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.
Yoshida
K
K
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Kharbanda
S
S
Kufe
D
D
D017209:Apoptosis; D002453:Cell Cycle; D003561:Cytarabine / Q000494:pharmacology; D004249:DNA Damage; D015536:Down-Regulation; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D010766:Phosphorylation / Q000187:drug effects; D011233:Precipitin Tests; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D020298:U937 Cells; D019061:src-Family Kinases / Q000378:metabolism*
D047908:Intracellular Signaling Peptides and Proteins; D011993:Recombinant Fusion Proteins; D003561:Cytarabine; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; C516724:PTPN11 protein, human; C509249:PTPN6 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases