PTPH1 Dephosphorylates and Cooperates with p38γ MAPK to Increase Ras Oncogenesis through PDZ-Mediated Interaction
- 31 March 2010
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 70 (7), 2901-2910
- https://doi.org/10.1158/0008-5472.can-09-3229
Abstract
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 p38γ mitogen-activated protein kinase (MAPK) and shown their cooperative oncogenic activity through direct binding. p38γ, 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 p38γ 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 p38γ-binding activity. Moreover, Ras increases both p38γ and PTPH1 protein expression and there is a coupling of increased p38γ 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 p38γ/PTPH1 complex may be a novel target for Ras-dependent malignancies. Cancer Res; 70(7); 2901–10Keywords
Other Versions
This publication has 31 references indexed in Scilit:
- SmgGDS is up-regulated in prostate carcinoma and promotes tumour phenotypes in prostate cancer cellsThe Journal of Pathology, 2009
- PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patientsCancer Cell, 2004
- Mutational Analysis of the Tyrosine Phosphatome in Colorectal CancersScience, 2004
- Stress- and mitogen-induced phosphorylation of the synapse-associated protein SAP90/PSD-95 by activation of SAPK3/p38gamma and ERK1/ERK2Biochemical Journal, 2004
- p38 MAPK Activation Selectively Induces Cell Death in K-ras-mutated Human Colon Cancer Cells through Regulation of Vitamin D ReceptorPublished by Elsevier BV ,2004
- PTPH1 Is a Predominant Protein-tyrosine Phosphatase Capable of Interacting with and Dephosphorylating the T Cell Receptor ζ SubunitPublished by Elsevier BV ,2004
- Mechanism of p38 MAP kinase activation in vivoGenes & Development, 2003
- Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemiaNature Genetics, 2003
- Targeting RAS signalling pathways in cancer therapyNature Reviews Cancer, 2003
- Crosstalk between cAMP-dependent kinase and MAP kinase through a protein tyrosine phosphataseNature, 1999