Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10827202 | Microvascular Research | 2008 | 7 Pages |
Abstract
We have previously reported that tissue inhibitor of metalloproteinases-2 (TIMP-2), an endogenous inhibitor of matrix metalloproteinase, modulates angiogenic responses through the MMP inhibition-independent activity. In this study, we investigate the molecular mechanisms of TIMP-2-mediated growth inhibition in response to fibroblast growth factor-2 (FGF-2). Pre-treatment with a protein tyrosine phosphatase inhibitor orthovanadate or expression of a dominant negative Shp-1 mutant fails to induce TIMP-2 inactivation of FGF-2 signaling pathways in human microvascular endothelial cells. We also show that TIMP-2 inhibition of FGF-2-induced p42/44MAPK activation and cell proliferation is associated with TIMP-2 binding to integrin α3β1 on endothelial cell surfaces, as demonstrated by use of anti-integrin α3 or β1 blocking antibodies, or disruption of integrin α3 expression by siRNA. Collectively, our results indicate that TIMP-2 inhibits FGF-2 signaling pathways through association with integrin α3β1 and Shp-1-dependent inhibition of p42/44MAPK signaling, which in turn, results in suppression of FGF-2-stimulated endothelial cell mitogenesis.
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Authors
Dong-Wan Seo, Soo Hyeon Kim, Seok-Hyun Eom, Hyun Jae Yoon, Young-Rak Cho, Pyeung-Hyeun Kim, Yong Kee Kim, Jeung-Whan Han, Tere Diaz, Bei-yang Wei, William G. Stetler-Stevenson,