Cbl-CIN85-endophilin complex mediates ligand-induced downregulation of EGF receptors
Cbl-CIN85-endophilin complex mediates ligand-induced downregulation of EGF receptors
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DOI：
10.1038/416183a
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发表时间：
2002-03-14
期刊：
影响因子：
64.8
通讯作者：
Dikic, I
中科院分区：
文献类型：
--
作者：
Soubeyran, P;Kowanetz, K;Dikic, I
Cbl是一种多接头蛋白，参与配体诱导的受体酪氨酸激酶下调。据认为，Cbl介导的活性受体的泛素化对于受体降解和受体诱导的信号转导的停止是必不可少的（1-5）。在这里，我们表明，Cbl另外调节表皮生长因子（EGF）受体的内吞作用。Cbl迅速募集CIN 85（Cbl相互作用蛋白85 K;参考文献6）和内亲蛋白（网格蛋白包被囊泡的调节组分（7-10）），与活化的EGF受体形成复合物，从而控制受体内化。CIN 85是组成性相关的endophilins，而CIN 85结合到远端羧基末端的Cbl EGF刺激增加。这些相互作用的抑制足以阻断EGF受体内化，延迟受体降解和增强EGF诱导的基因转录，而不干扰Cbl定向的受体泛素化。因此，Cbl的进化趋异C末端使用与Cbl的泛素连接酶活性在功能上可分离的机制来介导受体酪氨酸激酶的配体依赖性下调。
Cbl is a multi-adaptor protein involved in ligand-induced down-regulation of receptor tyrosine kinases. It is thought that Cbl-mediated ubiquitination of active receptors is essential for receptor degradation and cessation of receptor-induced signal transduction(1-5). Here we demonstrate that Cbl additionally regulates epidermal growth factor (EGF) receptor endocytosis. Cbl rapidly recruits CIN85 (Cbl-interacting protein of 85K; ref. 6) and endophilins (regulatory components of clathrin-coated vesicles(7-10)) to form a complex with activated EGF receptors, thus controlling receptor internalization. CIN85 was constitutively associated with endophilins, whereas CIN85 binding to the distal carboxy terminus of Cbl was increased on EGF stimulation. Inhibition of these interactions was sufficient to block EGF receptor internalization, delay receptor degradation and enhance EGF-induced gene transcription, without perturbing Cbl-directed receptor ubiquitination. Thus, the evolutionary divergent C terminus of Cbl uses a mechanism that is functionally separable from the ubiquitin ligase activity of Cbl to mediate ligand-dependent down-regulation of receptor tyrosine kinases.