ASK1 is required for sustained activations of JNK/p38 MAP kinases and apoptosis. EMBO Rep. 2001;2:222-228.

    Not in our library10.1093/embo-reports/kve046

  123. 123.

    O’Neill E., Rushworth L., Baccarini M., Kolch W. Role of the kinase MST2 in suppression of apoptosis by the proto-oncogene product Raf-1. Science. 2004;306:2267-2270.

    Not in our library10.1126/science.1103233

  124. 124.

    Yamaguchi O., Watanabe T., Nishida K., Kashiwase K., Higuchi Y., Takeda T., Hikoso S., Hirotani S., Asahi M., Taniike M., et al. Cardiac-specific disruption of the c-raf-1 gene induces cardiac dysfunction and apoptosis. J. Clin. Investig. 2004;114:937-943.

    Not in our library10.1172/jci200420317

  125. 125.

    Rauch J., Kolch W. Spatial regulation of ARAF controls the MST2-Hippo pathway. Small GTPases. 2019;10:243-248.

    Not in our library10.1080/21541248.2017.1288686

  126. 126.

    Rauch J., O’Neill E., Mack B., Matthias C., Munz M., Kolch W., Gires O. Heterogeneous nuclear ribonucleoprotein H blocks MST2-mediated apoptosis in cancer cells by regulating A-Raf transcription. Cancer Res. 2010;70:1679-1688.

    Not in our library10.1158/0008-5472.can-09-2740

  127. 127.

    Christofk H.R., Vander Heiden M.G., Harris M.H., Ramanathan A., Gerszten R.E., Wei R., Fleming M.D., Schreiber S.L., Cantley L.C. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature. 2008;452:230-233.

    Not in our library10.1038/nature06734

  128. 128.

    Le Mellay V., Houben R., Troppmair J., Hagemann C., Mazurek S., Frey U., Beigel J., Weber C., Benz R., Eigenbrodt E., et al. Regulation of glycolysis by Raf protein serine/threonine kinases. Adv. Enzyme Regul. 2002;42:317-332.

    Not in our library10.1016/s0065-2571(01)00036-x

  129. 129.

    Mercer K., Giblett S., Oakden A., Brown J., Marais R., Pritchard C. A-Raf and Raf-1 work together to influence transient ERK phosphorylation and Gl/S cell cycle progression. Oncogene. 2005;24:5207-5217.

    Not in our library10.1038/sj.onc.1208707

  130. 130.

    Wojnowski L., Stancato L.F., Larner A.C., Rapp U.R., Zimmer A. Overlapping and specific functions of Braf and Craf-1 proto-oncogenes during mouse embryogenesis. Mech. Dev. 2000;91:97-104.

    Not in our library10.1016/s0925-4773(99)00276-2

  131. 131.

    Mercer K., Giblett S., Green S., Lloyd D., DaRocha Dias S., Plumb M., Marais R., Pritchard C. Expression of endogenous oncogenic V600EB-raf induces proliferation and developmental defects in mice and transformation of primary fibroblasts. Cancer Res. 2005;65:11493-11500.

    Not in our library10.1158/0008-5472.can-05-2211

  132. 132.

    Cutler R.E., Stephens R.M., Saracino M.R., Morrison D.K. Autoregulation of the Raf-1 serine/threonine kinase. Proc. Natl. Acad. Sci. USA. 1998;95:9214-9219.

    Not in our library10.1073/pnas.95.16.9214

  133. 133.

    Morrison D.K., Cutler R.E. The complexity of Raf-1 regulation. Curr. Opin. Cell Biol. 1997;9:174-179.

    Not in our library10.1016/s0955-0674(97)80060-9

  134. 134.

    Jin T., Lavoie H., Sahmi M., David M., Hilt C., Hammell A., Therrien M. RAF inhibitors promote RAS-RAF interaction by allosterically disrupting RAF autoinhibition. Nat. Commun. 2017;8:1211.

    Not in our library10.1038/s41467-017-01274-0

  135. 135.

    Hey F., Pritchard C. A New Mode of RAF Autoregulation: A Further Complication in the Inhibitor Paradox. Cancer Cell. 2013;23:561-563.

    Not in our library10.1016/j.ccr.2013.04.021

  136. 136.

    Sanchez-Vega F., Mina M., Armenia J., Chatila W.K., Luna A., La K.C., Dimitriadoy S., Liu D.L., Kantheti H.S., Saghafinia S., et al. Oncogenic Signaling Pathways in The Cancer Genome Atlas. Cell. 2018;173:321-337.e10.

    Not in our library10.1016/j.cell.2018.03.035

  137. 137.

    Ahearn I.M., Haigis K., Bar-Sagi D., Philips M.R. Regulating the regulator: Post-translational modification of RAS. Nat. Rev. Mol. Cell Biol. 2011;13:39.

    Not in our library10.1038/nrm3255

  138. 138.

    Clark G.J., Drugan J.K., Terrell R.S., Bradham C., Der C.J., Bell R.M., Campbell S. Peptides containing a consensus Ras binding sequence from Raf-1 and theGTPase activating protein NF1 inhibit Ras function. Proc. Natl. Acad. Sci. USA. 1996;93:1577-1581.

    Not in our library10.1073/pnas.93.4.1577

  139. 139.

    Pacold M.E., Suire S., Perisic O., Lara-Gonzalez S., Davis C.T., Walker E.H., Hawkins P.T., Stephens L., Eccleston J.F., Williams R.L. Crystal Structure and Functional Analysis of Ras Binding to Its Effector Phosphoinositide 3-Kinase γ. Cell. 2000;103:931-944.

    Not in our library10.1016/s0092-8674(00)00196-3

  140. 140.

    Fabian J.R., Vojtek A.B., Cooper J.A., Morrison D.K. A single amino acid change in Raf-1 inhibits Ras binding and alters Raf-1 function. Proc. Natl. Acad. Sci. USA. 1994;91:5982-5986.

    Not in our library10.1073/pnas.91.13.5982

  141. 141.

    Im E., von Lintig F.C., Chen J., Zhuang S., Qui W., Chowdhury S., Worley P.F., Boss G.R., Pilz R.B. Rheb is in a high activation state and inhibits B-Raf kinase in mammalian cells. Oncogene. 2002;21:6356-6365.

    Not in our library10.1038/sj.onc.1205792

  142. 142.

    Vossler M.R., Yao H., York R.D., Pan M.-G., Rim C.S., Stork P.J.S. cAMP Activates MAP Kinase and Elk-1 through a B-Raf- and Rap1-Dependent Pathway. Cell. 1997;89:73-82.

    Not in our library10.1016/s0092-8674(00)80184-1

  143. 143.

    Fischer A., Hekman M., Kuhlmann J., Rubio I., Wiese S., Rapp U.R. B- and C-RAF Display Essential Differences in Their Binding to Ras: The isotype-specific n terminus of b-RAF facilitates ras binding. J. Biol. Chem. 2007;282:26503-26516.

    Not in our library10.1074/jbc.m607458200

  144. 144.

    Luo Z., Diaz B., Marshall M.S., Avruch J. An intact Raf zinc finger is required for optimal binding to processed Ras and for ras-dependent Raf activation in situ. Mol. Cell. Biol. 1997;17:46-53.

    Not in our library10.1128/mcb.17.1.46

  145. 145.

    Williams J.G., Drugan J.K., Yi G.S., Clark G.J., Der C.J., Campbell S.L. Elucidation of binding determinants and functional consequences of Ras/Raf-cysteine-rich domain interactions. J. Biol. Chem. 2000;275:22172-22179.

    Not in our library10.1074/jbc.m000397200

  146. 146.

    Winkler D.G., Cutler R.E., Drugan J.K., Campbell S., Morrison D.K., Cooper J.A. Identification of Residues in the Cysteine-rich Domain of Raf-1 That Control Ras Binding and Raf-1 Activity. J. Biol. Chem. 1998;273:21578-21584.

    Not in our library10.1074/jbc.273.34.21578

  147. 147.

    Thapar R., Williams J.G., Campbell S.L. NMR Characterization of Full-length Farnesylated and Non-farnesylated H-Ras and its Implications for Raf Activation. J. Mol. Biol. 2004;343:1391-1408.

    Not in our library10.1016/j.jmb.2004.08.106

  148. 148.

