Biochemical and Biophysical Research Communications
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
Section snippets
Materials and methods
Materials. IGF-1 was from PreproTech and PDGF-BB was purchased from BioScource. Wortmannin and PD98059 were from Calbiochem. The furin-like proprotein convertase inhibitor decanoyl-RVKR-chloromethylketone (dec-CMK) was from Bachem and the broad spectrum hydroxamate class MMP-inhibitor GM6001 (Ilomastat) was from Chemicon. All other chemicals were from Sigma. Cell culture media and materials were from Gibco. The monoclonal antibody directed against the hemopexin-like domain of MT1-MMP (clone
Furin-like proprotein convertases activate the IGF-1R in VSMCs
The presence of furin (Fig. 1A) and PC5 (Fig. 1B) mRNAs and protein levels (Fig. 1C) in VSMC cultures was confirmed by PCR and immunoblotting. To investigate the requirement of furin-like PCs for IGF-1R activation, VSMCs were rendered quiescent by serum-starvation and treated with the furin-like PC-inhibitor dec-CMK (50 μM), followed by incubation of cells in 10% FCS (24 h) in the presence of the inhibitor. In controls, the anti-IGF-1R antibody directed against the C-terminus detected almost
Discussion
The present study demonstrates that IGF-1 induces MT1-MMP/MMP-2 expression and activity in VSMCs via IGF-1R-mediated PI3-kinase signaling. Furthermore, we found that furin-like PCs control IGF-induced MT1-MMP in VSMCs through endoproteolytic activation of the pro-IGF-1R.
MMPs are major contributors to tissue remodeling in arteriosclerosis [10]. MT1-MMP plays a unique role, because in addition to its ability to cleave a number of ECM proteins within the vessel wall [10], membrane-anchored,
Acknowledgments
This work was supported by a grant from the Bundesministerium für Bildung und Forschung (BMBF) (CAN02/005) to P.S., E.F., and K.G. C.M. was supported by the Deutscher Akademischer Austauschdienst (DAAD). M.C. and N.G.S. were supported by Canadian Institutes of Health Research (CIHR) Grants MOP-44362 and MGP-44363, respectively.
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