Search results for BRAF

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Identifier: R-HSA-6802952
Species: Homo sapiens
In addition to the more prevalent point mutations, BRAF and RAF1 are also subject to activation as a result of translocation events that yield truncated or fusion products (Jones et al, 2008; Cin et al, 2011; Palanisamy et al, 2010; Ciampi et al, 2005; Stransky et al, 2014; Hutchinson et al, 2013; Zhang et al, 2013; Lee et al, 2012; Ricarte-Filho et al, 2013; reviewed in Lavoie and Therrien et al, 2015). In general these events put the C-terminal kinase domain of BRAF or RAF1 downstream of an N-terminal sequence provided by a partner protein. This removes the N-terminal region of the RAF protein, relieving the autoinhibition imposed by this region of the protein. In addition, some but not all of the fusion partner proteins have been shown to contain coiled-coil or other dimerization domains. Taken together, the fusion proteins are thought to dimerize constitutively and activate downstream signaling (Jones et al, 2008; Lee et al, 2012; Hutchinson et al, 2013; Ciampi et al, 2005; Cin et al, 2011; Stransky et al, 2014).
Identifier: R-HSA-6802948
Species: Homo sapiens
BRAF is mutated in about 8% of human cancers, with high prevalence in hairy cell leukemia, melanoma, papillary thyroid and ovarian carcinomas, colorectal cancer and a variety of other tumors (Davies et al, 2002; reviewed in Samatar and Poulikakos, 2014). Most BRAF mutations fall in the activation loop region of the kinase or the adjacent glycine rich region. These mutations promote increased kinase activity either by mimicking the effects of activation loop phosphorylations or by promoting the active conformation of the enzyme (Davies et al, 2002; Wan et al, 2004). Roughly 90% of BRAF mutants are represented by the single missense mutation BRAF V600E (Davies et al, 2002; Wan et al, 2004). Other highly active kinase mutants of BRAF include BRAF G469A and BRAF T599dup. G469 is in the glycine rich region of the kinase domain which plays a role in orienting ATP for catalysis, while T599 is one of the two conserved regulatory phosphorylation sites of the activation loop. Each of these mutants has highly enhanced basal kinase activities, phosphorylates MEK and ERK in vitro and in vivo and is transforming when expressed in vivo (Davies et al, 2002; Wan et al, 2004; Eisenhardt et al, 2011). Further functional characterization shows that these highly active mutants are largely resistant to disruption of the BRAF dimer interface, suggesting that they are able to act as monomers (Roring et al, 2012; Brummer et al, 2006; Freeman et al, 2013; Garnett et al, 2005). Activating BRAF mutations occur for the most part independently of RAS activating mutations, and RAS activity levels are generally low in BRAF mutant cells. Moreover, the kinase activity of these mutants is only slightly elevated by coexpression of G12V KRAS, and biological activity of the highly active BRAF mutants is independent of RAS binding (Brummer et al, 2006; Wan et al, 2004; Davies et al, 2002; Garnett et al, 2005). Although BRAF V600E is inhibited by RAF inhibitors such as vemurafenib, resistance frequently develops, in some cases mediated by the expression of a splice variant that lacks the RAS binding domain and shows elevated dimerization compared to the full length V600E mutant (Poulikakos et al, 2011; reviewed in Lito et al, 2013).