    Ding J., Tchaicheeyan O., Ambrosio L. Drosophila Raf’s N Terminus Contains a Novel Conserved Region and Can Contribute to Torso RTK Signaling. Genetics. 2010;184:717-729.

    Not in our library10.1534/genetics.109.111344

  149. 149.

    Kubicek M., Pacher M., Abraham D., Podar K., Eulitz M., Baccarini M. Dephosphorylation of Ser-259 regulates Raf-1 membrane association. J. Biol. Chem. 2002;277:7913-7919.

    Not in our library10.1074/jbc.m108733200

  150. 150.

    Tran N.H., Wu X., Frost J.A. B-Raf and Raf-1 Are Regulated by Distinct Autoregulatory Mechanisms. J. Biol. Chem. 2005;280:16244-16253.

    Not in our library10.1074/jbc.m501185200

  151. 151.

    Abraham D., Podar K., Pacher M., Kubicek M., Welzel N., Hemmings B.A., Dilworth S.M., Mischak H., Kolch W., Baccarini M. Raf-1-associated protein phosphatase 2A as a positive regulator of kinase activation. J. Biol. Chem. 2000;275:22300-22304.

    Not in our library10.1074/jbc.m003259200

  152. 152.

    Jaumot M., Hancock J.F. Protein phosphatases 1 and 2A promote Raf-1 activation by regulating 14-3-3 interactions. Oncogene. 2001;20:3949-3958.

    Not in our library10.1038/sj.onc.1204526

  153. 153.

    Ory S., Zhou M., Conrads T.P., Veenstra T.D., Morrison D.K. Protein Phosphatase 2A Positively Regulates Ras Signaling by Dephosphorylating KSR1 and Raf-1 on Critical 14-3-3 Binding Sites. Curr. Biol. 2003;13:1356-1364.

    Not in our library10.1016/s0960-9822(03)00535-9

  154. 154.

    Eisenhardt A.E., Sprenger A., Röring M., Herr R., Weinberg F., Köhler M., Braun S., Orth J., Diedrich B., Lanner U., et al. Phospho-proteomic analyses of B-Raf protein complexes reveal new regulatory principles. Oncotarget. 2016;7:26628-26652.

    Not in our library10.18632/oncotarget.8427

  155. 155.

    Luo Z., Tzivion G., Belshaw P.J., Vavvas D., Marshall M., Avruch J. Oligomerization activates c-Raf-1 through a Ras-dependent mechanism. Nature. 1996;383:181-185.

    Not in our library10.1038/383181a0

  156. 156.

    Farrar M.A., Alberola-lla J., Perlmutter R.M. Activation of the Raf-1 kinase cascade by coumermycin-induced dimerization. Nature. 1996;383:178-181.

    Not in our library10.1038/383178a0

  157. 157.

    Weber C.K., Slupsky J.R., Kalmes H.A., Rapp U.R. Active Ras Induces Heterodimerization of cRaf and BRaf 1. Cancer Res. 2001;61:3595-3598.

    Not in our library

  158. 158.

    Rajakulendran T., Sahmi M., Lefrançois M., Sicheri F., Therrien M. A dimerization-dependent mechanism drives RAF catalytic activation. Nature. 2009;461:542-545.

    Not in our library10.1038/nature08314

  159. 159.

    Rushworth L.K., Hindley A.D., O’Neill E., Kolch W. Regulation and role of Raf-1/B-Raf heterodimerization. Mol. Cell. Biol. 2006;26:2262-2272.

    Not in our library10.1128/mcb.26.6.2262-2272.2006

  160. 160.
    Kinase-Dead BRAF and Oncogenic RAS Cooperate to Drive Tumor Progression through CRAF · 2010
    No notice
  161. 161.

    Kwong L.N., Chin L. The Brothers RAF. Cell. 2010;2008-2010.

    Not in our library10.1016/j.cell.2010.01.013

  162. 162.

    Hu J., Yu H., Kornev A.P., Zhao J., Filbert E.L., Taylor S.S., Shaw A.S. Mutation that blocks ATP binding creates a pseudokinase stabilizing the scaffolding function of kinase suppressor of Ras, CRAF and BRAF. Proc. Natl. Acad. Sci. USA. 2011;108:6067-6072.

    Not in our library10.1073/pnas.1102554108

  163. 163.

    Baljuls A., Mahr R., Schwarzenau I., Müller T., Polzien L., Hekman M., Rapp U.R. Single Substitution within the RKTR Motif Impairs Kinase Activity but Promotes Dimerization of RAF Kinase. J. Biol. Chem. 2011;286:16491-16503.

    Not in our library10.1074/jbc.m110.194167

  164. 164.

    Jambrina P.G., Rauch N., Pilkington R., Rybakova K., Nguyen L.K., Kholodenko B.N., Buchete N.-V., Kolch W., Rosta E. Phosphorylation of RAF Kinase Dimers Drives Conformational Changes that Facilitate Transactivation. Angew. Chem. Int. Ed. 2016;55:983-986.

    Not in our library10.1002/anie.201509272

  165. 165.

    Poulikakos P.I., Persaud Y., Janakiraman M., Kong X., Ng C., Moriceau G., Shi H., Atefi M., Titz B., Gabay M.T., et al. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature. 2011;480:387-390.

    Not in our library10.1038/nature10662

  166. 166.

    Dunham I., Kundaje A., Aldred S.F., Collins P.J., Davis C.A., Doyle F., Epstein C.B., Frietze S., Harrow J., Kaul R., et al. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012;489:57-74.

    Not in our library10.1038/nature11247

  167. 167.

    Palanisamy N., Ateeq B., Kalyana-Sundaram S., Pflueger D., Ramnarayanan K., Shankar S., Han B., Cao Q., Cao X., Suleman K., et al. Rearrangements of the RAF kinase pathway in prostate cancer, gastric cancer and melanoma. Nat. Med. 2010;16:793-798.

    Not in our library10.1038/nm.2166

  168. 168.

    Jain P., Fierst T.M., Han H.J., Smith T.E., Vakil A., Storm P.B., Resnick A.C., Waanders A.J. CRAF gene fusions in pediatric low-grade gliomas define a distinct drug response based on dimerization profiles. Oncogene. 2017;36:6348-6358.

    Not in our library10.1038/onc.2017.276

  169. 169.
    The landscape of kinase fusions in cancer · 2014
    No notice
  170. 170.

    Tran N.H., Frost J.A. Phosphorylation of Raf-1 by p21-activated Kinase 1 and Src Regulates Raf-1 Autoinhibition. J. Biol. Chem. 2003;278:11221-11226.

    Not in our library10.1074/jbc.m210318200

  171. 171.

    Williams N.G., Roberts T.M., Li P. Both p21ras and pp60v-src are required, but neither alone is sufficient, to activate the Raf-1 kinase. Proc. Natl. Acad. Sci. USA. 1992;89:2922-2926.

    Not in our library10.1073/pnas.89.7.2922

  172. 172.

    Thompson P.A., Ledbetter J.A., Rapp U.R., Bolen J.B. The Raf-1 serine-threonine kinase is a substrate for the p56lck protein tyrosine kinase in human T-cells. Cell Growth Differ. 1991;2:609-617.

    Not in our library

  173. 173.

    Fabian J.R., Daar I.R.A., Morrison D.K. Critical Tyrosine Residues Regulate the Enzymatic and Biological Activity of Raf-1 Kinase. Mol. Cell. Biol. 1993;13:7170-7179.

    Not in our library10.1128/mcb.13.11.7170

  174. 174.

    Cleghon V., Morrison D.K. Raf-1 Interacts with Fyn and Src in a Non-phosphotyrosine-dependent Manner. J. Biol. Chem. 1994;269:17749-17755.

    Not in our library

  175. 175.

    Marais R., Light Y., Paterson H.F., Marshall C.J. Ras recruits Raf-1 to the plasma membrane for activation by tyrosine phosphorylation. EMBO J. 1995;14:3136-3145.

    Not in our library10.1002/j.1460-2075.1995.tb07316.x

  176. 176.

    Chiloeches A., Mason C.S., Marais R. S338 phosphorylation of Raf-1 is independent of phosphatidylinositol 3-kinase and Pak3. Mol. Cell. Biol. 2001;21:2423-2434.

    Not in our library10.1128/mcb.21.7.2423-2434.2001

  177. 177.

