Soubeyran Philippe, Kowanetz Katarzyna, Szymkiewicz Iwona, Langdon Wallace Y, Dikic Ivan
Ludwig Institute for Cancer Research, Box 595, Husargatan 3, Uppsala, S-75124, Sweden.
Nature. 2002 Mar 14;416(6877):183-7. doi: 10.1038/416183a.
Cbl is a multi-adaptor protein involved in ligand-induced downregulation 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. 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) 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 downregulation of receptor tyrosine kinases.
Cbl是一种多衔接蛋白，参与配体诱导的受体酪氨酸激酶下调。据认为，Cbl介导的活性受体泛素化对于受体降解和受体诱导的信号转导停止至关重要。在此我们证明，Cbl还调节表皮生长因子（EGF）受体的内吞作用。Cbl迅速募集CIN85（85K的Cbl相互作用蛋白；参考文献6）和内吞素（网格蛋白包被小泡的调节成分），与活化的EGF受体形成复合物，从而控制受体内化。CIN85与内吞素组成性结合，而在EGF刺激下，CIN85与Cbl远端羧基末端的结合增加。抑制这些相互作用足以阻断EGF受体内化、延迟受体降解并增强EGF诱导的基因转录，而不会干扰Cbl介导的受体泛素化。因此，Cbl进化上不同的C末端利用一种在功能上与Cbl泛素连接酶活性可分离的机制来介导配体依赖性受体酪氨酸激酶的下调。
