LRIG1 restricts growth factor signaling by enhancing receptor ubiquitylation and degradation

Gal Gur, Chanan Rubin, Menachem Katz, Ido Amit, Ami Citri, Jonas Nilsson, Ninette Amariglio, Roger Henriksson, Gideon Rechavi, Håkan Hedman, Ron Wides, Yosef Yarden*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

245 Scopus citations


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.

Original languageEnglish
Pages (from-to)3270-3281
Number of pages12
JournalEMBO Journal
Issue number16
StatePublished - 18 Aug 2004


FundersFunder number
National Cancer InstituteR01CA072981
National Cancer Institute


    • Cancer
    • Growth factor
    • Signal transduction
    • Tyrosine kinase
    • Ubiquitin ligase


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