Differential regulation of tyrosine phosphorylation in tumor cells by contortrostatin, a homodimeric disintegrin, and monomeric disintegrins echistatin and flavoridin.
The homodimeric disintegrin contortrostatin was compared directly to the monomeric disintegrins echistatin and flavoridin for the ability to affect protein tyrosine phosphorylation in tumor cells. It was observed that contortrostatin had a dramatic effect on the tyrosine phosphorylation status of several proteins in T24 human bladder cancer cells, including robust induction of phosphorylation of proteins in the range of 120-140 kDa. Echistatin alone had no effect on tyrosine phosphorylation in T24 cells, but dose-dependently inhibits the effects of contortrostatin when both are added simultaneously. Among the proteins that undergo tyrosine phosphorylation in response to contortrostatin treatment is CAS, a 130 kDa adapter protein involved in integrin signaling. Flavoridin alone was found to have no effect on CAS, but can completely block contortrostatin-induced phosphorylation of this protein in MDA-MB-435 cells. These observations strongly suggest that the homodimeric structure of contortrostatin functionally distinguishes it from other monomeric members of the disintegrin family.
Ritter
M R
MR
Department of Biochemistry and Molecular Biology, University of Southern Californa, Keck School of Medicine, 1303 N. Mission Road, Los Angeles, CA 90033, USA.
Markland
F S
FS
D003435:Crotalid Venoms / Q000494:pharmacology; D019483:Disintegrins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism*; D014757:Viper Venoms / Q000494:pharmacology*
D003435:Crotalid Venoms; D019483:Disintegrins; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D010975:Platelet Aggregation Inhibitors; D014757:Viper Venoms; C403494:contortrostatin; C057986:echistatin; C069044:flavoridin protein, Trimeresurus; D014443:Tyrosine