    Chaudhary A., King W.G., Mattaliano M.D., Frost J.A., Diaz B., Morrison D.K., Cobb M.H., Marshall M.S., Brugge J.S. Phosphatidylinositol 3-kinase regulates Raf1 through Pak phosphorylation of serine 338. Curr. Biol. 2000;10:551-554.

    Not in our library10.1016/s0960-9822(00)00475-9

  178. 178.

    King A.J., Sun H., Diaz B., Barnard D., Miao W., Bagrodia S., Marshall M.S. The protein kinase Pak3 positively regulates Raf-1 activity through phosphorylation of serine 338. Nature. 1998;396:180-183.

    Not in our library10.1038/24184

  179. 179.

    Xia K., Mukhopadhyay N.K., Inhorn R.C., Barber D.L., Rose P.E., Lee R.S., Narsimhan R.P., D’Andrea A.D., Griffin J.D., Roberts T.M. The cytokine-activated tyrosine kinase JAK2 activates Raf-1 in a p21ras-dependent manner. Proc. Natl. Acad. Sci. USA. 1996;93:11681-11686.

    Not in our library10.1073/pnas.93.21.11681

  180. 180.

    Ritt D.A., Zhou M., Conrads T.P., Veenstra T.D., Copeland T.D., Morrison D.K. CK2 Is a Component of the KSR1 Scaffold Complex that Contributes to Raf Kinase Activation. Curr. Biol. 2007;17:179-184.

    Not in our library10.1016/j.cub.2006.11.061

  181. 181.

    Salzano M., Rusciano M.R., Russo E., Bifulco M., Postiglione L., Vitale M. Calcium/calmodulin-dependent protein kinase II (CaMKII) phosphorylates Raf-1 at serine 338 and mediates Ras-stimulated Raf-1 activation. Cell Cycle. 2012;11:2100-2106.

    Not in our library10.4161/cc.20543

  182. 182.

    Baljuls A., Schmitz W., Mueller T., Zahedi R.P., Sickmann A., Hekman M., Rapp U.R. Positive Regulation of A-RAF by Phosphorylation of Isoform-specific Hinge Segment and Identification of Novel Phosphorylation Sites. J. Biol. Chem. 2008;283:27239-27254.

    Not in our library10.1074/jbc.m801782200

  183. 183.

    Zhang B.-H., Guan K.-L. Activation of B-Raf kinase requires phosphorylation of the conserved residues Thr598 and Ser601. EMBO J. 2000;19:5429-5439.

    Not in our library10.1093/emboj/19.20.5429

  184. 184.

    Chong H., Lee J., Guan K. Positive and negative regulation of Raf kinase activity and function by phosphorylation. EMBO J. 2001;20:3716-3727.

    Not in our library10.1093/emboj/20.14.3716

  185. 185.

    Köhler M., Röring M., Schorch B., Heilmann K., Stickel N., Fiala G.J., Schmitt L.C., Braun S., Ehrenfeld S., Uhl F.M., et al. Activation loop phosphorylation regulates B-Raf in vivo and transformation by B-Raf mutants. EMBO J. 2016;35:143-161.

    Not in our library10.15252/embj.201592097

  186. 186.

    Köhler M., Brummer T. B-Raf activation loop phosphorylation revisited. Cell Cycle. 2016;15:1171-1173.

    Not in our library10.1080/15384101.2016.1159111

  187. 187.

    Varga A., Baccarini M. Knock-in(g) RAF for a loop. EMBO J. 2016;35:118-120.

    Not in our library10.15252/embj.201593566

  188. 188.

    Grammatikakis N., Lin J., Grammatikakis A., Tsichlis P.N., Cochran B.H. p50 cdc37 Acting in Concert with Hsp90 Is Required for Raf-1 Function. Mol. Cell. Biol. 1999;19:1661-1672.

    Not in our library10.1128/mcb.19.3.1661

  189. 189.

    Da Rocha Dias S., Friedlos F., Light Y., Springer C., Workman P., Marais R. Activated B-RAF is an Hsp90 client protein that is targeted by the anticancer drug 17-allylamino-17-demethoxygeldanamycin. Cancer Res. 2005;65:10686-10691.

    Not in our library10.1158/0008-5472.can-05-2632

  190. 190.

    Dent P., Reardon D.B., Morrison D.K., Sturgill T.W. Regulation of Raf-1 and Raf-1 mutants by Ras-dependent and Ras-independent mechanisms in vitro. Mol. Cell. Biol. 1995;15:4125-4135.

    Not in our library10.1128/mcb.15.8.4125

  191. 191.

    Fantl W.J., Muslin A.J., Kikuchi A., Martin J.A., MacNicol A.M., Grosst R.W., Williams L.T. Activation of Raf-1 by 14-3-3 proteins. Nature. 1994;371:612-614.

    Not in our library10.1038/371612a0

  192. 192.

    Freed E., Symons M., Macdonald S.G., McCormick F., Ruggieri R. Binding of 14-3-3 proteins to the protein kinase Raf and effects on its activation. Science. 1994;265:1713-1716.

    Not in our library10.1126/science.8085158

  193. 193.

    Fu H., Xia K., Pallas D.C., Cui C., Conroy K., Narsimhan R.P., Mamon H., Collier R.J., Roberts T.M. Interaction of the protein kinase Raf-1 with 14-3-3 proteins. Science. 1994;266:126-129.

    Not in our library10.1126/science.7939632

  194. 194.

    Mandal A.K., Lee P., Chen J.A., Nillegoda N., Heller A., DiStasio S., Oen H., Victor J., Nair D.M., Brodsky J.L., et al. Cdc37 has distinct roles in protein kinase quality control that protect nascent chains from degradation and promote posttranslational maturation. J. Cell Biol. 2007;176:319-328.

    Not in our library10.1083/jcb.200604106

  195. 195.

    Diedrich B., Rigbolt K.T., Röring M., Herr R., Kaeser-Pebernard S., Gretzmeier C., Murphy R.F., Brummer T., Dengjel J. Discrete cytosolic macromolecular BRAF complexes exhibit distinct activities and composition. EMBO J. 2017;36:646-663.

    Not in our library10.15252/embj.201694732

  196. 196.

    Hunter T., Poon R.Y.C. Cdc37: A protein kinase chaperone? Trends Cell Biol. 1997;7:157-161.

    Not in our library10.1016/s0962-8924(97)01027-1

  197. 197.

    Grbovic O.M., Basso A.D., Sawai A., Ye Q., Friedlander P., Solit D., Rosen N. V600E B-Raf requires the Hsp90 chaperone for stability and is degraded in response to Hsp90 inhibitors. Proc. Natl. Acad. Sci. USA. 2006;103:57-62.

    Not in our library10.1073/pnas.0609973103

  198. 198.

    Smyth T., Paraiso K.H.T., Hearn K., Rodriguez-Lopez A.M., Munck J.M., Haarberg H.E., Sondak V.K., Thompson N.T., Azab M., Lyons J.F., et al. Inhibition of HSP90 by AT13387 Delays the Emergence of Resistance to BRAF Inhibitors and Overcomes Resistance to Dual BRAF and MEK Inhibition in Melanoma Models. Mol. Cancer Ther. 2014;13:2793-2804.

    Not in our library10.1158/1535-7163.mct-14-0452

  199. 199.

    Paraiso K.H.T., Haarberg H.E., Wood E., Rebecca V.W., Chen Y.A., Xiang Y., Ribas A., Lo R.S., Weber J.S., Sondak V.K., et al. The HSP90 Inhibitor XL888 Overcomes BRAF Inhibitor Resistance Mediated through Diverse Mechanisms. Clin. Cancer Res. 2012;18:2502-2514.

    Not in our library10.1158/1078-0432.ccr-11-2612

  200. 200.

    Sullivan R.J. Forestalling BRAF-Inhibitor Resistance in a Shocking Way. Clin. Cancer Res. 2018;24:5496-5498.

    Not in our library10.1158/1078-0432.ccr-18-1344

  201. 201.

    Kornfeld K., Hom D.B., Horvitz H.R. The ksr-1 gene encodes a novel protein kinase involved in Ras-mediated signaling in C. elegans. Cell. 1995;83:903-913.

    Not in our library10.1016/0092-8674(95)90206-6

  202. 202.

    Boudeau J., Miranda-Saavedra D., Barton G.J., Alessi D.R. Emerging roles of pseudokinases. Trends Cell Biol. 2006;16:443-452.

