由高激酶活性 BRAF 突变介导的信号转导
中文名称
通路描述
BRAF 突变约占人类癌症的 8%，在毛细胞白血病、黑色素瘤、乳头状甲状腺癌和卵巢癌、结肠癌等多种肿瘤中高发（Davies 等人，2002；综述 Samatar 和 Poulikakos，2014）。大多数 BRAF 突变位于激酶的激活环区域或其相邻的富含甘氨酸区域。这些突变通过模拟激活环磷酸化或促进酶活性构象来促进激酶活性的增加（Davies 等人，2002；Wan 等人，2004）。大约 90% 的 BRAF 突变由单个错义突变 BRAF V600E 代表（Davies 等人，2002；Wan 等人，2004）。其他高度活跃的 BRAF 激酶突变体包括 BRAF G469A 和 BRAF T599dup。G469 位于激酶域富含甘氨酸区域，参与 ATP 的定向以催化，而 T599 是激活环中两个保守的磷酸化位点之一。每个突变体都具有高度增强的基础激酶活性，在体外和体内磷酸化 MEK 和 ERK，并在体内表达时具有转化能力（Davies 等人，2002；Wan 等人，2004；Eisenhardt 等人，2011）。进一步的功能表征表明，这些高度活跃的突变体对破坏 BRAF 二聚界面的干扰具有高度抗性，表明它们能够作为单体起作用（Roring 等人，2012；Brummer 等人，2006；Freeman 等人，2013；Garnett 等人，2005）。激活的 BRAF 突变大多独立于 RAS 激活突变发生，且 BRAF 突变细胞中的 RAS 活性水平通常较低。此外，这些突变体的激酶活性仅略因 G12V KRAS 共表达而升高，且高度活跃的 BRAF 突变体的生物学活性与 RAS 结合无关（Brummer 等人，2006；Wan 等人，2004；Davies 等人，2002；Garnett 等人，2005）。尽管 BRAF V600E 被 RAF 抑制剂如 vemurafenib 抑制，但耐药性经常发展，在某些情况下由表达缺乏 RAS 结合域的剪接变体介导，该变体与全长 V600E 突变体的二聚化相比具有增强的二聚化（Poulikakos 等人，2011；综述 Lito 等人，2013）。
英文描述
Signaling by high-kinase activity BRAF mutants 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).
所含基因
30 个基因