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

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.

SPRY1 regulates mammary epithelial morphogenesis by modulating EGFR-dependent stromal paracrine signaling and ECM remodeling

“…Refer to Table S1 for stromal fibroblasts provide an essential component of the microenvironment for epithelial morphogenesis by promoting EGFR-dependent ECM remodeling via regulation of MMPs and other ECM remodeling enzymes including Lox genes. Our data showing up-regulation of Mmp2, Mmp11, Mmp14, Lox, and Lox3 are consistent with a previous report on regulation of Mmp expression and collagen contraction by EGFR-ERK signaling in mouse embryonic fibroblasts (48). Importantly, several Mmps, including Mmp2, Mmp3, and Mmp14, have been shown to regulate mammary epithelial branching in vivo (49,50).…”

Cordycepin inhibits TPA-induced matrix metalloproteinase-9 expression by suppressing the MAPK/AP-1 pathway in MCF-7 human breast cancer cells

“…MMP-9 activation has been shown to be especially associated with tumor progression and invasion, including mammary tumors (26). In previous reports, inflammatory cytokines, growth factors, or phorbol esters were shown to stimulate MMP-9 by activating different intracellular-signaling pathways in breast cancer cells (27)(28)(29). The inhibitory effect of MMP-9 expression is important for the development of a therapeutic experimental model of tumor metastasis.…”

Neprilysin Null Mice Develop Exaggerated Pulmonary Vascular Remodeling in Response to Chronic Hypoxia

“…In vitro, we however have found that, when NEP is genetically eliminated, PA SMCs exhibit greater expression of select proliferation-associated biomarkers (PCNA, pERK, c-fos, and c-jun). 59,60 This suggests that NEP depletion promotes a proliferative milieu. In addition, it was found that PA SMCs from NEP Ϫ/Ϫ mice grow much faster than do PA SMCs from NEP ϩ/ϩ mice, which corroborates our observation of enhanced expression of proliferation-associated biomarkers in these cells.…”