Faculty Collaboration Database

The p38 pathway provides negative feedback for Ras proliferative signaling. J Biol Chem 2000 Dec 15;275(50):38973-80

Date

09/09/2000

Pubmed ID

10978313

DOI

10.1074/jbc.M002856200

Scopus ID

2-s2.0-0034671847 (requires institutional sign-in at Scopus site)   162 Citations

Abstract

Ras activates three mitogen-activated protein kinases (MAPKs) including ERK, JNK, and p38. Whereas the essential roles of ERK and JNK in Ras signaling has been established, the contribution of p38 remains unclear. Here we demonstrate that the p38 pathway functions as a negative regulator of Ras proliferative signaling via a feedback mechanism. Oncogenic Ras activated p38 and two p38-activated protein kinases, MAPK-activated protein kinase 2 (MK2) and p38-related/activated protein kinase (PRAK). MK2 and PRAK in turn suppressed Ras-induced gene expression and cell proliferation, whereas two mutant PRAKs, unresponsive to Ras, had little effect. Moreover, the constitutive p38 activator MKK6 also suppressed Ras activity in a p38-dependent manner whereas arsenite, a potent chemical inducer of p38, inhibited proliferation only in a tumor cell line that required Ras activity. MEK was required for Ras stimulation of the p38 pathway. The p38 pathway inhibited Ras activity by blocking activation of JNK, without effect upon ERK, as evidenced by the fact that PRAK-mediated suppression of Ras-induced cell proliferation was reversed by coexpression of JNKK2 or JNK1. These studies thus establish a negative feedback mechanism by which Ras proliferative activity is regulated via signaling integrations of MAPK pathways.

Author List

Chen G, Hitomi M, Han J, Stacey DW

Author

Guan Chen PhD, MD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

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

3T3 Cells
Animals
Arsenites
Calcium-Calmodulin-Dependent Protein Kinases
Cell Division
DNA, Complementary
DNA-Binding Proteins
Enzyme Activation
Humans
Intracellular Signaling Peptides and Proteins
Luciferases
MAP Kinase Kinase 2
MAP Kinase Kinase 6
Mice
Mitogen-Activated Protein Kinase Kinases
Mitogen-Activated Protein Kinases
Models, Biological
Mutation
Nuclear Proteins
Phosphorylation
Precipitin Tests
Protein-Tyrosine Kinases
Serum Response Factor
Signal Transduction
Thymidine
Transfection
Tumor Cells, Cultured
p38 Mitogen-Activated Protein Kinases
ras Proteins