LRIG1 restricts growth factor signaling by enhancing receptor ubiquitylation and degradation

被引:233
作者
Gur, G
Rubin, C
Katz, M
Amit, I
Citri, A
Nilsson, J
Amariglio, N
Henriksson, R
Rechavi, G
Hedman, H
Wides, R
Yarden, Y
机构
[1] Weizmann Inst Sci, Dept Regulat Biol, IL-76100 Rehovot, Israel
[2] Umea Univ, Dept Radiat Sci, S-90187 Umea, Sweden
[3] Chaim Sheba Med Ctr, Dept Pediat Hematooncol & Funct Genom, Tel Aviv, Israel
[4] Sackler Sch Med, Tel Aviv, Israel
[5] Bar Ilan Univ, Dept Life Sci, Ramat Gan, Israel
关键词
cancer; growth factor; signal transduction; tyrosine kinase; ubiquitin ligase;
D O I
10.1038/sj.emboj.7600342
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:3270 / 3281
页数:12
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