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Molecular and Cellular Biology, December 2007, p. 8454-8465, Vol. 27, No. 24
0270-7306/07/$08.00+0     doi:10.1128/MCB.00821-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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 Complexes by MMP-2 Proteolysis{triangledown} ,{dagger}

Richard A. Dean,1 Georgina S. Butler,1 Yamina Hamma-Kourbali,2 Jean Delbé,2 David R. Brigstock,3 José Courty,2 and Christopher M. Overall1*

University of British Columbia, Centre for Blood Research, 4.401 Life Sciences Institute, 2350 Health Sciences Mall, Vancouver, British Columbia, Canada V6T 1Z3,1 Laboratoire de recherche sur la Croissance Cellulaire, la Réparation et la Régénération Tissulaires, CNRS UMR 7149, Université Paris XII, Avenue du Général de Gaulle, 94010 Crétail Cedex, France,2 Children's Research Institute, Room WA2022, 700 Children's Drive, Columbus, Ohio 432053

Received 9 May 2007/ Returned for modification 28 May 2007/ Accepted 5 September 2007

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.

* Corresponding author. Mailing address: University of British Columbia, Centre for Blood Research, 4.401 Life Sciences Institute, 2350 Health Sciences Mall, Vancouver, British Columbia, Canada V6T 1Z3. Phone: (604) 822-2958. Fax: (604) 822-7742. E-mail: chris.overall{at}ubc.ca

{triangledown} Published ahead of print on 1 October 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, December 2007, p. 8454-8465, Vol. 27, No. 24
0270-7306/07/$08.00+0     doi:10.1128/MCB.00821-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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