Activation of Src-family tyrosine kinases during Fas-induced apoptosis.
Stimulation of several human and murine hematopoietically derived cell lines with anti-Fas antibodies induced increased tyrosine phosphorylation of a panel of proteins observed in whole-cell lysates. In the human T cell line Jurkat, the activity of a 56-kDa tyrosine kinase was likewise activated by anti-Fas antibodies. Immunoprecipitation studies of anti-Fas-stimulated human Jurkat and murine 2B4.11 T cells revealed activation of the Src-family tyrosine kinases Lck and Fyn. Fas receptor-induced tyrosine phosphorylation of p120 c-cbl proto-oncogene product was observed in Jurkat T cells. Pharmacological experiments demonstrated that pretreatment of Jurkat cells with tyrphostins inhibited Fas-induced apoptosis; likewise, Lck activity was inhibited by tyrphostins in a dose-dependent fashion. Finally, Lck derived from unstimulated Jurkat T cells formed stable complexes with the intracellular domain of the Fas receptor. These data are consistent with the notion that expression and activation of members of the Src-family kinases is required for Fas-induced cell death in T lymphocytes and consistent with recent findings demonstrating decreased Fas-mediated thymocytic death in Fyn-knockout mice.
Schlottmann
K E
KE
Department of Microbiology, Ohio State University, USA.
Gulbins
E
E
Lau
S M
SM
Coggeshall
K M
KM
D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019833:Genistein; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051379:Mice; D009000:Monocytes / Q000166:cytology*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D050721:Proto-Oncogene Proteins c-cbl; D051076:Proto-Oncogene Proteins c-fyn; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology*; D044767:Ubiquitin-Protein Ligases; D019014:fas Receptor / Q000502:physiology*; D019061:src-Family Kinases / Q000378:metabolism*
D004791:Enzyme Inhibitors; D007529:Isoflavones; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D019014:fas Receptor; D019000:Phosphotyrosine; D019833:Genistein; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D011505:Protein-Tyrosine Kinases; C494957:FYN protein, human; C494960:Fyn protein, mouse; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051076:Proto-Oncogene Proteins c-fyn; D019061:src-Family Kinases; C067419:CBL protein, human; C493849:Cbl protein, mouse