Search results for BRAF

Showing 26 results out of 276

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Protein (4 results from a total of 113)

Identifier: R-HSA-167224
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: BRAF: P15056
Identifier: R-HSA-5675199
Species: Homo sapiens
Compartment: plasma membrane
Primary external reference: UniProt: BRAF: P15056
Identifier: R-HSA-5672676
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: BRAF: P15056
Identifier: R-HSA-8933622
Species: Homo sapiens
Compartment: plasma membrane
Primary external reference: UniProt: BRAF: P15056

Complex (4 results from a total of 68)

Identifier: R-HSA-170966
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-6802578
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-9610130
Species: Homo sapiens
Compartment: endosome membrane
Identifier: R-HSA-9610125
Species: Homo sapiens
Compartment: cytosol

Set (4 results from a total of 14)

Identifier: R-ALL-6802559
Compartment: cytosol
Identifier: R-HSA-6802629
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-6802657
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-6802631
Species: Homo sapiens
Compartment: cytosol

Pathway (4 results from a total of 12)

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-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-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)

Reaction (4 results from a total of 59)

Identifier: R-HSA-5675198
Species: Homo sapiens
Compartment: plasma membrane
BRAF is subject to MAPK-dependent phosphorylation that limits its activity. Phosphorylation of S151 inhibits binding of BRAF to activated RAS, while phosphorylation of T401, S750 and S753 abrogates heterodimerization with RAF1 (Ritt et al, 2010; Rushworth et al, 2006; Brummer et al, 2003).
Identifier: R-HSA-6802930
Species: Homo sapiens
Compartment: cytosol
RAF kinase inhibitors such as vemurafenib are clinically approved for treatment of BRAF-driven melanomas. Despite initial positive response to drug treatment, however, many tumors go on to develop resistance to the RAF inhibitors (Flaherty et al, 2010; Chapman et al, 2011; Sosman et al, 2012; Solit et al, 2011; reviewed in Lito et al, 2013). One mechanism that contributes to acquired resistance to RAF inhibitors is the expression of a splice variant of V600E that lacks the N-terminal RAS-binding domain. This variant displays increased RAS-independent dimerization and increased signaling relative to the full-length V600E, consistent with the notion that it is the monomeric form of BRAF that is sensitive to inhibition. Disruption of the dimer interface in this p61-V600E splice variant restores sensitivity to inhibition (Poulikakos et al, 2011; reviewed in Lito et al, 2013).
Other mechanisms of BRAF inhibitor resistance include mutational activation of NRAS or receptor tyrosine kinases, inactivation of the GAP protein NF1, or increased expression of RAF1 or BRAF (Nazarian et al, 2010; Maertens et al, 2013; Whittaker et al, 2013; Shi et al, 2012; Montagut et al, 2008; reviewed in Chapman, 2013; Lito et al, 2013).
Identifier: R-HSA-9610163
Species: Homo sapiens
Compartment: endosome membrane
After recruitment by RAP1 to the endosome, BRAF is activated, likely by autophosphorylation on the activation loop serines at 599 and 602 (Kao et al, 2001; reviewed in Matallanas, 2011).
Identifier: R-HSA-6803227
Species: Homo sapiens
Compartment: cytosol
After phosphorylation by MAP2Ks, the scaffolded kinase complex assembled by highly active BRAF mutants dissociates, as is the case for WT complexes (reviewed in Lavoie and Therrien et al, 2015).

ChemicalDrug (4 results from a total of 8)

Identifier: R-ALL-9657027
Compartment: cytosol
Identifier: R-ALL-6802253
Compartment: cytosol
Identifier: R-ALL-9657560
Compartment: cytosol
Identifier: R-ALL-9657527
Compartment: cytosol

Icon (2 results from a total of 2)

Species: Homo sapiens
Curator: Steve Jupe
Designer: Cristoffer Sevilla
BRAF icon
Serine/threonine-protein kinase B-raf
Species: Homo sapiens
Curator: Steve Jupe
Designer: Cristoffer Sevilla
ARAF,BRAF,RAF1 icon
Set of Serine/threonine-protein kinase A-Raf, Serine/threonine-protein kinase B-raf and RAF proto-oncogene serine/threonine-protein kinase
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