MCB Accepts, published online ahead of print on 5 February 2007
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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

Edwige Tellier, Anne Nègre-Salvayre, Beatrice Bocquet, Shigeyoshi Itohara, Yusuf A. Hannun, Robert Salvayre*, and Nathalie Augé*

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.


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Abstract

Neutral sphingomyelinase (nSMase), the initial enzyme of the sphingolipid signaling pathway, is thought to play a key role in cellular responses to TNF{alpha}, such as inflammation, proliferation and apoptosis. The mechanism of TNF{alpha}-induced nSMase activation is only partly understood. Using biochemical, molecular and pharmacological approaches, we find that nSMase activation triggered by TNF{alpha} is required for TNF{alpha}-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 ({alpha}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{alpha}-induced sphingolipid signaling, and they identify this system as a possible target to inhibit SMC proliferation in vascular diseases.




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