Inhibition of tyrosine phosphatases induces apoptosis independent from the CD95 system

The inhibition of protein tyrosine phosphatases by pervanadate, a potent activator of B- and T-cells through the induction of tyrosine phosphorylation and downstream signaling events in different activation cascades, efficiently induced apoptosis in lymphoid cell lines. Pervanadate elicited apoptosis could be blocked by the tyrosine kinase inhibitor herbimycin A, This apoptotic process involved the activation of caspases 3, 8 and 9, the induction of mitochondrial permeability transition, the release of cytochrome C and the fragmentation of chromosomal DNA, T-cells lacking the CD95 receptor or caspase-8 and T-cells stably overexpressing a transdominant negative form of the adaptor protein FADD were still susceptible to pervanadate-induced apoptosis, excluding the involvement of the CD95 system or other FADD-dependent death receptors. The apoptotic program initiated by the inhibition of tyrosine phosphatases did not require the presence of the tyrosine kinase p56(lck) or phosphatase CD45, whereas Bcl-2 overexpression protected T-cells from pervanadate-induced cytochrome C release, caspase-8 cleavage and apoptosis.