A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2.
Tissue inhibitor of metalloproteinases-3 (TIMP3) is one of four members of a family of proteins that were originally classified according to their ability to inhibit matrix metalloproteinases (MMP). TIMP3, which encodes a potent angiogenesis inhibitor, is mutated in Sorsby fundus dystrophy, a macular degenerative disease with submacular choroidal neovascularization. In this study we demonstrate the ability of TIMP3 to inhibit vascular endothelial factor (VEGF)-mediated angiogenesis and identify the potential mechanism by which this occurs: TIMP3 blocks the binding of VEGF to VEGF receptor-2 and inhibits downstream signaling and angiogenesis. This property seems to be independent of its MMP-inhibitory activity, indicating a new function for this molecule.
Qi
Jian Hua
JH
Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA.
Ebrahem
Quteba
Q
Moore
Nina
N
Murphy
Gillian
G
Claesson-Welsh
Lena
L
Bond
Mark
M
Baker
Andrew
A
Anand-Apte
Bela
B
D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D016228:Endothelial Growth Factors / Q000378:metabolism* / Q000494:pharmacology; D004727:Endothelium / Q000166:cytology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism* / Q000494:pharmacology; D008222:Lymphokines / Q000378:metabolism* / Q000494:pharmacology; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D039921:Neuropilins / Q000378:metabolism; D010766:Phosphorylation; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D019717:Tissue Inhibitor of Metalloproteinase-3; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D039921:Neuropilins; D011994:Recombinant Proteins; C088390:TIMP3 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3; D019714:Tissue Inhibitor of Metalloproteinases; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D040262:Receptors, Vascular Endothelial Growth Factor