Src promotes destruction of c-Cbl: Implications for oncogenic synergy between Src and growth factor receptors
Src promotes destruction of c-Cbl: Implications for oncogenic synergy between Src and growth factor receptors
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DOI：
10.1073/pnas.0437945100
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发表时间：
2003-03-04
影响因子：
11.1
通讯作者：
Yarden, Y
中科院分区：
文献类型：
--
作者：
Bao, J;Gur, G;Yarden, Y
细胞 Src 和表皮生长因子受体 (EGFR) 在某些人类恶性肿瘤的进展中协同作用，它们的共表达是相对侵袭性动物肿瘤的特征。我们的研究探讨了致癌合作的模式，并报告模型细胞系统中 c-Src 的过度表达导致 EGFR 在细胞表面的积累。潜在的机制涉及抑制配体诱导的受体下调的正常 c-Cbl 调节过程。响应 c-Src 的激活，c-Cbl 蛋白发生酪氨酸磷酸化，促进其泛素化和蛋白酶体破坏。因此，在 Src 转化细胞中，c-Cbl 对 EGFR 的泛素化受到抑制，并且受体分选内吞作用受到损害。总之，通过促进 c-Cbl 的破坏，c-Src 使 EGFR 能够逃避脱敏，这解释了 Src-EGFR 在肿瘤发生中的合作。
Cellular Src and epidermal growth factor receptor (EGFR) collaborate in the progression of certain human malignancies, and their cooverexpression characterizes relatively aggressive animal tumors. Our study addressed the mode of oncogenic cooperation and reports that overexpression of c-Src in model cellular systems results in the accumulation of EGFR at the cell surface. The underlying mechanism involves inhibition of the normal, c-Cbl-regulated process of ligand-induced receptor down-regulation. In response to activation of c-Src, c-Cbl proteins undergo tyrosine phosphorylation that promotes their ubiquitylation and proteasomal destruction. Consequently, ubiquitylation of EGFR by c-Cbl is restrained in Src-transformed cells, and receptor sorting to endocytosis is impaired. In conclusion, by promoting destruction of c-Cbl, c-Src enables EGFR to evade desensitization, which explains Src-EGFR collaboration in oncogenesis.