Open AccessIL-1beta Signals through the EGF Receptor and Activates Egr-1 through MMP-ADAM
Author(s) -
Estella Sanchez-Guerrero,
Elya Chen,
Maaike Kockx,
Si-Wei An,
Beng H. Chong,
Levon M. Khachigian
Publication year - 2012
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0039811
Subject(s) - gene knockdown , epidermal growth factor receptor , cancer research , matrix metalloproteinase , microbiology and biotechnology , signal transduction , biology , tyrosine kinase , epidermal growth factor , metalloproteinase , receptor , chemistry , gene , biochemistry
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 d isintegrin a nd a m etalloproteinase (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.