Identification of candidate angiogenic inhibitors processed by matrix metalloproteinase 2 (MMP-2) in cell-based proteomic screens: disruption of vascular endothelial growth factor (VEGF)/heparin affin regulatory peptide (pleiotrophin) and VEGF/Connective tissue growth factor angiogenic inhibitory co

Content Provider	Semantic Scholar
Author	Dean, Richard A. Butler, Georgina S. Hamma-Kourbali, Yamina Delbé, Jean Brigstock, David R. Courty, J. M. Overall, Christopher M.
Copyright Year	2007
Abstract	Matrix metalloproteinases (MMPs) exert both pro- and antiangiogenic 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 multidimensional liquid chromatography and tandem mass spectrometry we explored proteome differences between Mmp2-/- cells and 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 was biochemically confirmed, and the cleavage sites in heparin affin regulatory peptide (HARP; pleiotrophin) and connective tissue growth factor (CTGF) were sequenced by matrix-assisted laser desorption ionization-time of flight 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.
Starting Page	A20
Ending Page	A20
Page Count	1
File Format	PDF HTM / HTML
Alternate Webpage(s)	http://mcb.asm.org/content/27/24/8454.full.pdf
PubMed reference number	17908800v1
Volume Number	27
Issue Number	24
Journal	Molecular and cellular biology
Language	English
Access Restriction	Open
Subject Keyword	Angiogenesis Inhibition Angiogenesis Inhibitors Angiogenic Process Basement membrane CTGF gene Cell Proliferation Cleaved cell Cystatins Cytokine Signaling Process Endothelial Growth Factors Extracellular Matrix FST gene Insulin Isotopes Liquid Chromatography MMP2 gene Matrix Metalloproteinases Metalloproteases Pathologic Neovascularization Proteolysis Proteome Recombinant Pleiotrophin Sarcoma Tandem Mass Spectrometry VEGF protein, human connective tissue growth factor heparin
Content Type	Text
Resource Type	Article