TIMP-2 mediated inhibition of angiogenesis: an MMP-independent mechanism |
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Authors: | Seo Dong-Wan Li Hongmei Guedez Liliana Wingfield Paul T Diaz Tere Salloum Rita Wei Bei-yang Stetler-Stevenson William G |
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Affiliation: | National Cancer Institute, Center for Cancer Research, Vascular Biology Faculty and Laboratory of Pathology, Extracellular Matrix Pathology Section, National Institutes of Health, Bethesda, MD 20892, USA. |
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Abstract: | Tissue inhibitors of metalloproteinases (TIMPs) suppress matrix metalloproteinase (MMP) activity critical for extracellular matrix turnover associated with both physiologic and pathologic tissue remodeling. We demonstrate here that TIMP-2 abrogates angiogenic factor-induced endothelial cell proliferation in vitro and angiogenesis in vivo independent of MMP inhibition. These effects require alpha 3 beta 1 integrin-mediated binding of TIMP-2 to endothelial cells. Further, TIMP-2 induces a decrease in total protein tyrosine phosphatase (PTP) activity associated with beta1 integrin subunits as well as dissociation of the phosphatase SHP-1 from beta1. TIMP-2 treatment also results in a concomitant increase in PTP activity associated with tyrosine kinase receptors FGFR-1 and KDR. Our findings establish an unexpected, MMP-independent mechanism for TIMP-2 inhibition of endothelial cell proliferation in vitro and reveal an important component of the antiangiogenic effect of TIMP2 in vivo. |
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