整合素αvβ3.pdf

Human tumstatin and human endostatin exhibit distinct antiangiogenic activities mediated by v3 and 51 integrins Akulapalli Sudhakar, Hikaru Sugimoto, Changqing Yang, Julie Lively, Michael Zeisberg, and Raghu Kalluri* Program in Matrix Biology, Department of Medicine and Cancer Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215 Communicated by James D. Watson, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, February 14, 2003 (received for review December 12, 2002) Tumstatin and endostatin are two inhibitors of angiogenesis de- peptide (14). hTumstatin inhibits proliferation of endothelial rived from precursor human collagen molecules known as 3 chain cells and induces apoptosis in an v3 integrin dependent of type IV collagen and 1 chain of type XVIII collagen, respectively. manner (15). Apoptosis of endothelial cells by recombinant Although both these inhibitors are noncollagenous (NC1) domain hTumstatin is mediated by v3 integrin and the phosphatidyl- fragments of collagens, they only share a 14% amino acid homol- 3-kinase (PI3-kinase)AktmTOR pathway leading to protein ogy. In the present study we evaluated the functional receptors, synthesis inhibition (15). mechanism of action, and intracellular signaling induced by these Human endostatin (hEndostatin) is the NC1 domain of the 1 two collagen-derived inhibitors. Human tumstatin prevents angio- chain of type XVIII collagen and an inhibitor of tumor angio- genesis via inhibition of endothelial cell proliferation and promo- genesis and growth in mice (7, 16). hEndostatin is liberated from tion of apoptosis with no effect on migration, whereas human the collagenous domain by cleavage within a protease-sensitive endostatin prevents endothelial cell migration with no effect on