Role for furin in tumor necrosis factor alpha-induced activation of the matrix metalloproteinase/sphingolipid mitogenic pathway.

Abstract

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 (alpha1-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.

• Authors: Edwige Tellier, Anne Nègre-Salvayre, Beatrice Bocquet, Shigeyoshi Itohara, Yusuf A Hannun, Robert Salvayre, Nathalie Augé
• Journal: Molecular and cellular biology (Mol Cell Biol) Vol. 27 Issue 8 Pg. 2997-3007 (Apr 2007) ISSN: 0270-7306 [Print] United States
• PMID: 17283058 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Ceramides
• Lysophospholipids
• Mitogens
• Sphingolipids
• Sphingomyelins
• Tumor Necrosis Factor-alpha
• Brefeldin A
• sphingosine 1-phosphate
• Monensin
• SMPD3 protein, human
• Sphingomyelin Phosphodiesterase
• Furin
• Matrix Metalloproteinase 2
• Matrix Metalloproteinase 14
• Sphingosine

Topics

• Animals
• Brefeldin A (pharmacology)
• Cell Proliferation (drug effects)
• Ceramides (metabolism)
• Enzyme Activation (drug effects)
• Fibroblasts (cytology, drug effects, enzymology)
• Furin (metabolism)
• Humans
• Lysophospholipids (metabolism)
• Matrix Metalloproteinase 14 (metabolism)
• Matrix Metalloproteinase 2 (metabolism)
• Mice
• Mitogens (metabolism)
• Models, Biological
• Monensin (pharmacology)
• Myocytes, Smooth Muscle (drug effects, enzymology)
• Rabbits
• Signal Transduction (drug effects)
• Sphingolipids (metabolism)
• Sphingomyelin Phosphodiesterase (metabolism)
• Sphingomyelins (metabolism)
• Sphingosine (analogs & derivatives, metabolism)
• Tumor Necrosis Factor-alpha (pharmacology)
• trans-Golgi Network (drug effects)