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Signaling by high-kinase activity BRAF mutants

Summary

Organism

Homo sapiens (human)

Reactome

R-HSA-6802948

PubChem

R-HSA-6802948

Description

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).

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SPV: a JavaScript Signaling Pathway Visualizer, Bioinformatics, 2018

Displaying entries **1 - 10** of 22 in total

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UniProt ID	Protein Name	Gene Symbol	Pathway Viewer
P01111	GTPase NRas	HRAS1 NRAS	view
P01112	GTPase HRas	HRAS HRAS1	view
P02671	Fibrinogen alpha chain [Cleaved into: Fibrinopeptide A; Fibrinogen alpha chain]	FGA	view
P02675	Fibrinogen beta chain [Cleaved into: Fibrinopeptide B; Fibrinogen beta chain]	FGB HEL-S-78p	view
P02679	Fibrinogen gamma chain	FGG PRO2061	view
P02751	Fibronectin	FN FN1	view
P04049	RAF proto-oncogene serine/threonine-protein kinase	RAF RAF1	view
P04275	von Willebrand factor	F8VWF VWF	view
P05106	Integrin beta-3	GP3A ITGB3	view
P08514	Integrin alpha-IIb	GP2B ITGA2B ITGAB	view

Displaying **all 3** entries
GlyCosmos Lectin	UniProt ID	Lectin Name	Pathway Viewer
GL_005388	P02671	Fibrinogen alpha chain [Cleaved into: Fibrinopeptide A; Fibrinogen alpha chain]	view
GL_005389	P02675	Fibrinogen beta chain [Cleaved into: Fibrinopeptide B; Fibrinogen beta chain]	view
GL_005390	P02679	Fibrinogen gamma chain	view

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