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  • The EMBO Journal (2004) 23, 3270 - 3281
  • doi:10.1038/sj.emboj.7600342

Published online: 29 July 2004

LRIG1 restricts growth factor signaling by enhancing receptor ubiquitylation and degradation

Gal Gur1, Chanan Rubin1, Menachem Katz1, Ido Amit1, Ami Citri1, Jonas Nilsson2, Ninette Amariglio3, Roger Henriksson2, Gideon Rechavi3, Håkan Hedman2, Ron Wides4 and Yosef Yarden1

  1. Department of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel
  2. Department of Radiation Sciences, Umeå University, Sweden
  3. Department of Pediatric Hemato-Oncology and Functional Genomics, The Chaim Sheba Medical Center and Sackler School of Medicine, Tel Aviv University, Israel
  4. Department of Life Sciences, Bar-Ilan University, Ramat Gan, Israel

Correspondence to:

Yosef Yarden, Department of Biological Regulation, Candiotty Building (room 302), The Weizmann Institute of Science, 1 Hertzl Street, Rehovot 76100, Israel. Tel.: +972 8 934 3974; Fax: +972 8 934 2488; E-mail: yosef.yarden@weizmann.ac.il

Received 8 March 2004; Accepted 2 July 2004

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.

  • Keywords:

    • cancer,
    • growth factor,
    • signal transduction,
    • tyrosine kinase,
    • ubiquitin ligase