Two ubiquitously expressed protein tyrosine phosphatases, PTP-S2 and PTP-S4 (also known as TC45 and TC48, respectively), are alternately spliced products of the same gene. Overexpression of PTP-S2 by transient transfection induced chromatin condensation and nuclear fragmentation, typical of apoptosis. Expression of PTP-S4 resulted in a much lower number of cells with apoptotic phenotype. PTP-S2 induced apoptosis in MCF7 and A549 human tumor cell lines which are p53 positive but not in HeLa and SW620 cells which are p53 negative. Apoptosis induced by PTP-S2 in MCF7 cells was inhibited by cotransfection with mutant p53 (Arg-273 --> His) but not by wild type p53. PTP-S2 induced apoptosis was inhibited by antiapoptotic protein Bcl2 and certain inhibitors of caspases. These results suggest that the nuclear tyrosine phosphatase PTP-S2 induces p53 dependent, serum starvation independent and caspase mediated apoptosis.