IL-1beta signals through the EGF receptor and activates Egr-1 through MMP-ADAM.
The immediate-early gene Egr-1 controls the inducible expression of many genes implicated in the pathogenesis of a range of vascular disorders, yet our understanding of the mechanisms controlling the rapid expression of this prototypic zinc finger transcription factor is poor. Here we show that Egr-1 expression induced by IL-1beta is dependent on metalloproteinases (MMP) and a disintegrin and a metalloproteinase (ADAM). Pharmacologic MMP/ADAM inhibitors and siRNA knockdown prevent IL-1beta induction of Egr-1. Further, IL-1beta activates Egr-1 via the epidermal growth factor receptor (EGFR). This is blocked by EGFR tyrosine kinase inhibition and EGFR knockdown. IL-1beta induction of Egr-1 expression is reduced in murine embryonic fibroblasts (mEFs) deficient in ADAM17 despite unbiased expression of EGFR and IL-1RI in ADAM17-deficient and wild-type mEFs. Finally, we show that IL-1beta-inducible wound repair after mechanical injury requires both EGFR and MMP/ADAM. This study reports for the first time that Egr-1 induction by IL-1beta involves EGFR and MMP/ADAM-dependent EGFR phosphorylation.
Centre for Vascular Research, University of New South Wales, Sydney, Australia.
Estella
E
Sanchez-Guerrero
Elya
E
Chen
Maaike
M
Kockx
Si-Wei
SW
An
Beng H
BH
Chong
Levon M
LM
Khachigian
D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D004151:Dipeptides / Q000494:pharmacology; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism* / Q000494:pharmacology; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D020032:Tyrphostins / Q000494:pharmacology
D004151:Dipeptides; D051766:Early Growth Response Protein 1; D053583:Interleukin-1beta; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D011799:Quinazolines; D020032:Tyrphostins; C101044:RTKI cpd; D066246:ErbB Receptors; D051722:ADAM Proteins; D020782:Matrix Metalloproteinases