    Not in our library10.1016/j.tcb.2006.07.003

  203. 203.

    Michaud N.R., Therrien M., Cacace A., Edsall L.C., Spiegel S., Rubin G.M., Morrison D.K. KSR stimulates Raf-1 activity in a kinase-independent manner. Proc. Natl. Acad. Sci. USA. 1997;94:12792-12796.

    Not in our library10.1073/pnas.94.24.12792

  204. 204.

    Douziech M., Sahmi M., Laberge G., Therrien M. A KSR/CNK complex mediated by HYP, a novel SAM domain-containing protein, regulates RAS-dependent RAF activation in Drosophila. Genes Dev. 2006;20:807-819.

    Not in our library10.1101/gad.1390406

  205. 205.

    Sundaram M., Han M., The C. elegans ksr-1 gene encodes a novel raf-related kinase involved in Ras-mediated signal transduction. Cell. 1995;83:889-901.

    Not in our library10.1016/0092-8674(95)90205-8

  206. 206.

    Therrien M., Chang H.C., Solomon N.M., Karim F.D., Wassarman D.A., Rubin G.M. KSR, a novel protein kinase required for RAS signal transduction. Cell. 1995;83:879-888.

    Not in our library10.1016/0092-8674(95)90204-x

  207. 207.

    Lavoie H., Sahmi M., Maisonneuve P., Marullo S.A., Thevakumaran N., Jin T., Kurinov I., Sicheri F., Therrien M. MEK drives BRAF activation through allosteric control of KSR proteins. Nature. 2018;554:549-553.

    Not in our library10.1038/nature25478

  208. 208.

    Brennan D.F., Dar A.C., Hertz N.T., Chao W.C.H., Burlingame A.L., Shokat K.M., Barford D. A Raf-induced allosteric transition of KSR stimulates phosphorylation of MEK. Nature. 2011;472:366-369.

    Not in our library10.1038/nature09860

  209. 209.
    The dynamic and stress-adaptive signaling hub of 14-3-3: emerging mechanisms of regulation and context-dependent protein–protein interactions · 2018
    No notice
  210. 210.

    Yaffe M.B. How do 14-3-3 proteins work?—Gatekeeper phosphorylation and the molecular anvil hypothesis. FEBS Lett. 2002;513:53-57.

    Not in our library10.1016/s0014-5793(01)03288-4

  211. 211.

    Freeman A.K., Morrison D.K. 14-3-3 Proteins: Diverse functions in cell proliferation and cancer progression. Semin. Cell Dev. Biol. 2011;22:681-687.

    Not in our library10.1016/j.semcdb.2011.08.009

  212. 212.

    Mischak H., Seitz T., Janosch P., Eulitz M., Steen H., Schellerer M., Philipp A., Kolch W. Negative regulation of Raf-1 by phosphorylation of serine 621. Mol. Cell. Biol. 1996;16:5409-5418.

    Not in our library10.1128/mcb.16.10.5409

  213. 213.

    Park E., Rawson S., Li K., Kim B.-W., Ficarro S.B., Pino G.G.-D., Sharif H., Marto J.A., Jeon H., Eck M.J. Architecture of autoinhibited and active BRAF–MEK1–14-3-3 complexes. Nature. 2019;575:545-550.

    Not in our library10.1038/s41586-019-1660-y

  214. 214.

    Cook S.J., McCormick F. Inhibition by cAMP of Ras-dependent activation of Raf. Science. 1993;262:1069-1072.

    Not in our library10.1126/science.7694367

  215. 215.

    Dhillon A.S., Pollock C., Steen H., Shaw P.E., Mischak H., Kolch W. Cyclic AMP-dependent kinase regulates Raf-1 kinase mainly by phosphorylation of serine 259. Mol. Cell. Biol. 2002;22:3237-3246.

    Not in our library10.1128/mcb.22.10.3237-3246.2002

  216. 216.

    Wu J., Dent P., Jelinek T., Wolfman A., Weber M.J., Sturgill T.W. Inhibition of the EGF-activated MAP kinase signaling pathway by adenosine 3’,5’-monophosphate. Science. 1993;262:1065-1069.

    Not in our library10.1126/science.7694366

  217. 217.

    Zimmermann S., Moelling K. Phosphorylation and Regulation of Raf by Akt (Protein Kinase B). Science. 1999;286:1741-1744.

    Not in our library10.1126/science.286.5445.1741

  218. 218.

    Rommel C., Clarke B.A., Zimmermann S., Nuñez L., Rossman R., Reid K., Moelling K., Yancopoulos G.D., Glass D.J. Differentiation Stage-Specific Inhibition of the Raf-MEK-ERK Pathway by Akt. Science. 1999;286:1738-1741.

    Not in our library10.1126/science.286.5445.1738

  219. 219.

    Yuan J., Ng W.H., Yap J., Chia B., Huang X., Wang M., Hu J. The AMPK inhibitor overcomes the paradoxical effect of RAF inhibitors through blocking phospho–Ser-621 in the C terminus of CRAF. J. Biol. Chem. 2018;293:14276-14284.

    Not in our library10.1074/jbc.ra118.004597

  220. 220.

    Sprenkle A.B., Davies S.P., Carling D., Hardie D.G., Sturgill T.W. Identification of Raf-1 Ser621 kinase activity from NIH 3T3 cells as AMP-activated protein kinase. FEBS Lett. 1997;403:254-258.

    Not in our library10.1016/s0014-5793(97)00062-8

  221. 221.

    Romano D., Nguyen L.K., Matallanas D., Halasz M., Doherty C., Kholodenko B.N., Kolch W. Protein interaction switches coordinate Raf-1 and MST2/Hippo signalling. Nat. Cell Biol. 2014;16:673-684.

    Not in our library10.1038/ncb2986

  222. 222.

    Yuan J., Ng W.H., Tian Z., Yap J., Baccarini M., Chen Z., Hu J. Activating mutations in MEK1 enhance homodimerization and promote tumorigenesis. Sci. Signal. 2018;11:eaar6795.

    Not in our library10.1126/scisignal.aar6795

  223. 223.

    Röring M., Herr R., Fiala G.J., Heilmann K., Braun S., Eisenhardt A.E., Halbach S., Capper D., von Deimling A., Schamel W.W., et al. Distinct requirement for an intact dimer interface in wild-type, V600E and kinase-dead B-Raf signalling. EMBO J. 2012;31:2629-2647.

    Not in our library10.1038/emboj.2012.100

  224. 224.

    Dent P., Haser W., Haystead T.A., Vincent L.A., Roberts T.M., Sturgill T.W. Activation of mitogen-activated protein kinase kinase by v-Raf in NIH 3T3 cells and in vitro. Science. 1992;257:1404-1407.

    Not in our library10.1126/science.1326789

  225. 225.

    Haystead C.M.M., Wu J., Gregory P., Sturgill T.W., Haystead T.A.J. Functional expression of a MAP kinase kinase in COS cells and recognition by an anti-STE7/byrl antibody. FEBS Lett. 1993;317:12-16.

    Not in our library10.1016/0014-5793(93)81481-e

  226. 226.

    Papin C., Denouel A., Calothy G., Eychène A. Identification of signalling proteins interacting with B-Raf in the yeast two-hybrid system. Oncogene. 1996;12:2213-2221.

    Not in our library

  227. 227.

    Papin C., Eychne A., Brunet A., Pages G., Pouyssegur J., Calothy G., Barnier J.V. B-Raf protein isoforms interact with and phosphorylate Mek-1 on serine. Oncogene. 1995;10:1647-1651.

    Not in our library

  228. 228.

    Corbalan-Garcia S., Yang S.S., Degenhardt K.R., Bar-Sagi D. Identification of the mitogen-activated protein kinase phosphorylation sites on human Sos1 that regulate interaction with Grb2. Mol. Cell. Biol. 1996;16:5674-5682.

    Not in our library10.1128/mcb.16.10.5674

  229. 229.

    Saha M., Carriere A., Cheerathodi M., Zhang X., Lavoie G., Rush J., Roux P.P., Ballif B.A. RSK phosphorylates SOS1 creating 14-3-3-docking sites and negatively regulating MAPK activation. Biochem. J. 2012;447:159-166.

    Not in our library10.1042/bj20120938

  230. 230.

