Negative regulation of the SHPTP1 protein tyrosine phosphatase by protein kinase c δ in response to DNA damage

The SHPTP1 protein tyrosine phosphatase is activated by the c-Abl and Lyn tyrosine kinases in the cellular response to genotoxic stress. However, signaling mechanisms involved in the negative regulation of SHPTP1 are unknown. This study demonstrates that protein kinase C delta (PKC delta) associates with SHPTP1. The PKC delta catalytic domain binds directly to SHPTP1. The results also demonstrate that PKC delta is required, at least in part, for phosphorylation and inactivation of SHPTP1. The phosphatase activity of SHPTP1 was attenuated by coincubation with PKC delta in vitro. In addition, treatment of U-937 human myeloid leukemia cells with 1-beta -D-arabinofuranosylcytosine (ara-C) was associated with induction of the PKC delta kinase function and inhibition of SHPTP1 activity. Down-regulation of SHPTP1 by ara-C was blocked by the PKC delta inhibitor rottlerin but not by the PKC alpha and -beta inhibitor Go6976. Moreover, transient coexpression studies with a dominant-negative mutant of PKC delta demonstrate that the kinase activity of PKC delta is required for the down-regulation of SHPTP1. These findings support the functional interaction between PKC delta and SHPTP1 in the cellular response to DNA damage.