Contortrostatin, a snake venom disintegrin, induces αvβ3-mediated tyrosine phosphorylation of CAS and FAK in tumor cells

Alexander Dmitriyevich Verin, Csilla Csortos, Steve D. Durbin, Antonina Aydanyan, Peiyi Wang, Carolyn E. Patterson, Joe G.N. Garcia

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)28-37
Number of pages10
JournalJournal of Cellular Biochemistry
Volume79
Issue number1
DOIs
StatePublished - Sep 6 2000
Externally publishedYes

Fingerprint

Disintegrins
Snake Venoms
Phosphorylation
Tyrosine
Tumors
Cells
Integrins
Neoplasms
Chemical activation
contortrostatin
src-Family Kinases
Extracellular Matrix Proteins
Cell adhesion
Platelets
Platelet Aggregation
Cell Adhesion
Cell Movement
Agglomeration

Keywords

  • Integrin
  • Integrin signaling
  • Motility
  • Src
  • Vitronectin receptor
  • αvβ3

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Contortrostatin, a snake venom disintegrin, induces αvβ3-mediated tyrosine phosphorylation of CAS and FAK in tumor cells. / Verin, Alexander Dmitriyevich; Csortos, Csilla; Durbin, Steve D.; Aydanyan, Antonina; Wang, Peiyi; Patterson, Carolyn E.; Garcia, Joe G.N.

In: Journal of Cellular Biochemistry, Vol. 79, No. 1, 06.09.2000, p. 28-37.

Research output: Contribution to journalArticle

Verin, Alexander Dmitriyevich ; Csortos, Csilla ; Durbin, Steve D. ; Aydanyan, Antonina ; Wang, Peiyi ; Patterson, Carolyn E. ; Garcia, Joe G.N. / Contortrostatin, a snake venom disintegrin, induces αvβ3-mediated tyrosine phosphorylation of CAS and FAK in tumor cells. In: Journal of Cellular Biochemistry. 2000 ; Vol. 79, No. 1. pp. 28-37.
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