Cbl-b-dependent coordinated degradation of the epidermal growth factor receptor signaling complex
Cbl-b-dependent coordinated degradation of the epidermal growth factor receptor signaling complex
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DOI：
10.1074/jbc.m102641200
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发表时间：
2001-07-20
影响因子：
4.8
通讯作者：
Lipkowitz, S
中科院分区：
文献类型：
--
作者：
Ettenberg, SA;Magnifico, A;Lipkowitz, S
Cbl蛋白作为活化的表皮生长因子受体的泛素蛋白连接酶起作用，因此负调节其活性。在这里，我们表明，Cbl-b是泛素化和降解后激活的受体。表皮生长因子（EGF）诱导的Cbl-b降解需要完整的RING指和酪氨酸激酶结合结构域，并且需要Cbl-b蛋白与活化的EGF受体（EGFR）结合。EGFR和Cbl-b蛋白的降解都被溶酶体和蛋白酶体抑制剂阻断。EGFR信号传导复合物的其他组分（即Grb 2和Shc）也以EGF诱导的Cbl-b依赖性方式降解。我们的研究结果表明，Cbl-b的泛素蛋白连接酶的功能是由协调降解的Cbl-b蛋白沿着其底物。此外，数据表明，Cbl-b介导EGFR-信号传导复合物中多种蛋白质的降解。
Cbl proteins function as ubiquitin protein ligases for the activated epidermal growth factor receptor and, thus, negatively regulate its activity. Here we show that Cbl-b is ubiquitinated and degraded upon activation of the receptor. Epidermal growth factor (EGF)-induced Cbl-b degradation requires intact RING finger and tyrosine kinase binding domains and requires binding of the Cbl-b protein to the activated EGF receptor (EGFR), Degradation of both the EGFR and the Cbl-b protein is blocked by lysosomal and proteasomal inhibitors, Other components of the EGFR-signaling complex (i.e. Grb2 and Shc) are also degraded in an EGF-induced Cbl-b-dependent fashion. Our results suggest that the ubiquitin protein ligase function of Cbl-b is regulated by coordinated degradation of the Cbl-b protein along with its substrate. Furthermore, the data demonstrate that Cbl-b mediates degradation of multiple proteins in the EGFR-signaling complex.