Sprouty2 attenuates epidermal growth factor receptor ubiquitylation and endocytosis, and consequently enhances Ras/ERK signalling
Sprouty2 attenuates epidermal growth factor receptor ubiquitylation and endocytosis, and consequently enhances Ras/ERK signalling
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DOI：
10.1093/emboj/cdf493
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发表时间：
2002-09-16
期刊：
影响因子：
11.4
通讯作者：
Guy, GR
中科院分区：
文献类型：
--
作者：
Wong, ESM;Fong, CW;Guy, GR
Drosophila Sprouty（dSpry）是一种新型的成纤维细胞生长因子受体（FGFR）、表皮生长因子受体（EGFR）和Sevenless信号传导的拮抗剂，表面上是通过诱导Ras/MAPK通路的应答而实现的。已经克隆了四个哺乳动物发芽基因，它们似乎主要在FGF介导的肺和肢体形态发生中起抑制作用。本文提供的证据描述了人Sprouty 2（hSpry 2）和c-Cbl之间的直接关联的功能含义，及其对EGFR的细胞定位和信号传导能力的影响。与普遍认为Spry 2是受体酪氨酸激酶信号传导的一般抑制剂的观点相反，hSpry 2显示出废除EGFR泛素化和内吞作用，并维持EGF诱导的ERK信号传导，其在PC 12细胞的分化中达到高潮。相关证据显示，c-Cbl结合缺陷的hSpry 2DeltaN 11和mSpry 4均不能引起这些作用。hSpry 2与c-Cbl RING指结构域特异性相互作用，并从其在E3连接酶上的结合位点置换UbcH 7。我们得出结论，hSpry 2通过特异性地拦截c-Cbl介导的对受体下调的作用来增强EGFR信号传导。
Drosophila Sprouty (dSpry) was genetically identified as a novel antagonist of fibroblast growth factor receptor (FGFR), epidermal growth factor receptor (EGFR) and Sevenless signalling, ostensibly by eliciting its response on the Ras/MAPK pathway. Four mammalian sprouty genes have been cloned, which appear to play an inhibitory role mainly in FGF- mediated lung and limb morphogenesis. Evidence is presented herein that describes the functional implications of the direct association between human Sprouty2 (hSpry2) and c-Cbl, and its impact on the cellular localization and signalling capacity of EGFR. Contrary to the consensus view that Spry2 is a general inhibitor of receptor tyrosine kinase signalling, hSpry2 was shown to abrogate EGFR ubiquitylation and endocytosis, and sustain EGF-induced ERK signalling that culminates in differentiation of PC12 cells. Correlative evidence showed the failure of hSpry2DeltaN11 and mSpry4, both deficient in c-Cbl binding, to instigate these effects. hSpry2 interacts specifically with the c-Cbl RING finger domain and displaces UbcH7 from its binding site on the E3 ligase. We conclude that hSpry2 potentiates EGFR signalling by specifically intercepting c-Cbl-mediated effects on receptor down-regulation.