EGF‐R regulates MMP function in fibroblasts through MAPK and AP‐1 pathways

R Kajanne, P Miettinen, A Mehlem… - Journal of cellular …, 2007 - Wiley Online Library
R Kajanne, P Miettinen, A Mehlem, SK Leivonen, M Birrer, M Foschi, VM Kähäri, S Leppä
Journal of cellular physiology, 2007Wiley Online Library
EGF‐R regulates cell proliferation, migration, and invasion in fibroblasts. However, the
connection of EGF‐R with downstream signaling pathways mediating these responses has
remained elusive. Here we provide genetic and biochemical evidence that EGF‐R‐and AP‐
1‐mediated signals are required for MMP expression and collagen contraction in fibroblasts.
In EGF‐R (−/−) mouse embryonal fibroblasts, basal and inducible expression of several
MMPs, including MMP‐2,‐3, and‐14 is impaired in comparison to wild‐type counterparts …
Abstract
EGF‐R regulates cell proliferation, migration, and invasion in fibroblasts. However, the connection of EGF‐R with downstream signaling pathways mediating these responses has remained elusive. Here we provide genetic and biochemical evidence that EGF‐R‐ and AP‐1‐mediated signals are required for MMP expression and collagen contraction in fibroblasts. In EGF‐R (−/−) mouse embryonal fibroblasts, basal and inducible expression of several MMPs, including MMP‐2, ‐3, and ‐14 is impaired in comparison to wild‐type counterparts. The loss of MMP expression is associated with a suppression of EGF‐induced Erk and Jnk activities, and AP‐1 DNA‐binding and transactivation capacities. While inhibition of Jnk mainly prevents EGF‐induced phosphorylation of c‐Jun, inhibition of Erk pathway suppresses both the expression and phosphorylation of c‐Jun and c‐Fos proteins. Moreover, the expression of MMP‐3 and ‐14, and collagen contraction is partially prevented by Mek/Erk and Jnk inhibitors. However, Jnk inhibitor also suppresses cell growth independently of EGF‐R activity. The central role of AP‐1 as a mediator of EGF‐R signaling in fibroblasts is emphasized by the finding that expression of a dominant negative c‐Jun downregulates the expression of MMP‐3. Conversely, expression of a constitutively active Mek1 can induce MMP‐3 expression independently of upstream signals. The results indicate that ERK pathway and AP‐1 are downstream effectors of the EGF‐R‐mediated MMP‐3 expression and collagen contraction in fibroblasts. J. Cell. Physiol. 212: 489–497, 2007. © 2007 Wiley‐Liss, Inc.
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