Proprotein convertases regulate insulin-like growth factor 1-induced membrane-type 1 matrix metalloproteinase in VSMCs via endoproteolytic activation of the insulin-like growth factor-1 receptor

• Published in: Biochemical and biophysical research communications Vol. 321; no. 3; pp. 531 - 538
• Main Authors: Stawowy, Philipp, Kallisch, Heike, Kilimnik, Adam, Margeta, Christian, Seidah, Nabil G., Chrétien, Michel, Fleck, Eckart, Graf, Kristof
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27.08.2004
• Subjects: Animals; Cell Division; Cell Movement; Cells, Cultured; Enzyme Activation; Enzyme Inhibitors - pharmacology; Furin; Furin - metabolism; Insulin-like growth factor; Insulin-Like Growth Factor I - metabolism; Insulin-like growth factor receptor; Matrix Metalloproteinase 2 - metabolism; Matrix metalloproteinases; Matrix Metalloproteinases, Membrane-Associated; Metalloendopeptidases - metabolism; Mitogen-Activated Protein Kinases - metabolism; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - metabolism; Myocytes, Smooth Muscle - cytology; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - metabolism; Phosphatidylinositol 3-Kinases - metabolism; Platelet-Derived Growth Factor - metabolism; Proprotein Convertase 5 - metabolism; Proprotein convertases; Protein Precursors - metabolism; Proto-Oncogene Proteins c-sis; Rats; Rats, Sprague-Dawley; Receptor, IGF Type 1 - metabolism; Signal Transduction; Vascular smooth muscle cells; Insulin-like growth factor receptor; Proprotein convertases; Furin; Matrix metalloproteinases; Insulin-like growth factor; Vascular smooth muscle cells
• DOI: 10.1016/j.bbrc.2004.07.001
• ISSN: 0006-291X

The IGF-1 receptor (IGF-1R) and MT1-MMP are synthesized as larger precursor proproteins, which require endoproteolytic activation by the proprotein convertases (PCs) furin/PC5 to gain full biological activity. The aim of this study was to investigate the contribution of PCs to IGF-1R and/or MT1-MMP activation in vascular smooth muscle cells (VSMCs) as well as VSMC proliferation/migration, which are key elements in vascular remodeling. Furin and PC5 mRNAs and proteins were found in VSMCs. Inhibition of furin-like PCs with the specific pharmacological inhibitor dec-CMK inhibited IGF-1R endoproteolytic activation. Inhibition of IGF-1R maturation abrogated IGF-induced IGF-1R autophosphorylation, PI3-kinase and MAPK induction, as well as VSMC proliferation ( p < 0.05 vs. controls), whereas it had no effect of PDGF-stimulated signaling pathways or cell growth. Both, IGF-1 and PDGF-BB, induced MT1-MMP expression, but only IGF-1-mediated MT1-MMP induction was inhibited by dec-CMK. Induction of MMP-2 by IGF-1 was inhibited by the PI3-kinase inhibitor wortmannin, but not by the MEK-inhibitor PD98059. Dec-CMK inhibited VSMC chemotaxis comparable to the effects of the MMP-inhibitor GM6001 (both p < 0.05 vs. controls), supporting that MMPs are involved. In conclusion, this study demonstrates that targeting furin-like PCs and thus inhibiting IGF-1R activation is a novel target to inhibit IGF-1-mediated signaling and cell functions, such as IGF-1-induced MT1-MMP/MMP-2 in VSMCs.