PTPH1 Dephosphorylates and Cooperates with p38. MAPK to Increase Ras Oncogenesis through PDZ-Mediated Interaction

Protein phosphatases are believed to coordinate with kinases to execute biological functions, but examples of such integrated activities, however, are still missing. In this report, we have identified protein tyrosine phosphatase H1 (PTPH1) as a specific phosphatase for p38 gamma mitogen-activated protein kinase (MAPK) and shown their cooperative oncogenic activity through direct binding. p38 gamma, a Ras effector known to act independent of its phosphorylation, was first shown to require its unique PDZ-binding motif to increase Ras transformation. Yeast two-hybrid screening and in vitro and in vivo analyses further identified PTPH1 as a specific p38 gamma phosphatase through PDZ-mediated binding. Additional experiments showed that PTPH1 itself plays a role in Ras-dependent malignant growth in vitro and/or in mice by a mechanism depending on its p38 gamma-binding activity. Moreover, Ras increases both p38 gamma and PTPH1 protein expression and there is a coupling of increased p38 gamma and PTPH1 protein expression in primary colon cancer tissues. These results reveal a coordinative oncogenic activity of a MAPK with its specific phosphatase and suggest that PDZ-mediated p38 gamma/PTPH1 complex may be a novel target for Ras-dependent malignancies. Cancer Res; 70(7); 2901-10. (C) 2010 AACR.