Identifier: R-HSA-6802946
Species: Homo sapiens
In addition to the highly prevalent and activating V600E BRAF mutations, numerous moderately activating and less common mutations have also been identified in human cancers (Forbes et al, 2015). Unlike the case for their highly activating counterparts, signaling through these mutant versions of BRAF depends both upon RAS binding and RAF dimerization (Wan et al, 2004; Freeman et al, 2013; Roring et al, 2012; reviewed in Lito et al, 2013; Lavoie and Therrien, 2015)
Identifier: R-HSA-6802955
Species: Homo sapiens
While BRAF-specific inhibitors inhibit MAPK/ERK activation in the presence of the BRAF V600E mutant, paradoxical activation of ERK signaling has been observed after treatment of cells with inhibitor in the presence of WT BRAF (Wan et al, 2004; Garnett et al, 2005; Heidorn et al, 2010; Hazivassiliou et al, 2010; Poulikakos et al, 2010). This paradoxical ERK activation is also seen in cells expressing kinase-dead or impaired versions of BRAF such as D594V, which occur with low frequency in some cancers (Wan et al, 2004; Heidorn et al, 2010). Unlike BRAF V600E, which occurs exclusively of activating RAS mutations, kinase-impaired versions of BRAF are coincident with RAS mutations in human cancers, and indeed, paradoxical activation of ERK signaling in the presence of inactive BRAF is enhanced in the presence of oncogenic RAS (Heidorn et al, 2010; reviewed in Holderfield et al, 2014). Although the details remain to be worked out, paradoxical ERK activation in the presence of inactive BRAF appears to rely on enhanced dimerization with and transactivation of CRAF (Heidorn et al, 2010; Hazivassiliou et al, 2010; Poulikakos et al, 2010; Roring et al, 2012; Rajakulendran et al, 2009; Holderfield et al, 2013; Freeman et al, 2013; reviewed in Roskoski, 2010; Samatar and Poulikakos, 2014; Lavoie and Therrien, 2015). RAF inhibitors can promote association of RAF-RAS interaction and enhanced RAF dimerization through disruption of intramolecular interactions between the kinase domain and its N-terminal regulatory region. Moreover, specific BRAF inhibitors can only occupy one protomer within the transcactivated BRAF dimer due to negative co-operativity leading to paradoxical ERK activation. (Karoulia et al, 2016; Jin et al, 2017, reviewed in Karoulia et al, 2017).
Identifier: R-HSA-9854907
Species: Homo sapiens
MITF contributes to cellular energetics by regulating the expression of genes such as PPARGC1A, a regulator of mitochondrial biogenesis. MITF-dependent PPARGC1A expression shifts cells towards oxidative phosphorylation (Haq et al, 2013; Vazquez et al, 2013). MITF also promotes the expression of SIRT1, an NAD-dependent deacetylase that acts as a rheostat for cellular energetics. SIRT1 contributes to proliferation and inhibition of senescence in part through its regulation of p300 (Ohanna et al, 2014; Bouras et al, 2005).
Identifier: R-HSA-5673000
Species: Homo sapiens
Mammals have three RAF isoforms, A, B and C, that are activated downstream of RAS and stimulate the MAPK pathway. Although CRAF (also known as RAF-1) was the first identified and remains perhaps the best studied, BRAF is most similar to the RAF expressed in other organisms. Notably, MAPK (ERK) activation is more compromised in BRAF-deficient cells than in CRAF or ARAF deficient cells (Bonner et al, 1985; Mikula et al, 2001, Huser et al, 2001, Mercer et al, 2002; reviewed in Leicht et al, 2007; Matallanas et al, 2011; Cseh et al, 2014). Consistent with its important role in MAPK pathway activation, mutations in the BRAF gene, but not in those for A- or CRAF, are associated with cancer development (Davies et al, 2002; reviewed in Leicht et al, 2007). ARAF and CRAF may have arisen through gene duplication events, and may play additional roles in MAPK-independent signaling (Hindley and Kolch, 2002; Murakami and Morrison, 2001).
Despite divergences in function, all mammalian RAF proteins share three conserved regions (CRs) and each interacts with RAS and MEK proteins, although with different affinities. The N-terminal CR1 contains a RAS-binding domain (RBD) and a cysteine-rich domain (CRD) that mediate interactions with RAS and the phospholipid membrane. CR2 contains inhibitory phosphorylation sites that impact RAS binding and RAF activation, while the C-terminal CR3 contains the bi-lobed kinase domain with its activation loop, and an adjacent upstream "N-terminal acidic motif" -S(S/G)YY in C- and A-RAF,respectively, and SSDD in B-RAF - that is required for RAF activation (Tran et al, 2005; Dhillon et al, 2002; Chong et al, 2001; Cutler et al, 1998; Chong et al, 2003; reviewed in Matallanas et al, 2011).

Regulation of RAF activity involves multiple phosphorylation and dephosphorylation events, intramolecular conformational changes, homo- and heterodimerization between RAF monomers and changes to protein binding partners, including scaffolding proteins which bring pathway members together (reviewed in Matallanas et al, 2011; Cseh et al, 2014). The details of this regulation are not completely known and differ slightly from one RAF isoform to another. Briefly, in the inactive state, RAF phosphorylation on conserved serine residues in CR2 promote an interaction with 14-3-3 dimers, maintaining the kinase in a closed conformation. Upon RAS activation, these sites are dephosphorylated, allowing the RAF CRD and RBD to bind RAS and phospholipids, facilitating membrane recruitment. RAF activation requires homo- or heterodimerization, which promotes autophosphorylation in the activation loop of the receiving monomer. Of the three isoforms, only BRAF is able to initiate this allosteric activation of other RAF monomers (Hu et al, 2013; Heidorn et al, 2010; Garnett et al, 2005). This activity depends on negative charge in the N-terminal acidic region (NtA; S(S/G)YY or SSDD) adjacent to the kinase domain. In BRAF, this region carries permanent negative charge due to the presence of the two aspartate residues in place of the tyrosine residues of A- and CRAF. In addition, unique to BRAF, one of the serine residues of the NtA is constitutively phosphorylated. In A- and CRAF, residues in this region are subject to phosphorylation by activated MEK downstream of RAF activation, establishing a positive feedback loop and allowing activated A- and CRAF monomers to act as transactivators in turn (Hu et al, 2013; reviewed in Cseh et al, 2014). RAF signaling is terminated through dephosphorylation of the NtA region and phosphorylation of the residues that mediate the inhibitory interaction with 14-3-3, promoting a return to the inactive state (reviewed in Matallanas et al, 2011; Cseh et al, 2014).
Identifier: R-HSA-5673001
Species: Homo sapiens
The RAS-RAF-MEK-ERK pathway regulates processes such as proliferation, differentiation, survival, senescence and cell motility in response to growth factors, hormones and cytokines, among others. Binding of these stimuli to receptors in the plasma membrane promotes the GEF-mediated activation of RAS at the plasma membrane and initiates the three-tiered kinase cascade of the conventional MAPK cascades. GTP-bound RAS recruits RAF (the MAPK kinase kinase), and promotes its dimerization and activation (reviewed in Cseh et al, 2014; Roskoski, 2010; McKay and Morrison, 2007; Wellbrock et al, 2004). Activated RAF phosphorylates the MAPK kinase proteins MEK1 and MEK2 (also known as MAP2K1 and MAP2K2), which in turn phophorylate the proline-directed kinases ERK1 and 2 (also known as MAPK3 and MAPK1) (reviewed in Roskoski, 2012a, b; Kryiakis and Avruch, 2012). Activated ERK proteins may undergo dimerization and have identified targets in both the nucleus and the cytosol; consistent with this, a proportion of activated ERK protein relocalizes to the nucleus in response to stimuli (reviewed in Roskoski 2012b; Turjanski et al, 2007; Plotnikov et al, 2010; Cargnello et al, 2011). Although initially seen as a linear cascade originating at the plasma membrane and culminating in the nucleus, the RAS/RAF MAPK cascade is now also known to be activated from various intracellular location. Temporal and spatial specificity of the cascade is achieved in part through the interaction of pathway components with numerous scaffolding proteins (reviewed in McKay and Morrison, 2007; Brown and Sacks, 2009).
The importance of the RAS/RAF MAPK cascade is highlighted by the fact that components of this pathway are mutated with high frequency in a large number of human cancers. Activating mutations in RAS are found in approximately one third of human cancers, while ~8% of tumors express an activated form of BRAF (Roberts and Der, 2007; Davies et al, 2002; Cantwell-Dorris et al, 2011).
Identifier: R-HSA-2559582
Species: Homo sapiens
The culture medium of senescent cells in enriched in secreted proteins when compared with the culture medium of quiescent i.e. presenescent cells and these secreted proteins constitute the so-called senescence-associated secretory phenotype (SASP), also known as the senescence messaging secretome (SMS). SASP components include inflammatory and immune-modulatory cytokines (e.g. IL6 and IL8), growth factors (e.g. IGFBPs), shed cell surface molecules (e.g. TNF receptors) and survival factors. While the SASP exhibits a wide ranging profile, it is not significantly affected by the type of senescence trigger (oncogenic signalling, oxidative stress or DNA damage) or the cell type (epithelial vs. mesenchymal) (Coppe et al. 2008). However, as both oxidative stress and oncogenic signaling induce DNA damage, the persistent DNA damage may be a deciding SASP initiator (Rodier et al. 2009). SASP components function in an autocrine manner, reinforcing the senescent phenotype (Kuilman et al. 2008, Acosta et al. 2008), and in the paracrine manner, where they may promote epithelial-to-mesenchymal transition (EMT) and malignancy in the nearby premalignant or malignant cells (Coppe et al. 2008). Interleukin-1-alpha (IL1A), a minor SASP component whose transcription is stimulated by the AP-1 (FOS:JUN) complex (Bailly et al. 1996), can cause paracrine senescence through IL1 and inflammasome signaling (Acosta et al. 2013).

