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

doi:10.1038/sj.emboj.7600342

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 journal › Article › peer-review

247 Scopus citations

Abstract

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 language	English
Pages (from-to)	3270-3281
Number of pages	12
Journal	EMBO Journal
Volume	23
Issue number	16
DOIs	https://doi.org/10.1038/sj.emboj.7600342
State	Published - 18 Aug 2004
Externally published	Yes

Keywords

Cancer
Growth factor
Signal transduction
Tyrosine kinase
Ubiquitin ligase

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/sj.emboj.7600342

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title = "LRIG1 restricts growth factor signaling by enhancing receptor ubiquitylation and degradation",

abstract = "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.",

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doi = "10.1038/sj.emboj.7600342",

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AU - Gur, Gal

AU - Rubin, Chanan

AU - Katz, Menachem

AU - Amit, Ido

AU - Citri, Ami

AU - Nilsson, Jonas

AU - Amariglio, Ninette

AU - Henriksson, Roger

AU - Rechavi, Gideon

AU - Hedman, Håkan

AU - Wides, Ron

AU - Yarden, Yosef

PY - 2004/8/18

Y1 - 2004/8/18

N2 - 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.

AB - 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.

KW - Cancer

KW - Growth factor

KW - Signal transduction

KW - Tyrosine kinase

KW - Ubiquitin ligase

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LRIG1 restricts growth factor signaling by enhancing receptor ubiquitylation and degradation

Abstract

Keywords

UN SDGs

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