TY - JOUR
T1 - Contortrostatin, a snake venom disintegrin, induces αvβ3-mediated tyrosine phosphorylation of CAS and FAK in tumor cells
AU - Verin, Alexander Dmitriyevich
AU - Csortos, Csilla
AU - Durbin, Steve D.
AU - Aydanyan, Antonina
AU - Wang, Peiyi
AU - Patterson, Carolyn E.
AU - Garcia, Joe G.N.
PY - 2000
Y1 - 2000
N2 - Contortrostatin is a homodimeric disintegrin that inhibits platelet aggregation and cell adhesion to extracellular matrix proteins by blocking integrins. The effect of contortrostatin on integrin-mediated signaling in tumor cells was investigated by studying tyrosine phosphorylation events and activation of specific signaling molecules. We found that at concentrations as low as 1 nM, soluble contortrostatin activates integrin signals leading to increased tyrosine phosphorylation of FAK and CAS, and that these signals are abolished by inhibiting Src family kinases. Using transfected 293 cells expressing specific integrins, it was determined that contortrostatin-generated signals are mediated exclusively by the αvβ3 integrin. This observation was extended by showing that cells lacking αvβ3, but expressing αvβ5 and α5β1, do not respond in this way to contortrostatin treatment. In cells expressing αvβ3, blocking contortrostatin binding with antibodies against αvβ3 completely abrogates contortrostatin signals. Monovalent disintegrins echistatin and flavoridin were incapable of affecting tyrosine phosphorylation alone, but when added simultaneously with contortrostatin, completely inhibited contortrostatin-initiated signals. We propose that the homodimeric nature of contortrostatin imparts the ability to crosslink αvβ3 integrins, causing Src activation and hyperphosphorylation of FAK and CAS. This activity may represent a novel mechanism by which tumor cell motility can be inhibited. (C) 2000 Wiley-Liss, Inc.
AB - Contortrostatin is a homodimeric disintegrin that inhibits platelet aggregation and cell adhesion to extracellular matrix proteins by blocking integrins. The effect of contortrostatin on integrin-mediated signaling in tumor cells was investigated by studying tyrosine phosphorylation events and activation of specific signaling molecules. We found that at concentrations as low as 1 nM, soluble contortrostatin activates integrin signals leading to increased tyrosine phosphorylation of FAK and CAS, and that these signals are abolished by inhibiting Src family kinases. Using transfected 293 cells expressing specific integrins, it was determined that contortrostatin-generated signals are mediated exclusively by the αvβ3 integrin. This observation was extended by showing that cells lacking αvβ3, but expressing αvβ5 and α5β1, do not respond in this way to contortrostatin treatment. In cells expressing αvβ3, blocking contortrostatin binding with antibodies against αvβ3 completely abrogates contortrostatin signals. Monovalent disintegrins echistatin and flavoridin were incapable of affecting tyrosine phosphorylation alone, but when added simultaneously with contortrostatin, completely inhibited contortrostatin-initiated signals. We propose that the homodimeric nature of contortrostatin imparts the ability to crosslink αvβ3 integrins, causing Src activation and hyperphosphorylation of FAK and CAS. This activity may represent a novel mechanism by which tumor cell motility can be inhibited. (C) 2000 Wiley-Liss, Inc.
KW - Integrin
KW - Integrin signaling
KW - Motility
KW - Src
KW - Vitronectin receptor
KW - αvβ3
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U2 - 10.1002/1097-4644(2000)79:1<28::AID-JCB40>3.0.CO;2-Y
DO - 10.1002/1097-4644(2000)79:1<28::AID-JCB40>3.0.CO;2-Y
M3 - Article
C2 - 10906753
AN - SCOPUS:0033840533
SN - 0730-2312
VL - 79
SP - 28
EP - 37
JO - Journal of cellular biochemistry
JF - Journal of cellular biochemistry
IS - 1
ER -