Faculty Collaboration Database

p38γ Mitogen-activated protein kinase signals through phosphorylating its phosphatase PTPH1 in regulating ras protein oncogenesis and stress response. J Biol Chem 2012 Aug 10;287(33):27895-905

Date

06/26/2012

Pubmed ID

22730326

Pubmed Central ID

PMC3431700

DOI

10.1074/jbc.M111.335794

Scopus ID

2-s2.0-84865009345 (requires institutional sign-in at Scopus site)   23 Citations

Abstract

Phosphatase plays a crucial role in determining cellular fate by inactivating its substrate kinase, but it is not known whether a kinase can vice versa phosphorylate its phosphatase to execute this function. Protein-tyrosine phosphatase H1 (PTPH1) is a specific phosphatase of p38γ mitogen-activated protein kinase (MAPK) through PDZ binding, and here, we show that p38γ is also a PTPH1 kinase through which it executes its oncogenic activity and regulates stress response. PTPH1 was identified as a substrate of p38γ by unbiased proteomic analysis, and its resultant phosphorylation at Ser-459 occurs in vitro and in vivo through their complex formation. Genetic and pharmacological analyses showed further that Ser-459 phosphorylation is directly regulated by Ras signaling and is important for Ras, p38γ, and PTPH1 oncogenic activity. Moreover, experiments with physiological stimuli revealed a novel stress pathway from p38γ to PTPH1/Ser-459 phosphorylation in regulating cell growth and cell death by a mechanism dependent on cellular environments but independent of canonical MAPK activities. These results thus reveal a new mechanism by which a MAPK regulates Ras oncogenesis and stress response through directly phosphorylating its phosphatase.

Author List

Hou S, Suresh PS, Qi X, Lepp A, Mirza SP, 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

Animals
Cell Line, Tumor
Cell Transformation, Neoplastic
Humans
MAP Kinase Signaling System
Mice
Mice, Knockout
Mitogen-Activated Protein Kinase 12
Phosphorylation
Protein Tyrosine Phosphatase, Non-Receptor Type 3
Stress, Physiological
ras Proteins