Cdc42 and PAK-mediated Signaling Leads to Jun Kinase and p38 Mitogen-activated Protein Kinase Activation

doi:10.1074/jbc.270.47.27995

Cdc42 and PAK-mediated Signaling Leads to Jun Kinase and p38 Mitogen-activated Protein Kinase Activation (*)

From the (1) Department of Pharmacology, Cornell University, Ithaca, New York 14853-6401 and
(2) Howard Hughes Medical Institute and Program in Molecular Medicine, Department of Biochemistry and Molecular Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605

** To whom correspondence should be addressed. Tel.: 607-253-3888; Fax: 607-253-3659.

Abstract

The PAK family of protein kinases has been suggested as a potential target of the Cdc42 and Rac GTPases based on studies in vitro. We show that PAK-3 is activated by Cdc42 in vivo. Both, activated (GTPase-defective) Cdc42 and a constitutively active PAK-3 mutant stimulated the activity of Jun kinase 1 (JNK1) in transfected cells. Activated Cdc42 also stimulated the activity of the related p38 mitogen-activated protein kinase but was a less effective activator of ERK2. The effect of Cdc42 on JNK activity was similar to that of the potent inflammatory cytokine interleukin-1 (IL-1). The observation that a dominant-negative Cdc42 mutant inhibited IL-1 activation of JNK1 indicates a role for Cdc42 in IL-1 signaling. These results suggest that Cdc42 and PAK may mediate the effects of cytokines on transcriptional regulation.

Footnotes

↵^§ These authors contributed equally to this study.
↵^¶ Investigator of the Howard Hughes Medical Institute.
↵* This work was supported by National Cancer Institute Grants CA58396 and CA65861 (to R. J. D.) and GM47458 and GM40654 (to R. A. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵⁽⁾J. Chernoff, personal communication.
↵⁽⁾ The abbreviations used are:

MAP

mitogen-activated protein

JNK

Jun amino-terminal kinase

MEKK

MAP kinase kinase kinase

HA

hemagglutinin

PBD

p21 binding domain

IL

interleukin

mAb

monoclonal antibody

MBP

myelin basic protein

GST

glutathione S-transferase

PAGE

polyacrylamide gel electrophoresis

GTPS

guanosine 5′-3-O-(thio)triphosphate

WT

wild type.
↵⁽⁾S. Bagrodia, S. Pelech, and R. A. Cerione, unpublished observations.
↵⁽⁾S. Bagrodia, unpublished observations.
- Received August 1, 1995.
- Revision received September 11, 1995.