    Brummer T., Naegele H., Reth M., Misawa Y. Identification of novel ERK-mediated feedback phosphorylation sites at the C-terminus of B-Raf. Oncogene. 2003;22:8823-8834.

    Not in our library10.1038/sj.onc.1207185

  231. 231.

    Dougherty M.K., Müller J., Ritt D.A., Zhou M., Zhou X.Z., Copeland T.D., Conrads T.P., Veenstra T.D., Lu K.P., Morrison D.K. Regulation of Raf-1 by Direct Feedback Phosphorylation. Mol. Cell. 2005;17:215-224.

    Not in our library10.1016/j.molcel.2004.11.055

  232. 232.

    Ritt D.A., Monson D.M., Specht S.I., Morrison D.K. Impact of Feedback Phosphorylation and Raf Heterodimerization on Normal and Mutant B-Raf Signaling. Mol. Cell. Biol. 2010;30:806-819.

    Not in our library10.1128/mcb.00569-09

  233. 233.

    Ritt D.A., Abreu-Blanco M.T., Bindu L., Durrant D.E., Zhou M., Specht S.I., Stephen A.G., Holderfield M., Morrison D.K., Abreu-blanco T., et al. Inhibition of Ras/Raf/MEK/ERK Pathway Signaling by a Stress-Induced Phospho-Regulatory Circuit. Mol. Cell. 2016;64:875-887.

    Not in our library10.1016/j.molcel.2016.10.029

  234. 234.

    Holderfield M., Merritt H., Chan J., Wallroth M., Tandeske L., Zhai H., Tellew J., Hardy S., Hekmat-Nejad M., Stuart D.D., et al. RAF Inhibitors Activate the MAPK Pathway by Relieving Inhibitory Autophosphorylation. Cancer Cell. 2013;23:594-602.

    Not in our library10.1016/j.ccr.2013.03.033

  235. 235.

    Tassin T.C., Benavides D.R., Plattner F., Nishi A., Bibb J.A. Regulation of ERK kinase by MEK1 kinase inhibition in the brain. J. Biol. Chem. 2015;290:16319-16329.

    Not in our library10.1074/jbc.m115.654897

  236. 236.

    Von Kriegsheim A., Pitt A., Grindlay G.J., Kolch W., Dhillon A.S. Regulation of the Raf-MEK-ERK pathway by protein phosphatase 5. Nat. Cell Biol. 2006;8:1011-1016.

    Not in our library10.1038/ncb1465

  237. 237.
    DUSPs, to MAP kinases and beyond · 2012
    No notice
  238. 238.

    Zhang Z., Kobayashi S., Borczuk A.C., Leidner R.S., LaFramboise T., Levine A.D., Halmos B. Dual specificity phosphatase 6 (DUSP6) is an ETS-regulated negative feedback mediator of oncogenic ERK signaling in lung cancer cells. Carcinogenesis. 2010;31:577-586.

    Not in our library10.1093/carcin/bgq020

  239. 239.

    Ekerot M., Stavridis M.P., Delavaine L., Mitchell M.P., Staples C., Owens D.M., Keenan I.D., Dickinson R.J., Storey K.G., Keyse S.M. Negative-feedback regulation of FGF signalling by DUSP6/MKP-3 is driven by ERK1/2 and mediated by Ets factor binding to a conserved site within the DUSP6/MKP-3 gene promoter. Biochem. J. 2008;412:287-298.

    Not in our library10.1042/bj20071512

  240. 240.

    Hacohen N., Kramer S., Sutherland D., Hiromi Y., Krasnow M.A. sprouty Encodes a Novel Antagonist of FGF Signaling that Patterns Apical Branching of the Drosophila Airways. Cell. 1998;92:253-263.

    Not in our library10.1016/s0092-8674(00)80919-8

  241. 241.

    Yusoff P., Lao D.-H., Ong S.H., Wong E.S.M., Lim J., Lo T.L., Leong H.F., Fong C.W., Guy G.R. Sprouty2 Inhibits the Ras/MAP Kinase Pathway by Inhibiting the Activation of Raf. J. Biol. Chem. 2002;277:3195-3201.

    Not in our library10.1074/jbc.m108368200

  242. 242.

    Sasaki A., Taketomi T., Kato R., Saeki K., Nonami A., Sasaki M., Kuriyama M., Saito N., Shibuya M., Yoshimura A. Mammalian Sprouty4 suppresses Ras-independent ERK activation by binding to Raf1. Nat. Cell Biol. 2003;5:427-432.

    Not in our library10.1038/ncb978

  243. 243.

    Simanshu D.K., Nissley D.V., McCormick F. RAS Proteins and Their Regulators in Human Disease. Cell. 2017;170:1-8.

    Not in our library10.1016/j.cell.2017.06.009

  244. 244.

    Haigis K.M., Kendall K.R., Wang Y., Cheung A., Haigis M.C., Glickman J.N., Niwa-Kawakita M., Sweet-Cordero A., Sebolt-Leopold J., Shannon K.M., et al. Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon. Nat. Genet. 2008;40:600-608.

    Not in our library10.1038/ng.115

  245. 245.

    Drosten M., Simón-Carrasco L., Hernández-Porras I., Lechuga C.G., Blasco M.T., Jacob H.K.C., Fabbiano S., Potenza N., Bustelo X.R., Guerra C., et al. H-Ras and K-Ras Oncoproteins Induce Different Tumor Spectra When Driven by the Same Regulatory Sequences. Cancer Res. 2017;77:707-718.

    Not in our library10.1158/0008-5472.can-16-2925

  246. 246.

    Scheffzek K., Ahmadian M.R., Kabsch W., Wiesmüller L., Lautwein A., Schmitz F., Wittinghofer A. The Ras-RasGAP complex: Structural basis for GTPase activation and its loss in oncogenic ras mutants. Science. 1997;277:333-338.

    Not in our library10.1126/science.277.5324.333

  247. 247.

    Rabara D., Tran T.H., Dharmaiah S., Stephens R.M., McCormick F., Simanshu D.K., Holderfield M. KRAS G13D sensitivity to neurofibromin-mediated GTP hydrolysis. Proc. Natl. Acad. Sci. USA. 2019;116:22122-22131.

    Not in our library10.1073/pnas.1908353116

  248. 248.

    Gremer L., Gilsbach B., Reza Ahmadian M., Wittinghofer A. Fluoride complexes of oncogenic Ras mutants to study the Ras-RasGAP interaction. Biol. Chem. 2008;389:1163.

    Not in our library10.1515/bc.2008.132

  249. 249.

    Fukushima T., Suzuki S., Mashiko M., Ohtake T., Endo Y., Takebayashi Y., Sekikawa K., Hagiwara K., Takenoshita S. BRAF mutations in papillary carcinomas of the thyroid. Oncogene. 2003;22:6455-6457.

    Not in our library10.1038/sj.onc.1206739

  250. 250.

    Forbes S.A., Bindal N., Bamford S., Cole C., Kok C.Y., Beare D., Jia M., Shepherd R., Leung K., Menzies A., et al. COSMIC: Mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer. Nucl. Acids Res. 2010;39:D945-D950.

    Not in our library10.1093/nar/gkq929

  251. 251.

    Flaherty K.T., McArthur G. BRAF, a target in melanoma. Cancer. 2010;116:4902-4913.

    Not in our library10.1002/cncr.25261

  252. 252.

    Wan P.T., Garnett M.J., Roe S.M., Lee S., Niculescu-Duvaz D., Good V.M., Project C.G., Jones C.M., Marshall C.J., Springer C.J., et al. Mechanism of Activation of the RAF-ERK Signaling Pathway by Oncogenic Mutations of B-RAF. Cell. 2004;116:855-867.

    Not in our library10.1016/s0092-8674(04)00215-6

  253. 253.

    Lavoie H., Therrien M. Regulation of RAF protein kinases in ERK signalling. Nat. Rev. Mol. Cell Biol. 2015;16:281-298.

    Not in our library10.1038/nrm3979

  254. 254.

    Ikenoue T., Hikiba Y., Kanai F., Tanaka Y., Imamura J., Imamura T., Ohta M., Ijichi H., Tateishi K., Kawakami T., et al. Functional Analysis of Mutations within the Kinase Activation Segment of B-Raf in Human Colorectal Tumors. Cancer Res. 2003;63:8132-8137.

    Not in our library

  255. 255.

