Structural Basis for the Functions of Endogenous Angiogenesis Inhibitors

  1. M.A. GRANT and
  2. R. KALLUR*,
  1. *Center for Matrix Biology and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115
  2. Division of Molecular and Vascular Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215
  3. Department of Biological Chemistry and Molecular Pharmacology and Harvard–MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, Massachusetts 02115

Abstract

Tipping the angiogenic balance between pro- and antiangiogenic stimuli to favor vasculature induction and enhanced angiogenesisis a key event in the growth and progression of tumors. Recently, we demonstrated that the genetic loss of normalphysiological levels of individual endogenous inhibitors of angiogenesis leads to a change in the balance between proangiogenicstimulators and their inhibitors, thus favoring enhanced angiogensis and increased tumor growth. Therefore, these endogenousangiogenesis inhibitors provide a physiological threshold against the induction of angiogenesis. The antiangiogenicactivities of endostatin, tumstatin, and thrombospondin-1 are evaluated and correlated with their three-dimensional structureand active sites, deriving a structural basis for their activities. Collectively, structural analysis of all three inhibitors demonstratesthat the active antiangiogenic sites on these molecules are exposed on the surface and available to bind their putativeintegrin receptors on proliferating endothelial cells.

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