Cellular stimulation via CD95 involves activation of phospho-inositide-3-kinase.
Several distinct intracellular pathways have been recently shown to be activated during CD95/Fas/APO-1-mediated apoptosis. Here, we demonstrate that CD95 ligation induces a rapid and transient tyrosine phosphorylation and activation of phosphoinositide-3-kinase (PI-3-K) in Jurkat T lymphocytes or CD95-sensitive glioma cells. Experiments using p56lck-deficient or p56lck-reconstituted Jurkat clones and the tyrosine kinase inhibitor herbimycin A revealed that tyrosine phosphorylation and activation of PI-3-K by CD95 depends on expression of Src-like tyrosine kinases, in particular p56lck. PI-3-K stimulation seems to be critical for CD95 receptor signalling since, first, inhibition of PI-3-K prevents CD95-mediated apoptosis and, second, CD95 receptor ligation fails to induce tyrosine phosphorylation or activation of PI-3-K in CD95-resistant glioma cells. Thus, PI-3-K activation may be an early signalling event during CD95-induced apoptosis, and failure to stimulate PI-3-K may predict tumor cell resistance to CD95-triggered apoptosis.
Gulbins
E
E
Department of Physiology, University of Tuebingen, Gmelinstrasse 5, D-72076 Tuebingen, Germany.
Hermisson
M
M
Brenner
B
B
Grassmé
H U
HU
Linderkamp
O
O
Dichgans
J
J
Weller
M
M
Lang
F
F
D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D053938:DNA Fragmentation; D004789:Enzyme Activation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D005910:Glioma / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011233:Precipitin Tests; D014162:Transfection / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism; D019014:fas Receptor / Q000235:genetics / Q000502:physiology*
D004791:Enzyme Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D014443:Tyrosine; D019014:fas Receptor