Plasmin Activates the Lymphangiogenic Growth Factors VEGF-C and VEGF-D

Author:

McColl Bradley K.1,Baldwin Megan E.1,Roufail Sally1,Freeman Craig2,Moritz Robert L.3,Simpson Richard J.3,Alitalo Kari4,Stacker Steven A.1,Achen Marc G.1

Affiliation:

1. Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Melbourne, Victoria 3050, Australia

2. Cancer and Vascular Biology Group, Division of Immunology and Genetics, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT 2061, Australia

3. Joint Proteomics Laboratory, Ludwig Institute for Cancer Research and the Walter and Eliza Hall Institute of Medical Research, Victoria 3050, Australia

4. Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Biomedicum Helsinki, FIN-00014, University of Helsinki, Helsinki, Finland

Abstract

Vascular endothelial growth factor (VEGF) C and VEGF-D stimulate lymphangiogenesis and angiogenesis in tissues and tumors by activating the endothelial cell surface receptor tyrosine kinases VEGF receptor (VEGFR) 2 and VEGFR-3. These growth factors are secreted as full-length inactive forms consisting of NH2- and COOH-terminal propeptides and a central VEGF homology domain (VHD) containing receptor binding sites. Proteolytic cleavage removes the propeptides to generate mature forms, consisting of dimers of the VEGF homology domain, that bind receptors with much greater affinity than the full-length forms. Therefore, proteolytic processing activates VEGF-C and VEGF-D, although the proteases involved were unknown. Here, we report that the serine protease plasmin cleaved both propeptides from the VEGF homology domain of human VEGF-D and thereby generated a mature form exhibiting greatly enhanced binding and cross-linking of VEGFR-2 and VEGFR-3 in comparison to full-length material. Plasmin also activated VEGF-C. As lymphangiogenic growth factors promote the metastatic spread of cancer via the lymphatics, the proteolytic activation of these molecules represents a potential target for antimetastatic agents. Identification of an enzyme that activates the lymphangiogenic growth factors will facilitate development of inhibitors of metastasis.

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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