Specific interaction of angiostatin with integrin alpha(v)beta(3) in endothelial cells.
Angiostatin, the N-terminal four kringles (K1-4) of plasminogen, blocks tumor-mediated angiogenesis and has great therapeutic potential. However, angiostatin's mechanism of anti-angiogenic action is unclear. We found that bovine arterial endothelial (BAE) cells adhere to angiostatin in an integrin-dependent manner and that integrins alpha(v)beta(3), alpha(9)beta(1), and to a lesser extent alpha(4)beta(1), specifically bind to angiostatin. alpha(v)beta(3) is a predominant receptor for angiostatin on BAE cells, since a function-blocking antibody to alpha(v)beta(3) effectively blocks adhesion of BAE cells to angiostatin, but an antibody to alpha(9)beta(1) does not. epsilon-Aminocaproic acid, a Lys analogue, effectively blocks angiostatin binding to BAE cells, indicating that an unoccupied Lys-binding site of the kringles may be required for integrin binding. It is known that other plasminogen fragments containing three or five kringles (K1-3 or K1-5) have an anti-angiogenic effect, but plasminogen itself does not. We found that K1-3 and K1-5 bind to alpha(v)beta(3), but plasminogen does not. These results suggest that the anti-angiogenic action of angiostatin may be mediated via interaction with alpha(v)beta(3). Angiostatin binding to alpha(v)beta(3) does not strongly induce stress-fiber formation, suggesting that angiostatin may prevent angiogenesis by perturbing the alpha(v)beta(3)-mediated signal transduction that may be necessary for angiogenesis.
Tarui
T
T
Department of Vascular Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, USA.
Miles
L A
LA
Takada
Y
Y
D020533:Angiogenesis Inhibitors / Q000378:metabolism*; D043168:Angiostatins; D000818:Animals; D016466:CHO Cells; D002417:Cattle; D006224:Cricetinae; D004730:Endothelium, Vascular / Q000378:metabolism*; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D018082:Kringles; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D010958:Plasminogen / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D019030:Receptors, Vitronectin / Q000378:metabolism*; D012995:Solubility; D022502:Stress Fibers / Q000187:drug effects
D020533:Angiogenesis Inhibitors; D016023:Integrins; D010446:Peptide Fragments; D019030:Receptors, Vitronectin; D043168:Angiostatins; D010958:Plasminogen