Here, transcriptional regulatory processes that mediate the SASP are annotated. DNA damage triggers ATM-mediated activation of TP53, resulting in the increased level of CDKN1A (p21). CDKN1A-mediated inhibition of CDK2 prevents phosphorylation and inactivation of the Cdh1:APC/C complex, allowing it to ubiquitinate and target for degradation EHMT1 and EHMT2 histone methyltransferases. As EHMT1 and EHMT2 methylate and silence the promoters of IL6 and IL8 genes, degradation of these methyltransferases relieves the inhibition of IL6 and IL8 transcription (Takahashi et al. 2012). In addition, oncogenic RAS signaling activates the CEBPB (C/EBP-beta) transcription factor (Nakajima et al. 1993, Lee et al. 2010), which binds promoters of IL6 and IL8 genes and stimulates their transcription (Kuilman et al. 2008, Lee et al. 2010). CEBPB also stimulates the transcription of CDKN2B (p15-INK4B), reinforcing the cell cycle arrest (Kuilman et al. 2008). CEBPB transcription factor has three isoforms, due to three alternative translation start sites. The CEBPB-1 isoform (C/EBP-beta-1) seems to be exclusively involved in growth arrest and senescence, while the CEBPB-2 (C/EBP-beta-2) isoform may promote cellular proliferation (Atwood and Sealy 2010 and 2011). IL6 signaling stimulates the transcription of CEBPB (Niehof et al. 2001), creating a positive feedback loop (Kuilman et al. 2009, Lee et al. 2010). NF-kappa-B transcription factor is also activated in senescence (Chien et al. 2011) through IL1 signaling (Jimi et al. 1996, Hartupee et al. 2008, Orjalo et al. 2009). NF-kappa-B binds IL6 and IL8 promoters and cooperates with CEBPB transcription factor in the induction of IL6 and IL8 transcription (Matsusaka et al. 1993, Acosta et al. 2008). Besides IL6 and IL8, their receptors are also upregulated in senescence (Kuilman et al. 2008, Acosta et al. 2008) and IL6 and IL8 may be master regulators of the SASP.

IGFBP7 is also an SASP component that is upregulated in response to oncogenic RAS-RAF-MAPK signaling and oxidative stress, as its transcription is directly stimulated by the AP-1 (JUN:FOS) transcription factor. IGFBP7 negatively regulates RAS-RAF (BRAF)-MAPK signaling and is important for the establishment of senescence in melanocytes (Wajapeyee et al. 2008).

Please refer to Young and Narita 2009 for a recent review.

Identifier: R-HSA-9664565
Species: Homo sapiens
Mutations in the kinase domain (KD) of ERBB2 result in constitutive activation of ERBB2 signaling, facilitate heterodimerization of ERBB2 with other EGFR family members and increase the signaling intensity, leading to cellular transformation (Kancha et al. 2011).
Only a subset of potential heterodimerization partners has been tested for most ERBB2 KD mutant proteins, so our annotations here are correspondingly limited. ERBB2 L755S and ERBB2 V777L cancer variants were shown to heterodimerize with ERBB3 (HER3) at a higher rate than wild type ERBB2 (Croessmann et al. 2019). Increased activity of ERBB2 L755S, ERBB2 L755P, ERBB2 V777L, ERBB2 D769H, ERBB2 D769Y, ERBB2 V842I, ERBB2 R896C and ERBB2 G778_P780dup in the presence of either EGFR (Kancha et al. 2011, Bose et al. 2013) or ERBB3 (Kancha et al. 2011, Bose et al. 2013, Collier et al. 2013) as a heterodimerization partner was also observed. The interplay of ERBB2 G778_P780dup, ERBB2 I767M and ERBB2 R896C with ERBB3 has not been tested. ERBB2 L869R mutant shows increased activity in the presence of ERBB3, which is further augmented in the presence of dimerization-facilitating ERBB3 E928G mutants (Hanker et al. 2017). The interplay of ERBB2 L869R with EGFR has not been tested. Heterodimerization of ERBB2 KD mutants with ERBB4 has not been tested and ERBB4 is a candidate heterodimerization partner for these KD variants.