    Andreadi C., Cheung L.-K., Giblett S., Patel B., Jin H., Mercer K., Kamata T., Lee P., Williams A., McMahon M., et al. The intermediate-activity (L597V)BRAF mutant acts as an epistatic modifier of oncogenic RAS by enhancing signaling through the RAF/MEK/ERK pathway. Genes Dev. 2012;26:1945-1958.

    Not in our library10.1101/gad.193458.112

  256. 256.

    Dahlman K.B., Xia J., Hutchinson K., Ng C., Hucks D., Jia P., Atefi M., Su Z., Branch S., Lyle P.L., et al. BRAF L597 Mutations in Melanoma Are Associated with Sensitivity to MEK Inhibitors. Cancer Discov. 2012;2:791-797.

    Not in our library10.1158/2159-8290.cd-12-0097

  257. 257.

    Houben R., Becker J., Kappel A., Terheyden P., Brocker E.-B., Goetz R., Rapp U. Constitutive activation of the Ras-Raf signaling pathway in metastatic melanoma is associated with poor prognosis. J. Carcinog. 2004;3:6.

    Not in our library10.1186/1477-3163-3-6

  258. 258.

    Ikenoue T., Hikiba Y., Kanai F., Aragaki J., Tanaka Y., Imamura J., Imamura T., Ohta M., Ijichi H., Tateishi K., et al. Different Effects of Point Mutations within the B-Raf Glycine-Rich Loop in Colorectal Tumors on Mitogen-Activated Protein/Extracellular Signal-Regulated Kinase Kinase/Extracellular Signal-Regulated Kinase and Nuclear Factor κB Pathway and Cellular Transfo. Cancer Res. 2004;64:3428-3435.

    Not in our library10.1158/0008-5472.can-03-3591

  259. 259.

    Noeparast A., Teugels E., Giron P., Verschelden G., Brakeleer S. De, Decoster L., Grève J. De Non-V600 BRAF mutations recurrently found in lung cancer predict sensitivity to the combination of Trametinib and Dabrafenib. Oncotarget. 2016;8:60094-60108.

    Not in our library10.18632/oncotarget.11635

  260. 260.

    Swofford B.P., Homsi J. Uncommon BRAF Mutations Associated with Durable Response to Immunotherapy in Patients with Metastatic Melanoma. Case Rep. Oncol. Med. 2017;2017:8241624.

    Not in our library10.1155/2017/8241624

  261. 261.

    Smalley K.S.M., Xiao M., Villanueva J., Nguyen T.K., Flaherty K.T., Letrero R., Van Belle P., Elder D.E., Wang Y., Nathanson K.L., et al. CRAF inhibition induces apoptosis in melanoma cells with non-V600E BRAF mutations. Oncogene. 2009;28:85-94.

    Not in our library10.1038/onc.2008.362

  262. 262.

    Yao Z., Torres N.M., Tao A., Gao Y., Luo L., Li Q., de Stanchina E., Abdel-Wahab O., Solit D.B., Poulikakos P.I., et al. BRAF Mutants Evade ERK-Dependent Feedback by Different Mechanisms that Determine Their Sensitivity to Pharmacologic Inhibition. Cancer Cell. 2015;28:370-383.

    Not in our library10.1016/j.ccell.2015.08.001

  263. 263.

    Jones D.T.W., Kocialkowski S., Liu L., Pearson D.M., Bäcklund L.M., Ichimura K., Collins V.P. Tandem Duplication Producing a Novel Oncogenic BRAF Fusion Gene Defines the Majority of Pilocytic Astrocytomas. Cancer Res. 2008;68:8673-8677.

    Not in our library10.1158/0008-5472.can-08-2097

  264. 264.

    Cin H., Meyer C., Herr R., Janzarik W.G., Lambert S., Jones D.T.W., Jacob K., Benner A., Witt H., Remke M., et al. Oncogenic FAM131B–BRAF fusion resulting from 7q34 deletion comprises an alternative mechanism of MAPK pathway activation in pilocytic astrocytoma. Acta Neuropathol. 2011;121:763-774.

    Not in our library10.1007/s00401-011-0817-z

  265. 265.

    Ciampi R., Knauf J.A., Kerler R., Gandhi M., Zhu Z., Nikiforova M.N., Rabes H.M., Fagin J.A., Nikiforov Y.E. Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer. J. Clin. Investig. 2005;115:94-101.

    Not in our library10.1172/jci23237

  266. 266.

    Zehir A., Benayed R., Shah R.H., Syed A., Middha S., Kim H.R., Srinivasan P., Gao J., Chakravarty D., Devlin S.M., et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat. Med. 2017;23:703.

    Not in our library10.1038/nm.4333

  267. 267.

    Sarkozy A., Carta C., Moretti S., Zampino G., Digilio M.C., Pantaleoni F., Scioletti A.P., Esposito G., Cordeddu V., Lepri F., et al. Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: Molecular diversity and associated phenotypic spectrum. Hum. Mutat. 2009;30:695-702.

    Not in our library10.1002/humu.20955

  268. 268.

    Travers T., López C.A., Van Q.N., Neale C., Tonelli M., Stephen A.G., Gnanakaran S. Molecular recognition of RAS/RAF complex at the membrane: Role of RAF cysteine-rich domain. Sci. Rep. 2018;8:8461.

    Not in our library10.1038/s41598-018-26832-4

  269. 269.

    Fetics S.K., Guterres H., Kearney B.M., Buhrman G., Ma B., Nussinov R., Mattos C. Allosteric effects of the oncogenic rasq61l mutant on raf-RBD. Structure. 2015;23:505-516.

    Not in our library10.1016/j.str.2014.12.017

  270. 270.

    Leicht D.T., Balan V., Kaplun A., Singh-Gupta V., Kaplun L., Dobson M., Tzivion G. Raf kinases: Function, regulation and role in human cancer. Biochim. Biophys. Acta Mol. Cell Res. 2007;1773:1196-1212.

    Not in our library10.1016/j.bbamcr.2007.05.001

  271. 271.

    Molzan M., Schumacher B., Ottmann C., Baljuls A., Polzien L., Weyand M., Thiel P., Rose R., Rose M., Kuhenne P., et al. Impaired Binding of 14-3-3 to C-RAF in Noonan Syndrome Suggests New Approaches in Diseases with Increased Ras Signaling. Mol. Cell. Biol. 2010;30:4698-4711.

    Not in our library10.1128/mcb.01636-09

  272. 272.

    Brown N.A., Furtado L.V., Betz B.L., Kiel M.J., Weigelin H.C., Lim M.S., Elenitoba-Johnson K.S.J. High prevalence of somatic MAK1 mutations in BRAF V600E–negative Langerhans cell histiocytosis. Blood. 2014;124:1655-1658.

    Not in our library10.1182/blood-2014-05-577361

  273. 273.

    Brenan L., Andreev A., Cohen O., Pantel S., Kamburov A., Cacchiarelli D., Persky N.S., Zhu C., Bagul M., Goetz E.M., et al. Phenotypic Characterization of a Comprehensive Set of MAPK1/ERK2 Missense Mutants. Cell Rep. 2016;17:1171-1183.

    Not in our library10.1016/j.celrep.2016.09.061

  274. 274.

    Cox A.D., Fesik S.W., Kimmelman A.C., Luo J., Der C.J. Drugging the undruggable RAS: Mission Possible? Nat. Rev. Drug Discov. 2014;13:828-851.

    Not in our library10.1038/nrd4389

  275. 275.

    Ostrem J.M., Peters U., Sos M.L., Wells J.A., Shokat K.M. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature. 2013;503:548.

    Not in our library10.1038/nature12796

  276. 276.

    Fakih M., O’Neil B., Price T.J., Falchook G.S., Desai J., Kuo J., Govindan R., Rasmussen E., Morrow P.K.H., Ngang J., et al. Phase 1 study evaluating the safety, tolerability, pharmacokinetics (PK), and efficacy of AMG 510, a novel small molecule KRASG12C inhibitor, in advanced solid tumors. J. Clin. Oncol. 2019;37:3003.

    Not in our library10.1200/jco.2019.37.15_suppl.3003

  277. 277.

    Christensen J.G., Fell J.B., Marx M.A., Fischer J., Hallin J., Calinisan A., Baer B., Burkhard M., Blake J., Vigers G., et al. Abstract LB-271: Insight towards therapeutic susceptibility of KRAS mutant cancers from MRTX1257, a novel KRAS G12C mutant selective small molecule inhibitor. Cancer Res. 2019;79.

