LRIG1 restricts growth factor signaling by enhancing receptor ubiquitylation and degradation
LRIG1 restricts growth factor signaling by enhancing receptor ubiquitylation and degradation
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DOI：
10.1038/sj.emboj.7600342
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发表时间：
2004-08-18
期刊：
影响因子：
11.4
通讯作者：
Yarden, Y
中科院分区：
文献类型：
--
作者：
Gur, G;Rubin, C;Yarden, Y
在果蝇卵子发生过程中，Kekkon蛋白对表皮生长因子受体（EGFR）起负向调节作用。其在哺乳动物中的结构相关蛋白LRIG1是一种跨膜蛋白，在啮齿动物中该蛋白失活会促进皮肤增生，这表明它参与了对EGFR的调节。我们报道了在表皮生长因子（EGF）刺激下LRIG1的转录本和蛋白质上调，并且所编码的蛋白质与哺乳动物的四种EGFR直系同源物存在物理关联。LRIG1上调之后是EGFR的泛素化增强和降解。其潜在机制涉及c - Cbl的募集，c - Cbl是一种E3泛素连接酶，它同时使EGFR和LRIG1泛素化并将它们分选进行降解。我们得出结论，LRIG1在哺乳动物中是作为受体酪氨酸激酶信号传导的反馈负向衰减器而进化的。
Kekkon proteins negatively regulate the epidermal growth factor receptor ( EGFR) during oogenesis in Drosophila. Their structural relative in mammals, LRIG1, is a transmembrane protein whose inactivation in rodents promotes skin hyperplasia, suggesting involvement in EGFR regulation. We report upregulation of LRIG1 transcript and protein upon EGF stimulation, and physical association of the encoded protein with the four EGFR orthologs of mammals. Upregulation of LRIG1 is followed by enhanced ubiquitylation and degradation of EGFR. The underlying mechanism involves recruitment of c-Cbl, an E3 ubiquitin ligase that simultaneously ubiquitylates EGFR and LRIG1 and sorts them for degradation. We conclude that LRIG1 evolved in mammals as a feedback negative attenuator of signaling by receptor tyrosine kinases.