S156C mutation in tissue inhibitor of metalloproteinases-3 induces increased angiogenesis.
Tissue Inhibitor of metalloproteinases-3 (TIMP-3) is a potent matrix-bound angiogenesis inhibitor. Mutations in TIMP-3 cause Sorsby Fundus Dystrophy, a dominant inherited, early onset macular degenerative disease, with choroidal neovascularization causing a loss of vision in the majority of patients. Here we report that expression of S156C TIMP-3 mutation in endothelial cells results in an abnormal localization of the protein, increased glycosylation, decreased matrix metalloproteinase inhibitory activity, and increased vascular endothelial growth factor (VEGF) binding with a consequent increase in VEGF-dependent migration and tube formation. These enhanced signaling events appear to be mediated as a consequence of a post-transcriptionally regulated increase in the expression of membrane-associated VEGFR-2 in endothelial cells of Timp-3(156/156) mutant mice as well as in human Sorsby fundus dystrophy eyes. Understanding the mechanism(s) by which mutant TIMP-3 can induce abnormal neovascularization provides important insight into the pathophysiology of a number of diseases with increased angiogenesis.
Qi
Jian Hua
JH
Department of Opthalmology, Cole Eye Institute, Cleveland Clinic Lerner College of Medicine at Case Western Reserve University, Cleveland, Ohio 44195, USA.
Dai
Ganying
G
Luthert
Philip
P
Chaurasia
Shyam
S
Hollyfield
Joe
J
Weber
Bernhard H F
BH
Stöhr
Heidi
H
Anand-Apte
Bela
B
D000199:Actins / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000166:cytology; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D005123:Eye / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D006031:Glycosylation; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism; D017354:Point Mutation; D011485:Protein Binding; D013552:Swine; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
D000199:Actins; C088390:TIMP3 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2