PDGFRA 跨膜、胞质区和激酶区突变体的信号传导
中文名称
通路描述
PDGFRA 是一种 III 型跨膜受体酪氨酸激酶。胞外域由 5 个免疫球蛋白（IG）结构域组成，参与二聚化和配体结合。胞内区包含一个胞质区，在无配体时发挥抑制受体自抑制的作用，以及一个双叶激酶区，具有激活环和催化裂隙（综述 Klug et al, 2018）。配体结合后，PDGFRA 发生二聚化和至少 11 个胞内酪氨酸残基的自磷酸化。这些磷酸化残基是 PDGFRA 响应信号通路下游效应体的结合位点（综述 Klug et al, 2018; Roskoski, 2018）。PDGFRA 在多种癌症中发生激活突变，包括胃肠道间质瘤（GIST）、黑色素瘤和血液系统癌症（综述 Corless et al, 2011; Wang et al, 2016; Roskoski, 2018）。PDGFRA 中最常见的突变位于胞质区胞质区 V561、激酶区小叶 N659 和激酶区激活环 D842。PDGFRA 还受激酶区激活环片段短缺失的影响（综述 Roskoski, 2018）。激活的蛋白可能从细胞膜信号传导，类似于野生型受体，但也有证据表明，一些突变体，特别是 D842V 和 V561D，主要定位于高尔基体膜（Bahlawane et al, 2014）。激活的 PDGFRA 突变体在无配体存在的情况下持续信号传导（综述 Roskoski, 2018; Wang et al, 2016; Klug et al, 2018）。
英文描述
Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants PDGFRA is a type III transmembrane receptor tyrosine kinase. The extracellular domain consists of 5 immunoglobulin (IG) domains that contribute to dimerization and ligand binding. The intracellular region has a juxtamembrane domain that plays a role in autoinhibiting the receptor in the absence of ligand, and a bi-lobed kinase region with an activation loop and the catalytic cleft (reviewed in Klug et al, 2018). Upon ligand binding, PDGFRA undergoes dimerization and transautophosphorylation at at least 11 tyrosine residues in the intracellular domain. These phosphorylated residues are binding sites for downstream effectors of PDGFRA-responsive signaling pathways (reviewed in Klug et al, 2018; Roskoski, 2018).
PDGFRA is subject to activating mutations in a number of cancers, including gastrointestinal stromal tumors (GIST), melanoma and haematological cancers (reviewed in Corless et al, 2011; Wang et al, 2016; Roskoski, 2018). The most prevalent mutations in PDGFRA are at residue V561 in the juxtamembrane domain, N659 in the small lobe of the kinase domain and D842 in the activation loop of the kinase domain. PDGFRA is also subject to short deletions in the activation loop segment (reviewed in Roskoski, 2018). Acitvated forms of the protein may signal from the plasma membrane, similar to the wild type receptor, however there is also evidence that some mutants, notably D842V and V561D localize primarily to the Golgi membrane (Bahlawane et al, 2014). Activated PDGFRA mutants signal constitutively in the absence of ligand (reviewed in Roskoski, 2018; Wang et al, 2016; Klug et al, 2018).
PDGFRA is subject to activating mutations in a number of cancers, including gastrointestinal stromal tumors (GIST), melanoma and haematological cancers (reviewed in Corless et al, 2011; Wang et al, 2016; Roskoski, 2018). The most prevalent mutations in PDGFRA are at residue V561 in the juxtamembrane domain, N659 in the small lobe of the kinase domain and D842 in the activation loop of the kinase domain. PDGFRA is also subject to short deletions in the activation loop segment (reviewed in Roskoski, 2018). Acitvated forms of the protein may signal from the plasma membrane, similar to the wild type receptor, however there is also evidence that some mutants, notably D842V and V561D localize primarily to the Golgi membrane (Bahlawane et al, 2014). Activated PDGFRA mutants signal constitutively in the absence of ligand (reviewed in Roskoski, 2018; Wang et al, 2016; Klug et al, 2018).
所含基因
7 个基因