Plasmin activates the lymphangiogenic growth factors VEGF-C and VEGF-D.
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.
McColl
Bradley K
BK
Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Melbourne, Victoria 3050, Australia. Marc.achen@ludwig.edu.au
Baldwin
Megan E
ME
Roufail
Sally
S
Freeman
Craig
C
Moritz
Robert L
RL
Simpson
Richard J
RJ
Alitalo
Kari
K
Stacker
Steven A
SA
Achen
Marc G
MG
D000818:Animals; D016228:Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism*; D005341:Fibrinolysin / Q000378:metabolism*; D006801:Humans; D008208:Lymphatic System / Q000502:physiology*; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D042582:Vascular Endothelial Growth Factor C; D042643:Vascular Endothelial Growth Factor D; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism
D016228:Endothelial Growth Factors; D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins; D042582:Vascular Endothelial Growth Factor C; D042643:Vascular Endothelial Growth Factor D; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3; D005341:Fibrinolysin