Ubiquitin ligase activity and tyrosine phosphorylation underlie suppression of growth factor signaling by c-Cbl/Sli-1
Ubiquitin ligase activity and tyrosine phosphorylation underlie suppression of growth factor signaling by c-Cbl/Sli-1
复制标题
DOI：
10.1016/s1097-2765(00)80231-2
复制
发表时间：
1999-12-01
期刊：
影响因子：
16
通讯作者：
Yarden, Y
中科院分区：
文献类型：
--
作者：
Levkowitz, G;Waterman, H;Yarden, Y
受体脱敏是通过配体-受体复合物的加速内吞和降解来实现的。体外重建系统表明，Cbl衔接蛋白直接控制下调的表皮生长因子（EGFR）的受体，通过招募泛素激活和共轭酶。我们推断一个连续的过程中启动的EGFR在先前确定的溶酶体靶向基序，随后招聘Cbl的自磷酸化。随后是c-Cbl在其RING指侧翼位点的酪氨酸磷酸化，这使得受体泛素化和降解成为可能。尽管Cbl家族的所有三个成员都可以增强泛素化，但两种致癌Cbl变体（其RING指缺陷且磷酸化位点缺失）不能使EGFR脱敏。我们的研究确定Cbl蛋白作为泛素连接机制的组成部分，并暗示它们同样抑制许多其他信号通路。
Receptor desensitization is accomplished by accelerated endocytosis and degradation of ligand-receptor complexes. An in vitro reconstituted system indicates that Cbl adaptor proteins directly control downregulation of the receptor for the epidermal growth factor (EGFR) by recruiting ubiquitin-activating and -conjugating enzymes. We infer a sequential process initiated by autophosphorylation of EGFR at a previously identified lysosome-targeting motif that subsequently recruits Cbl. This is followed by tyrosine phosphorylation of c-Cbl at a site flanking its RING finger, which enables receptor ubiquitination and degradation. Whereas ail three members of the Cbl family can enhance ubiquitination, two oncogenic Cbl variants, whose RING fingers are defective and phosphorylation sites are missing, are unable to desensitize EGFR. Our study identifies Cbl proteins as components of the ubiquitin ligation machinery and implies that they similarly suppress many other signaling pathways.