| First Author | Qi JH | Year | 2009 |
| Journal | J Biol Chem | Volume | 284 |
| Issue | 30 | Pages | 19927-36 |
| PubMed ID | 19478078 | Mgi Jnum | J:152625 |
| Mgi Id | MGI:4359328 | Doi | 10.1074/jbc.M109.013763 |
| Citation | Qi JH, et al. (2009) S156C mutation in tissue inhibitor of metalloproteinases-3 induces increased angiogenesis. J Biol Chem 284(30):19927-36 |
| abstractText | 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. |
