LRIG1 restricts growth factor signaling by enhancing receptor ubiquitylation and degradation.
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.
Gur
Gal
G
Department of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel.
Rubin
Chanan
C
Katz
Menachem
M
Amit
Ido
I
Citri
Ami
A
Nilsson
Jonas
J
Amariglio
Ninette
N
Henriksson
Roger
R
Rechavi
Gideon
G
Hedman
Håkan
H
Wides
Ron
R
Yarden
Yosef
Y
D001665:Binding Sites; D002460:Cell Line; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000378:metabolism*; D019143:Evolution, Molecular; D006801:Humans; D008024:Ligands; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D018739:Oncogene Proteins v-erbB / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013379:Substrate Specificity; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
C484445:LRIG1 protein, human; D008024:Ligands; D008562:Membrane Glycoproteins; D018739:Oncogene Proteins v-erbB; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D025801:Ubiquitin; D019000:Phosphotyrosine; D004815:Epidermal Growth Factor; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D066246:ErbB Receptors; D046988:Proteasome Endopeptidase Complex