Functional interaction between SHPTP1 and the Lyn tyrosine kinase in the apoptotic response to DNA damage

The LYN protein-tyrosine kinase is activated in the cellular response to DNA-damaging agents. Here we demonstrate that LYN associates constitutively with the SHPTP1 protein-tyrosine Phosphatase. The SH3 domain of LYN interacts directly with SHPTP1. The results show that LYN phosphorylates SHPTP1 at the C-terminal Tyr-564 site. Lyn-mediated phosphorylation of SHPTP1 stimulates SHPTP1 tyrosine Phosphatase activity. We also demonstrate that treatment of cells with 1-beta-D-arabinofuranosylcytosine and other genotoxic agents induces Lyn-dependent phosphorylation and activation of SHPTP1. The significance of the Lyn-SHPTP1 interaction is supported by the demonstration that activation of LYN contributes in part to the apoptotic response to ara-C treatment and that SHPTP1 attenuates this response. These findings support a functional interaction between LYN and SHPTP1 in the response to DNA damage.