Faculty Collaboration Database

PTPH1 dephosphorylates and cooperates with p38gamma MAPK to increase ras oncogenesis through PDZ-mediated interaction. Cancer Res 2010 Apr 01;70(7):2901-10

Date

03/25/2010

Pubmed ID

20332238

Pubmed Central ID

PMC2848905

DOI

10.1158/0008-5472.CAN-09-3229

Scopus ID

2-s2.0-77950794747 (requires institutional sign-in at Scopus site)   65 Citations

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 p38gamma mitogen-activated protein kinase (MAPK) and shown their cooperative oncogenic activity through direct binding. p38gamma, 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 p38gamma 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 p38gamma-binding activity. Moreover, Ras increases both p38gamma and PTPH1 protein expression and there is a coupling of increased p38gamma 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 p38gamma/PTPH1 complex may be a novel target for Ras-dependent malignancies.

Author List

Hou SW, Zhi HY, Pohl N, Loesch M, Qi XM, Li RS, Basir Z, Chen G

Authors

Guan Chen MD, PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Xiao-Mei Qi MD Associate Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Cell Growth Processes
Cell Transformation, Neoplastic
Colonic Neoplasms
Genes, ras
HCT116 Cells
Humans
MAP Kinase Signaling System
Mitogen-Activated Protein Kinase 12
PDZ Domains
Phosphorylation
Protein Interaction Domains and Motifs
Protein Tyrosine Phosphatase, Non-Receptor Type 3
RNA, Small Interfering
ras Proteins