ERBB2 H878Y mutant has ten times higher kinase activity than the wild type ERBB2 (Hu, Wan et al. 2015; Hu, Hu et al. 2015), but its heterodimerization properties have not been studied and it is therefore annotated as a candidate.
Ligand requirements have not been studied in the context of heterodimerization of ERBB2 KD mutants, but it is assumed that ligands are required.
The signaling properties of ERBB2 L755M (Gonzalez-Alonso et al. 2015), ERBB2 L755W (COSMIC database: Forbes et al. 2017), ERBB2 V777E (Dietz et al. 2017), ERBB2 V777M (Lee et al. 2006, Ross et al. 2016, Zehir et al. 2017), ERBB2 D769N (Tschui et al. 2015), ERBB2 V842E (Siroy et al. 2015), ERBB2 R896H (Cancer Genome Atlas Research Network 2011), ERBB2 L869Q (Lee et al. 2006) and ERBB2 H878R (Trowe et al. 2008, Zehir et al. 2017) have not been experimentally tested, but they are predicted to be pathogenic (COSMIC database: Forbes et al. 2017) and they are annotated as candidates. ERBB2 T733I (Trowe et al. 2008), ERBB2 T798I (Trowe et al. 2008, Hanker et al. 2017) and ERBB2 T798M (Hanker et al. 2017) usually occur as secondary ERBB2 mutations and are responsible for treatment failure. On their own, ERBB2 T733I and ERBB2 T798I appear to be weakly transforming compared with the other ERBB2 KD mutants. As their signaling properties have been poorly studied, ERBB2 T733I, ERBB2 T798I and ERBB2 T798M are annotated as candidates.
The binding of ERBB2 KD mutants to ERBIN and the HSP90:CDC37 chaperone:co-chaperone complex has not been tested but is assumed to occur similarly to the wild type ERBB2.
Signaling by ERBB2 KD mutants has been organized into subpathways based on the current knowledge of biology of these mutants (heterodimerization, downstream signaling, drug interaction) and on the sequence similarity of their mutations.
Identifier: R-HSA-8878159
Species: Homo sapiens
The transcription factor RUNX3 is a RUNX family member. All RUNX family members, RUNX1, RUNX2 and RUNX3, possess a highly conserved Runt domain, involved in DNA binding. For a more detailed description of the structure of RUNX proteins, please refer to the pathway 'Transcriptional regulation by RUNX1'. Similar to RUNX1 and RUNX2, RUNX3 forms a transcriptionally active heterodimer with CBFB (CBF-beta). Studies in mice have shown that RUNX3 plays a role in neurogenesis and development of T lymphocytes. RUNX3 is implicated as a tumor suppressor gene in various human malignancies.
During nervous system formation, the Cbfb:Runx3 complex is involved in development of mouse proprioceptive dorsal root ganglion neurons by regulating expression of Ntrk3 (Neurotrophic tyrosine kinase receptor type 3) and possibly other genes (Inoue et al. 2002, Kramer et al. 2006, Nakamura et al. 2008, Dykes et al. 2011, Ogihara et al. 2016). It is not yet known whether RUNX3 is involved in human neuronal development and neuronal disorders.
RUNX3 plays a major role in immune response. RUNX3 regulates development of T lymphocytes. In mouse hematopoietic stem cells, expression of Runx3 is regulated by the transcription factor TAL1 (Landry et al. 2008). RUNX3 promotes the CD8+ lineage fate in developing thymocytes. In the CD4+ thymocyte lineage in mice, the transcription factor ThPOK induces transcription of SOCS family members, which repress Runx3 expression (Luckey et al. 2014). RUNX3, along with RUNX1 and ETS1, is implicated in regulation of transcription of the CD6 gene, encoding a lymphocyte surface receptor expressed on developing and mature T cells (Arman et al. 2009). RUNX3 and ThPOK regulate intestinal CD4+ T cell immunity in a TGF-beta and retinoic acid-dependent manner, which is important for cellular defense against intestinal pathogens (Reis et al. 2013). Besides T lymphocytes, RUNX3 is a key transcription factor in the commitment of innate lymphoid cells ILC1 and ILC3 (Ebihara et al. 2015). RUNX3 regulates expression of CD11A and CD49D integrin genes, involved in immune and inflammatory responses (Dominguez-Soto et al. 2005). RUNX3 is involved in mouse TGF-beta-mediated dendritic cell function and its deficiency is linked to airway inflammation (Fainaru et al. 2004).
