Several distinct intracellular pathways have been recently shown to be
activated during CD95/Fas/APO-1-mediated apoptosis. Here, we demonstr
ate that CD95 ligation induces a rapid and transient tyrosine phosphor
ylation and activation of phosphoinositide-3-kinase (PI-3-K) in Jurkat
T lymphocytes or CD95-sensitive glioma cells. Experiments using p561c
k-deficient or p561ck-reconstituted Jurkat clones and the tyrosine kin
ase inhibitor herbimycin A revealed that tyrosine phosphorylation and
activation of PI-3-K by CD95 depends on expression of Src-like tyrosin
e kinases, in particular p561ck. PI-3-K stimulation seems to be critic
al for CD95 receptor signalling since, first, inhibition of PI-3-K pre
vents CD95-mediated apoptosis and, second, CD95 receptor ligation fail
s to induce tyrosine phosphorylation or activation of PI-3-K in CD95-r
esistant glioma cells. Thus, PI-3-K activation may be an early signall
ing event during CD95-induced apoptosis, and failure to stimulate PI-3
-K may predict tumor cell resistance to CD95-triggered apoptosis.