Inhibition of tyrosine phosphatases antagonizes CD95-mediated apoptosis

Ligation of the CD95 receptor resulted in a transient increase of cellular tyrosine phosphorylation. The inhibition of protein tyrosine phosphatases b y pervanadate, a potent activator of B cells and T cells through the induct ion of tyrosine phosphorylation and downstream signaling events in the acti vation cascade, antagonized CD95-triggered apoptosis. Pervanadate exerted i ts inhibitory effect only during the early phase of apoptosis prior to the CD95-induced decrease of the mitochondrial transmembrane potential. Inhibit ion of tyrosine phosphatases delayed the cleavage and activation of caspase -8 and caspase-3 and antagonized the tyrosine dephosphorylation of the CD95 receptor-associated phosphoproteins p61 and p89/92. In contrast, ligation of the tumor necrosis factor (TNF) receptor resulted in a continuous tyrosi ne dephosphorylation of cellular proteins. Pervanadate-induced tyrosine pho sphorylation increased the TNF-alpha-induced cytotoxicity and NF-kappa B ac tivation, suggesting that it stimulates early signaling events prior to the separation of the two signaling pathways.