TIMP-2 mediated inhibition of angiogenesis: an MMP-independent mechanism

Speaker: 陳宇楓                        

Commentator: 張文粲 老師               

Time: 2003/9/24  14:00-15:00

Place: 601教室

Abstract:

Tissue inhibitor of metalloproteinases-2 (TIMP-2), a protease inhibitor that binds to the active form of type IV collagenase, have been found to inhibit the proliferation of human microvascular endothelial cell (hMVEC) in vitro and exhibit antiangiogenic effect in vivo. The inhibition of hMVEC proliferation was independent of MMP inhibitory activity. The goal of the current study was to explore the mechanism of TIMP-2 mediated inhibition of angiogenesis. It required a₃b₁integrin-mediated binding of TIMP-2 to endothelial cells. The binding effect induced a decrease in total protein tyrosine phosphatase (PTP) activity associated with b₁integrin subunits as well as dissociation of the phosphatase SHP-1 from b₁. Moreover, treatment of TIMP-2 resulted in a concomitant increase in PTP activity associated with tyrosine kinase receptors FGFR-1 and KDR. These findings implicate a direct role for SHP-1 in mediating the suppressive effects of TIMP-2 on hMVEC mitogenic responses. This study may partially explain the failure of these synthetic MMP inhibitors in these clinical trials. TIMP-2 mediated mitogenic suppression of endothelial cell growth suggests possible new strategies for the development of antiangiogenic therapies, in addition to synthetic metalloproteinase inhibitors.

Reference:

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