S156C mutation in tissue inhibitor of metalloproteinases-3 induces increased angiogenesis. J Biol Chem 2009 Jul 24;284(30):19927-36
Date
05/30/2009Pubmed ID
19478078Pubmed Central ID
PMC2740418DOI
10.1074/jbc.M109.013763Scopus ID
2-s2.0-67749133887 (requires institutional sign-in at Scopus site) 42 CitationsAbstract
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.
Author List
Qi JH, Dai G, Luthert P, Chaurasia S, Hollyfield J, Weber BH, Stöhr H, Anand-Apte BAuthor
Shyam S. Chaurasia PhD Professor in the Ophthalmology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
ActinsAnimals
Aorta
Cell Movement
Cell Proliferation
Cells, Cultured
Endothelial Cells
Eye
Gene Expression
Glycosylation
Humans
Macular Degeneration
Mice
Neovascularization, Pathologic
Point Mutation
Protein Binding
Swine
Tissue Inhibitor of Metalloproteinase-3
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factor Receptor-2
