cbl-b inhibits EGF-receptor-induced apoptosis by enhancing ubiquitination and degradation of activated receptors.
cbl-b inhibits EGF-receptor-induced apoptosis by enhancing ubiquitination and degradation of activated receptors.
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DOI：
10.1006/mcbr.1999.0157
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发表时间：
1999-08-01
期刊：
影响因子：
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通讯作者：
Lipkowitz, S
中科院分区：
文献类型：
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作者：
Ettenberg, S A;Rubinstein, Y R;Lipkowitz, S
对秀丽隐杆线虫和果蝇的研究表明，cbl 蛋白是表皮生长因子受体 (EGFR) 功能的抑制剂。在这里，我们描述了cbl-b（c-cbl原癌基因的同源物）的过度表达抑制MDA-MB-468乳腺癌细胞中EGFR诱导的细胞凋亡。 cbl-b 的过度表达导致 EGF 刺激后 EGFR 激活的持续时间缩短。磷酸化 EGFR 数量的减少以及多个下游信号传导途径的抑制证明了这一点。 cbl-b 对信号传导的抑制是由于激活的 EGFR 泛素化和降解增加所致。 cbl-b 过表达对细胞凋亡和 EGFR 信号转导的抑制作用可通过阻断 EGFR 的蛋白酶体降解来逆转。这些数据证明cbl-b抑制EGFR诱导的细胞凋亡的机制是通过EGFR的激活依赖性降解。他们暗示这种机制可能是 cbl 蛋白调节细胞内信号传导的通用机制。
Studies in C. elegans and Drosophila melanogaster suggest that cbl proteins are inhibitors of epidermal growth factor receptor (EGFR) function. Here we describe that overexpression of cbl-b, a homologue of the c-cbl protooncogene, inhibits EGFR-induced apoptosis in MDA-MB-468 breast cancer cells. Overexpression of cbl-b results in a shortened duration of EGFR activation upon EGF stimulation. This is demonstrated by decreased amounts of phosphorylated EGFR as well as by inhibition of multiple downstream signaling pathways. The inhibition of signaling by cbl-b results from increased ubiquitination and degradation of the activated EGFR. The inhibitory effects of cbl-b overexpression on apoptosis and on EGFR signaling are reversed by blocking proteosomal degradation of the EGFR. These data demonstrate that the mechanism by which cbl-b inhibits EGFR-induced apoptosis is by activation-dependent degradation of the EGFR. They imply that this mechanism may be a general one whereby cbl proteins regulate intracellular signaling.