    Not in our library10.1158/1538-7445.am2019-lb-271

  278. 278.
    KRAS Mutant Pancreatic Cancer: No Lone Path to an Effective Treatment · 2016
    No notice
  279. 279.

    Gibbs J.B., Oliff A., Kohl N.E. Farnesyltransferase inhibitors: Ras research yields a potential cancer therapeutic. Cell. 1994;77:175-178.

    Not in our library10.1016/0092-8674(94)90308-5

  280. 280.

    Furfine E.S., Leban J.J., Landavazo A., Moomaw J.F., Casey P.J. Protein farnesyltransferase: Kinetics of farnesyl pyrophosphate binding and product release. Biochemistry. 1995;34:6857-6862.

    Not in our library10.1021/bi00020a032

  281. 281.

    Long S.B., Casey P.J., Beese L.S. Cocrystal Structure of Protein Farnesyltransferase Complexed with a Farnesyl Diphosphate Substrate. Biochemistry. 1998;37:9612-9618.

    Not in our library10.1021/bi980708e

  282. 282.

    Long S.B., Casey P.J., Beese L.S. Reaction path of protein farnesyltransferase at atomic resolution. Nature. 2002;419:645-650.

    Not in our library10.1038/nature00986

  283. 283.

    Mijimolle N., Velasco J., Dubus P., Guerra C., Weinbaum C.A., Casey P.J., Campuzano V., Barbacid M. Protein farnesyltransferase in embryogenesis, adult homeostasis, and tumor development. Cancer Cell. 2005;7:313-324.

    Not in our library10.1016/j.ccr.2005.03.004

  284. 284.

    Whyte D.B., Kirschmeier P., Hockenberry T.N., Nunez-Oliva I., James L., Catino J.J., Bishop W.R., Pai J.-K. K- and N-Ras Are Geranylgeranylated in Cells Treated with Farnesyl Protein Transferase Inhibitors. J. Biol. Chem. 1997;272:14459-14464.

    Not in our library10.1074/jbc.272.22.14459

  285. 285.

    Fiordalisi J.J., Johnson R.L., Weinbaum C.A., Sakabe K., Chen Z., Casey P.J., Cox A.D. High affinity for farnesyltransferase and alternative prenylation contribute individually to K-Ras4B resistance to farnesyltransferase inhibitors. J. Biol. Chem. 2003;278:41718-41727.

    Not in our library10.1074/jbc.m305733200

  286. 286.

    Berndt N., Hamilton A.D., Sebti S.M. Targeting protein prenylation for cancer therapy. Nat. Rev. Cancer. 2011;11:775-791.

    Not in our library10.1038/nrc3151

  287. 287.

    Peterson Y.K., Kelly P., Weinbaum C.A., Casey P.J. A Novel Protein Geranylgeranyltransferase-I Inhibitor with High Potency, Selectivity, and Cellular Activity. J. Biol. Chem. 2006;281:12445-12450.

    Not in our library10.1074/jbc.m600168200

  288. 288.

    Sjogren A.-K.M., Andersson K.M.E., Liu M., Cutts B.A., Karlsson C., Wahlstrom A.M., Dalin M., Weinbaum C., Casey P.J., Tarkowski A., et al. GGTase-I deficiency reduces tumor formation and improves survival in mice with K-RAS–induced lung cancer. J. Clin. Investig. 2007;117:1294-1304.

    Not in our library10.1172/jci30868

  289. 289.

    Lobell R.B., Liu D., Buser C.A., Davide J.P., DePuy E., Hamilton K., Koblan K.S., Lee Y., Mosser S., Motzel S.L., et al. Preclinical and Clinical Pharmacodynamic Assessment of L-778,123, a Dual Inhibitor of Farnesyl:Protein Transferase and Geranylgeranyl: Protein Transferase Type-I. Mol. Cancer Ther. 2002;1:747-758.

    Not in our library

  290. 290.

    Wahlstrom A.M., Cutts B.A., Liu M., Lindskog A., Karlsson C., Sjogren A.-K.M., Andersson K.M.E., Young S.G., Bergo M.O. Inactivating Icmt ameliorates K-RAS–induced myeloproliferative disease. Blood. 2008;112:1357-1365.

    Not in our library10.1182/blood-2007-06-094060

  291. 291.

    Bergman J.A., Hahne K., Song J., Hrycyna C.A., Gibbs R.A. S-Farnesyl-Thiopropionic Acid Triazoles as Potent Inhibitors of Isoprenylcysteine Carboxyl Methyltransferase. ACS Med. Chem. Lett. 2012;3:15-19.

    Not in our library10.1021/ml200106d

  292. 292.

    Lau H.Y., Ramanujulu P.M., Guo D., Yang T., Wirawan M., Casey P.J., Go M.-L., Wang M. An improved isoprenylcysteine carboxylmethyltransferase inhibitor induces cancer cell death and attenuates tumor growth in vivo. Cancer Biol. Ther. 2014;15:1280-1291.

    Not in our library10.4161/cbt.29692

  293. 293.

    Wang M., Hossain M.S., Tan W., Coolman B., Zhou J., Liu S., Casey P.J. Inhibition of isoprenylcysteine carboxylmethyltransferase induces autophagic-dependent apoptosis and impairs tumor growth. Oncogene. 2010;29:4959-4970.

    Not in our library10.1038/onc.2010.247

  294. 294.

    Athuluri-Divakar S.K., Vasquez-Del Carpio R., Dutta K., Baker S.J., Cosenza S.C., Basu I., Gupta Y.K., Reddy M.V.R., Ueno L., Hart J.R., et al. A Small Molecule RAS-Mimetic Disrupts RAS Association with Effector Proteins to Block Signaling. Cell. 2016;165:643-655.

    Not in our library10.1016/j.cell.2016.03.045

  295. 295.

    Keeton A.B., Salter E.A., Piazza G.A. The RAS–Effector Interaction as a Drug Target. Cancer Res. 2017;77:221-226.

    Not in our library10.1158/0008-5472.can-16-0938

  296. 296.

    Kato-Stankiewicz J., Hakimi I., Zhi G., Zhang J., Serebriiskii I., Guo L., Edamatsu H., Koide H., Menon S., Eckl R., et al. Inhibitors of Ras/Raf-1 interaction identified by two-hybrid screening revert Ras-dependent transformation phenotypes in human cancer cells. Proc. Natl. Acad. Sci. USA. 2002;99:14398-14403.

    Not in our library10.1073/pnas.222222699

  297. 297.

    Wang W., Fang G., Rudolph J. Ras inhibition via direct Ras binding—Is there a path forward? Bioorg. Med. Chem. Lett. 2012;22:5766-5776.

    Not in our library10.1016/j.bmcl.2012.07.082

  298. 298.

    Bryant K.L., Stalnecker C.A., Zeitouni D., Klomp J.E., Peng S., Tikunov A.P., Gunda V., Pierobon M., Waters A.M., George S.D., et al. Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer. Nat. Med. 2019;25:628-640.

    Not in our library10.1038/s41591-019-0368-8

  299. 299.

    Kinsey C.G., Camolotto S.A., Boespflug A.M., Guillen K.P., Foth M., Truong A., Schuman S.S., Shea J.E., Seipp M.T., Yap J.T., et al. Protective autophagy elicited by RAF→MEK→ERK inhibition suggests a treatment strategy for RAS-driven cancers. Nat. Med. 2019;25:620-627.

    Not in our library10.1038/s41591-019-0367-9

  300. 300.

    Wang M., Tan W., Zhou J., Leow J., Go M., Lee H.S., Casey P.J. A Small Molecule Inhibitor of Isoprenylcysteine Carboxymethyltransferase Induces Autophagic Cell Death in PC3 Prostate Cancer Cells. J. Biol. Chem. 2008;283:18678-18684.

    Not in our library10.1074/jbc.m801855200

  301. 301.

    Teh J.T., Zhu W.L., Ilkayeva O.R., Li Y., Gooding J., Casey P.J., Summers S.A., Newgard C.B., Wang M. Isoprenylcysteine carboxylmethyltransferase regulates mitochondrial respiration and cancer cell metabolism. Oncogene. 2015;34:3296-3304.

