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

被引:429
作者
Seo, DW
Li, HM
Guedez, L
Wingfield, PT
Diaz, T
Salloum, R
Wei, BY
Stetler-Stevenson, WG [1 ]
机构
[1] NCI, Canc Res Ctr, Vasc Biol Fac, Extracellular Matrix Pathol Sect, Bethesda, MD 20892 USA
[2] NCI, Canc Res Ctr, Pathol Lab, Extracellular Matrix Pathol Sect, Bethesda, MD 20892 USA
[3] NIAMSD, Prot Express Lab, Bethesda, MD 20892 USA
关键词
D O I
10.1016/S0092-8674(03)00551-8
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 alpha3beta1 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.
引用
收藏
页码:171 / 180
页数:10
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