Earlier we have shown that the epidermal growth factor receptor was unable to retain its phospho Tyr signal after the assembly of staphylococcal alpha-hemolysin (alpha-HL). However, the nature of the protein tyrosine phosphatase (PTPase) or its identity is not known. In this report, we demonstrate that the alpha-HL elevates the activity of receptor like protein tyrosine phosphatase sigma (rPTPsigma). The alpha-HL induced dephosphorylation is prominent only in intact A431 cells. The PTPase activity is not inhibited if the alpha-HL treatment precedes PTPase inhibitor treatments. The anti-EGFr immunoprecipitates have exhibited higher PTPase activity after alpha-HL treatment of A431 cells. Interestingly, PTPase activity of anti-EGFr immunoprecipitates from the A431 cells expressing the antisense message of rPTPsigma has not increased despite alpha-HL treatment, confirming the role of rPTPsigma in the dephosphorylation of EGFr. The studies presented here will be useful in understanding the process of signal modulation by the assembly of alpha-HL. (C) 2004 Elsevier Inc. All rights reserved.