This Article Full Text (PDF) Other Versions of this Article: MCB.01485-06v1 27/8/2997    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Tellier, E. Articles by Augé, N. Search for Related Content PubMed PubMed Citation Articles by Tellier, E. Articles by Augé, N.

 Previous Article  |  Next Article 

Mol. Cell. Biol. doi:10.1128/MCB.01485-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

A role for furin in TNFalpha-induced activation of the MMP/sphingolipid mitogenic pathway

INSERM UMR-466, Dept of Biochemistry, IFR-31, CHU Rangueil, Toulouse, France; RIKEN Brain Research Institute, Wako-Shi, Saitama 351-0198, Japan; Medical University South Carolina, Dept of Biochemistry and Molecular Biology, Charleston, SC, 29425, USA

^* To whom correspondence should be addressed. Email: salvayre{at}rangueil.inserm.fr. augenath{at}rangueil.inserm.fr.

	Abstract

Neutral sphingomyelinase (nSMase), the initial enzyme of the sphingolipid signaling pathway, is thought to play a key role in cellular responses to TNF, such as inflammation, proliferation and apoptosis. The mechanism of TNF-induced nSMase activation is only partly understood. Using biochemical, molecular and pharmacological approaches, we find that nSMase activation triggered by TNF is required for TNF-induced proliferation and in turn requires a proteolytic cascade involving furin, MT1-MMP and MMP2, and leading finally to ERK1/2 phosphorylation and DNA synthesis, in smooth muscle cells (SMC) and fibroblasts. Pharmacological and molecular inhibitors of MMPs (Batimastat), furin (1-PDX inhibitor-transfected SMC), MT1-MMP (SMC overexpressing a catalytically inactive iMT1-MMP), MMP2 (fibroblasts from MMP2^-/- mice), and siRNA strategies (siRNAs targeting furin, MT1-MMP, MMP2 and nSMase) resulted in near complete inhibition of the activation of nSMase, SK-1, ERK1/2 and of subsequent DNA synthesis. Exogenous MT1-MMP activated nSMase and SMC proliferation in normal but not in MMP2^-/- fibroblasts, whereas exogenous MMP2 was active on both normal and MMP2^-/- fibroblasts.

Altogether these findings highlight a pivotal role for furin, MT1-MMP and MMP2 in TNF-induced sphingolipid signaling, and they identify this system as a possible target to inhibit SMC proliferation in vascular diseases.