c-Cbl/Sli-1 regulates endocytic sorting and ubiquitination of the epidermal growth factor receptor
c-Cbl/Sli-1 regulates endocytic sorting and ubiquitination of the epidermal growth factor receptor
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DOI：
10.1101/gad.12.23.3663
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发表时间：
1998-12-01
影响因子：
10.5
通讯作者：
Yarden, Y
中科院分区：
文献类型：
--
作者：
Levkowitz, G;Waterman, H;Yarden, Y
配体诱导的两种生长因子受体ErbB-1和ErbB-3的下调与c-Cbl的不同招募能力有关，c-Cbl的无脊椎动物同源物是ErbB的负调控因子。我们报道，配体诱导的内化ErbB-1的降解，而不是ErbB-3，是通过瞬时将一小部分c-Cb1动员到含有ErbB-1的内吞体内而介导的。这种募集依赖于受体的酪氨酸激酶活性和完整的羧基末端区域。另一种命运是将内化的ERBbs循环到细胞表面。CBL介导的受体分选涉及泛素分子的共价连接，以及随后的溶酶体和蛋白酶体降解。致癌病毒形式的Cbl通过将内吞的受体分流到循环途径来抑制下调。这些结果揭示了一种内体分选机制，能够控制生长因子受体的命运，从而控制信号的效力。
Ligand-induced down-regulation of two growth factor receptors, EGF receptor (ErbB-1) and ErbB-3, correlates with differential ability to recruit c-Cbl, whose invertebrate orthologs are negative regulators of ErbB. We report that ligand-induced degradation of internalized ErbB-1, but not ErbB-3, is mediated by transient mobilization of a minor fraction of c-Cbl into ErbB-1-containing endosomes. This recruitment depends on the receptor's tyrosine kinase activity and an intact carboxy-terminal region. The alternative fate is recycling of internalized ErbBs to the cell surface. Cbl-mediated receptor sorting involves covalent attachment of ubiquitin molecules, and subsequent lysosomal and proteasomal degradation. The oncogenic viral form of Cbl inhibits down-regulation by shunting endocytosed receptors to the recycling pathway. These results reveal an endosomal sorting machinery capable of controlling the fate, and, hence, signaling potency, of growth factor receptors.