Contortrostatin, a homodimeric disintegrin, actively disrupts focal adhesion and cytoskeletal structure and inhibits cell motility through a novel mechanism.
Integrins play a major role in the regulation of cell motility. They physically link the extracellular environment to the cytoskeleton and participate in large protein complexes known as focal adhesions. In this report, it is demonstrated that treatment of tumor cells with the homodimeric disintegrin contortrostatin induces integrin-mediated tyrosine phosphorylation events and causes severe disruptions in the actin cytoskeleton and disassembly of focal adhesion structures without affecting cellular adhesion to a reconstituted basement membrane. Included in this disruption is the tyrosine phosphorylation and altered subcellular localization of FAK. Through use of transfected 293 cells with specific integrin expression profiles and anti-alphavbeta3 mAbs, we demonstrate that these events are mediated exclusively by the alphavbeta3 integrin and are likely the result of contortrostatin-mediated crosslinking of this receptor at the cell surface, since monovalent disintegrins, flavoridin or echistatin do not induce such effects. Further, it is shown that contortrostatin potently inhibits motility in cells expressing the alphavbeta33 integrin. The results of this study describe a novel integrin-mediated mechanism by which cell motility can be inhibited and suggest an alternative approach to therapeutic intervention for cancer invasion and metastasis.
Ritter
M R
MR
Department of Biochemistry and Molecular Biology and Norris Comprehensive Cancer Center, University of Southern California, Keck School of Medicine, Los Angeles 90033, USA.
Zhou
Q
Q
Markland
F S
FS
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D002448:Cell Adhesion; D002460:Cell Line; D002465:Cell Movement; D003599:Cytoskeleton / Q000378:metabolism; D019281:Dimerization; D019483:Disintegrins / Q000737:chemistry* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D010766:Phosphorylation; D011233:Precipitin Tests; D019030:Receptors, Vitronectin / Q000737:chemistry / Q000378:metabolism*; D012911:Snakes; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism
D000911:Antibodies, Monoclonal; D019483:Disintegrins; D019030:Receptors, Vitronectin; C403494:contortrostatin; D014443:Tyrosine