    Not in our library10.1038/onc.2014.260

  302. 302.

    Manu K.A., Chai T.F., Teh J.T., Zhu W.L., Casey P.J., Wang M. Inhibition of Isoprenylcysteine Carboxylmethyltransferase Induces Cell-Cycle Arrest and Apoptosis through p21 and p21-Regulated BNIP3 Induction in Pancreatic Cancer. Mol. Cancer Ther. 2017;16:914-923.

    Not in our library10.1158/1535-7163.mct-16-0703

  303. 303.

    Thompson N., Adams D.J., Ranzani M. Synthetic lethality: Emerging targets and opportunities in melanoma. Pigment Cell Melanoma Res. 2017;30:183-193.

    Not in our library10.1111/pcmr.12573

  304. 304.

    Shen J.P., Zhao D., Sasik R., Luebeck J., Birmingham A., Bojorquez-Gomez A., Licon K., Klepper K., Pekin D., Beckett A.N., et al. Combinatorial CRISPR-Cas9 screens for de novo mapping of genetic interactions. Nat. Methods. 2017;14:573-576.

    Not in our library10.1038/nmeth.4225

  305. 305.

    Flaherty K., Puzanov I., Sosman J., Kim K., Ribas A., McArthur G., Lee R.J., Grippo J.F., Nolop K., Chapman P. Phase I study of PLX4032: Proof of concept for V600E BRAF mutation as a therapeutic target in human cancer. J. Clin. Oncol. 2009;27:9000.

    Not in our library10.1200/jco.2009.27.15_suppl.9000

  306. 306.

    Tsai J., Lee J.T., Wang W., Zhang J., Cho H., Mamo S., Bremer R., Gillette S., Kong J., Haass N.K., et al. Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proc. Natl. Acad. Sci. USA. 2008;105:3041-3046.

    Not in our library10.1073/pnas.0711741105

  307. 307.

    Hauschild A., Grob J.-J., Demidov L.V., Jouary T., Gutzmer R., Millward M., Rutkowski P., Blank C.U., Miller W.H., Kaempgen E., et al. Dabrafenib in BRAF mutated metastatic melanoma: A multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380:358-365.

    Not in our library10.1016/s0140-6736(12)60868-x

  308. 308.

    Li Z., Jiang K., Zhu X., Lin G., Song F., Zhao Y., Piao Y., Liu J., Cheng W., Bi X., et al. Encorafenib (LGX818), a potent BRAF inhibitor, induces senescence accompanied by autophagy in BRAFV600E melanoma cells. Cancer Lett. 2016;370:332-344.

    Not in our library10.1016/j.canlet.2015.11.015

  309. 309.

    Wang L., Leite de Oliveira R., Huijberts S., Bosdriesz E., Pencheva N., Brunen D., Bosma A., Song J.Y., Zevenhoven J., Los-de Vries G.T., et al. An Acquired Vulnerability of Drug-Resistant Melanoma with Therapeutic Potential. Cell. 2018;173:1413-1425.e14.

    Not in our library10.1016/j.cell.2018.04.012

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    Seghers A.C., Wilgenhof S., Lebbé C., Neyns B. Successful rechallenge in two patients with BRAF-V600-mutant melanoma who experienced previous progression during treatment with a selective BRAF inhibitor. Melanoma Res. 2012;22:466-472.

    Not in our library10.1097/cmr.0b013e3283541541

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    Peng S.-B., Henry J.R., Kaufman M.D., Lu W.-P., Smith B.D., Vogeti S., Rutkoski T.J., Wise S., Chun L., Zhang Y., et al. Inhibition of RAF Isoforms and Active Dimers by LY3009120 Leads to Anti-tumor Activities in RAS or BRAF Mutant Cancers. Cancer Cell. 2015;28:384-398.

    Not in our library10.1016/j.ccell.2015.08.002

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    Okaniwa M., Hirose M., Arita T., Yabuki M., Nakamura A., Takagi T., Kawamoto T., Uchiyama N., Sumita A., Tsutsumi S., et al. Discovery of a Selective Kinase Inhibitor (TAK-632) Targeting Pan-RAF Inhibition: Design, Synthesis, and Biological Evaluation of C-7-Substituted 1,3-Benzothiazole Derivatives. J. Med. Chem. 2013;56:6478-6494.

    Not in our library10.1021/jm400778d

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    Sun Y., Alberta J.A., Pilarz C., Calligaris D., Chadwick E.J., Ramkissoon S.H., Ramkissoon L.A., Garcia V.M., Mazzola E., Goumnerova L., et al. A brain-penetrant RAF dimer antagonist for the noncanonical BRAF oncoprotein of pediatric low-grade astrocytomas. Neuro. Oncol. 2017;19:774-785.

    Not in our library10.1093/neuonc/now261

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    Dean E.J., Banerji U., Girotti R., Niculescu-Duvaz I., Lopes F., Davies L., Niculescu-Duvaz D., Dhomen N., Ellis S., Ali Z., et al. A Phase 1 first-in-human trial to evaluate the safety and tolerability of CCT3833, an oral panRAF inhibitor, in patients with advanced solid tumours, including metastatic melanoma. J. Clin. Oncol. 2016;34:TPS9597.

    Not in our library10.1200/jco.2016.34.15_suppl.tps9597

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    Saturno G., Lopes F., Girotti M.R., Niculescu-Duvaz I., Niculescu-Duvaz D., Zambon A., Davies L., Johnson L., Preece N., Viros A., et al. Therapeutic efficacy of the paradox-breaking panRAF and SRC drug CCT3833/BAL3833 in KRAS-driven cancer models. Eur. J. Cancer. 2016;61:S199.

    Not in our library10.1016/s0959-8049(16)61703-3

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    Ramurthy S., Taft B.R., Aversa R.J., Barsanti P.A., Burger M.T., Lou Y., Nishiguchi G.A., Rico A., Setti L., Smith A., et al. Design and Discovery of N-(3-(2-(2-Hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide, a Selective, Efficacious, and Well-Tolerated RAF Inhibitor Targeting RAS Mutant Cancers: The Path to the Clinic. J. Med. Chem. 2019.

    Not in our library10.1021/acs.jmedchem.9b00161

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    Williams T.E., Subramanian S., Verhagen J., McBride C.M., Costales A., Sung L., Antonios-McCrea W., McKenna M., Louie A.K., Ramurthy S., et al. Discovery of RAF265: A Potent mut-B-RAF Inhibitor for the Treatment of Metastatic Melanoma. ACS Med. Chem. Lett. 2015;6:961-965.

    Not in our library10.1021/ml500526p

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    Yao Z., Gao Y., Su W., Yaeger R., Tao J., Na N., Zhang Y., Zhang C., Rymar A., Tao A., et al. RAF inhibitor PLX8394 selectively disrupts BRAF dimers and RAS-independent BRAF-mutant-driven signaling. Nat. Med. 2019;25:284-291.

    Not in our library10.1038/s41591-018-0274-5

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    Tutuka C.S.A., Andrews M.C., Mariadason J.M., Ioannidis P., Hudson C., Cebon J., Behren A. PLX8394, a new generation BRAF inhibitor, selectively inhibits BRAF in colonic adenocarcinoma cells and prevents paradoxical MAPK pathway activation. Mol. Cancer. 2017;16:112.

    Not in our library10.1186/s12943-017-0684-x

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    Zhang C., Spevak W., Zhang Y., Burton E.A., Ma Y., Habets G., Zhang J., Lin J., Ewing T., Matusow B., et al. RAF inhibitors that evade paradoxical MAPK pathway activation. Nature. 2015;526.

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    Current Development Status of MEK Inhibitors · 2017
    No notice
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    Welsh S.J., Corrie P.G. Management of BRAF and MEK inhibitor toxicities in patients with metastatic melanoma. Ther. Adv. Med. Oncol. 2015;7:122-136.

    Not in our library10.1177/1758834014566428

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    Wang P.-F., Qiu H.-Y., Zhu H.-L. A patent review of BRAF inhibitors: 2013–2018. Expert Opin. Ther. Pat. 2019;29:595-603.

    Not in our library10.1080/13543776.2019.1640680

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    Molina-Arcas M., Downward J. How to fool a wonder drug: Truncate and dimerize. Cancer Cell. 2012;21:7-9.

    Not in our library10.1016/j.ccr.2011.12.017

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