TIMP-2 mediated inhibition of angiogenesis: an MMP-independent mechanism.
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.
Seo
Dong-Wan
DW
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.
Li
Hongmei
H
Guedez
Liliana
L
Wingfield
Paul T
PT
Diaz
Tere
T
Salloum
Rita
R
Wei
Bei-yang
BY
Stetler-Stevenson
William G
WG
D020533:Angiogenesis Inhibitors / Q000235:genetics / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000166:cytology; D016228:Endothelial Growth Factors / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D039201:Integrin alpha3beta1 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000187:drug effects / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000494:pharmacology; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor; D011994:Recombinant Proteins / Q000494:pharmacology; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000494:pharmacology*; D014638:Vanadates / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D039201:Integrin alpha3beta1; D047908:Intracellular Signaling Peptides and Proteins; D017468:Receptors, Fibroblast Growth Factor; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D019716:Tissue Inhibitor of Metalloproteinase-2; D014638:Vanadates; C496348:FGFR1 protein, human; C496349:Fgfr1 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D040301:Vascular Endothelial Growth Factor Receptor-2; C509249:PTPN6 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C509248:Ptpn6 protein, mouse; D020782:Matrix Metalloproteinases