Identification of Candidate Angiogenic Inhibitors Processed by MMP-2 in Cell Based Proteomic Screens: Disruption of VEGF/HARP (Pleiotrophin) and VEGF / CTGF Angiogenic Inhibitory Complexes by MMP-2 Proteolysis. - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Molecular and Cellular Biology Année : 2007

Identification of Candidate Angiogenic Inhibitors Processed by MMP-2 in Cell Based Proteomic Screens: Disruption of VEGF/HARP (Pleiotrophin) and VEGF / CTGF Angiogenic Inhibitory Complexes by MMP-2 Proteolysis.

Résumé

Matrix metalloproteinases (MMPs) exert both pro- and anti-angiogenic functions by the release of cytokines or proteolytically-generated angiogenic inhibitors from extracellular matrix and basement membrane remodeling. In the Mmp2 -/- mouse neovascularization is greatly reduced, but the mechanistic aspects of this remain unclear. Using isotope coded affinity tag labeling of proteins analyzed by multi-dimensional liquid chromatography and tandem mass spectrometry we explored proteome differences of Mmp2 -/- cells with those rescued by MMP-2 transfection. Proteome signatures that are hallmarks of proteolysis revealed cleavage of many known MMP-2 substrates in the cellular context. Proteomic evidence of MMP-2 processing of novel substrates was found. Insulin-like growth factor binding protein-6, follistatin-like 1 and cystatin C protein cleavage by MMP-2 were biochemically confirmed and the cleavage sites in heparin affin regulatory peptide (HARP/pleiotrophin) and connective tissue growth factor (CTGF) were sequenced by MALDI-TOF mass spectrometry. MMP-2 processing of HARP and CTGF released vascular endothelial growth factor (VEGF) from angiogenic inhibitory complexes. The cleaved HARP N-terminal domain increased HARP-induced cell proliferation, whereas the HARP C-terminal domain was antagonistic and decreased cell proliferation and migration. Hence the unmasking of cytokines, such as VEGF, by metalloproteinase processing of their binding proteins is a new mechanism in the control of cytokine activation and angiogenesis.

Dates et versions

hal-00187899 , version 1 (15-11-2007)

Identifiants

Citer

Richard A Dean, Georgina S Butler, Yamina Hamma-Kourbali, Jean Delbé, David R Brigstock, et al.. Identification of Candidate Angiogenic Inhibitors Processed by MMP-2 in Cell Based Proteomic Screens: Disruption of VEGF/HARP (Pleiotrophin) and VEGF / CTGF Angiogenic Inhibitory Complexes by MMP-2 Proteolysis.. Molecular and Cellular Biology, 2007, epub ahead of print. ⟨10.1128/MCB.00821-07⟩. ⟨hal-00187899⟩

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