Levkowitz G, Waterman H, Zamir E, Kam Z, Oved S, Langdon W Y, Beguinot L, Geiger B, Yarden Y
Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
Genes Dev. 1998 Dec 1;12(23):3663-74. doi: 10.1101/gad.12.23.3663.
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.
配体诱导的两种生长因子受体——表皮生长因子受体（ErbB-1）和ErbB-3的下调，与募集c-Cbl的不同能力相关，其无脊椎动物直系同源物是ErbB的负调节因子。我们报告称，配体诱导的内化ErbB-1而非ErbB-3的降解，是由一小部分c-Cbl短暂转运至含ErbB-1的内体介导的。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。另一种命运是内化的ErbBs循环至细胞表面。Cbl介导的受体内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。致癌性病毒形式的Cbl通过将内吞的受体分流至循环途径来抑制下调。这些结果揭示了一种能够控制生长因子受体命运及信号传导能力的内体分选机制。