In addition to its developmental role, RUNX3 is implicated as a tumor suppressor. The loss of RUNX3 expression and function was first causally linked to the genesis and progression of human gastric cancer (Li et al. 2002). Expression of RUNX3 increases in human pancreatic islet of Langerhans cells but not in pancreatic adenocarcinoma cells in response to differentiation stimulus (serum withdrawal) (Levkovitz et al. 2010). Hypermethylation of the RUNX3 gene is associated with an increased risk for progression of Barrett's esophagus to esophageal adenocarcinoma (Schulmann et al. 2005). Hypermethylation-mediated silencing of the RUNX3 gene expression is also frequent in granulosa cell tumors (Dhillon et al. 2004) and has also been reported in colon cancer (Weisenberger et al. 2006), breast cancer (Lau et al. 2006, Huang et al. 2012), bladder cancer (Wolff et al. 2008) and gastric cancer (Li et al. 2002). In colorectal cancer, RUNX3 is one of the five markers in a gene panel used to classify CpG island methylator phenotype (CIMP+) (Weisenberger et al. 2006).
RUNX3 and CBFB are frequently downregulated in gastric cancer. RUNX3 cooperates with TGF-beta to maintain homeostasis in the stomach and is involved in TGF-beta-induced cell cycle arrest of stomach epithelial cells. Runx3 knockout mice exhibit decreased sensitivity to TGF-beta and develop gastric epithelial hyperplasia (Li et al. 2002, Chi et al. 2005). RUNX3-mediated inhibition of binding of TEADs:YAP1 complexes to target promoters is also implicated in gastric cancer suppression (Qiao et al. 2016).
RUNX3 is a negative regulator of NOTCH signaling and RUNX3-mediated inhibition of NOTCH activity may play a tumor suppressor role in hepatocellular carcinoma (Gao et al. 2010, Nishina et al. 2011).
In addition to RUNX3 silencing through promoter hypermethylation in breast cancer (Lau et al. 2006), Runx3+/- mice are predisposed to breast cancer development. RUNX3 downregulates estrogen receptor alpha (ESR1) protein levels in a proteasome-dependent manner (Huang et al. 2012).
Besides its tumor suppressor role, mainly manifested through its negative effect on cell proliferation, RUNX3 can promote cancer cell invasion by stimulating expression of genes involved in metastasis, such as osteopontin (SPP1) (Whittle et al. 2015).
Identifier: R-HSA-5674499
Species: Homo sapiens
MAPK pathway activation is limited by a number of negative feedback loops established by MAPK-dependent phosphorylations. Known substrates of activated MAPK proteins that lie upstream in the RAF/MAPK pathway include SOS, RAF1, BRAF, and MAP2K1 (Buday et al, 1995; Dong et al, 1996; Dougherty et al, 2005; Sturm et al, 2010; Fritsche-Guenther et al, 2011; Rushworth et al, 2006; Brummer et al, 2003; Ritt et al, 2010; Catalanotti et al, 2009)
Identifier: R-HSA-187706
Species: Homo sapiens
RIT and RIN are two small guanine nucleotide binding proteins that share more than 50% sequence identity with RAS, including highly conserved core effector domains. Unlike RAS, the C termini of RIT and RIN lack a typical prenylation motif (CAAX, XXCC, or CXC) required for the association of RAS proteins with the plasma membrane. RIT is expressed in all tissues, whereas RIN is neuron-specific. They have similar signalling properties and are activated by NGF through unknown exchange factors. They signal to ERKs and p38 MAP kinase. They mainly lead to p38 activation via the BRAF-MEK kinase cascade.
Identifier: R-HSA-6802957
Species: Homo sapiens
The importance of the RAS/RAF/MAPK cascade in regulating cellular proliferation, differentiation and survival is highlighted by the fact that components of the pathway are mutated with high frequency in a large number of human cancers. Activating mutations in RAS are found in approximately one third of human cancers, while ~8% of tumors express an activated form of BRAF. RAS pathway activation is also achieved in a smaller subset of cancers by loss-of-function mutations in negative regulators of RAS signaling, such as the RAS GAP NF1(reviewed in Prior et al, 2012; Pylayeva-Gupta et al, 2011; Stephen et al, 2014; Lavoie and Therrien, 2015; Lito et al, 2013; Samatar and Poulikakos, 2014; Maertens and Cichowski, 2014).
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