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Molecular and Cellular Biology, April 2007, p. 2997-3007, Vol. 27, No. 8
0270-7306/07/$08.00+0     doi:10.1128/MCB.01485-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Role for Furin in Tumor Necrosis Factor Alpha-Induced Activation of the Matrix Metalloproteinase/Sphingolipid Mitogenic Pathway{triangledown}

Edwige Tellier,1 Anne Nègre-Salvayre,1 Beatrice Bocquet,1 Shigeyoshi Itohara,2 Yusuf A. Hannun,3 Robert Salvayre,1 and Nathalie Augé1*

INSERM UMR-466, Department of Biochemistry, IFR-31, CHU Rangueil, Toulouse, France,1 RIKEN Brain Research Institute, Wako-Shi, Saitama 351-0198, Japan,2 Medical University of South Carolina, Department of Biochemistry and Molecular Biology, Charleston, South Carolina 294253

Received 10 August 2006/ Returned for modification 21 November 2006/ Accepted 22 January 2007

Neutral sphingomyelinase (nSMase), the initial enzyme of the sphingolipid signaling pathway, is thought to play a key role in cellular responses to tumor necrosis factor alpha (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 found that nSMase activation triggered by TNF-{alpha} is required for TNF-{alpha}-induced proliferation and in turn requires a proteolytic cascade involving furin, membrane type 1 matrix metalloproteinase (MT1-MMP), and MMP2, and leading finally to extracellular signal-regulated kinase 1/2 (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 MT1-MMP), MMP2 (fibroblasts from MMP2–/– mice), and small interfering RNA (siRNA) strategies (siRNAs targeting furin, MT1-MMP, MMP2, and nSMase) resulted in near-complete inhibition of the activation of nSMase, sphingosine kinase-1, and 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.

* Corresponding author. Mailing address: INSERM U466, Biochimie, IFR-31, CHU Rangueil, 1, Avenue Jean Poulhès, TSA-50032, 31059 Toulouse Cedex 9, France. Phone: (33) 561-32-27-05. Fax: (33) 561-32-20-84. E-mail: augenath{at}rangueil.inserm.fr

{triangledown} Published ahead of print on 5 February 2007.

Molecular and Cellular Biology, April 2007, p. 2997-3007, Vol. 27, No. 8
0270-7306/07/$08.00+0     doi:10.1128/MCB.01485-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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