Structural basis for the functions of endogenous angiogenesis inhibitors.
Tipping the angiogenic balance between pro- and antiangiogenic stimuli to favor vasculature induction and enhanced angiogenesis is a key event in the growth and progression of tumors. Recently, we demonstrated that the genetic loss of normal physiological levels of individual endogenous inhibitors of angiogenesis leads to a change in the balance between proangiogenic stimulators and their inhibitors, thus favoring enhanced angiogensis and increased tumor growth. Therefore, these endogenous angiogenesis inhibitors provide a physiological threshold against the induction of angiogenesis. The antiangiogenic activities of endostatin, tumstatin, and thrombospondin-1 are evaluated and correlated with their three-dimensional structure and active sites, deriving a structural basis for their activities. Collectively, structural analysis of all three inhibitors demonstrates that the active antiangiogenic sites on these molecules are exposed on the surface and available to bind their putative integrin receptors on proliferating endothelial cells.
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Center for Matrix Biology and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115, USA.
Kalluri
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D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001324:Autoantigens / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D024141:Collagen Type IV / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D043169:Endostatins / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000098:blood supply; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D019700:Thrombospondin 1 / Q000737:chemistry / Q000235:genetics / Q000502:physiology
D020533:Angiogenesis Inhibitors; D001324:Autoantigens; D024141:Collagen Type IV; D043169:Endostatins; D019700:Thrombospondin 1; C057112:type IV collagen alpha3 chain