Rho Family GTPases Regulate p38 Mitogen-activated Protein Kinase through the Downstream Mediator Pak1 (*)
- Shengjia Zhang(1)(2),
- Jiahuai Han(1)(§),
- Mary Ann Sells,
- Jonathan Chernoff,
- Ulla G. Knaus(1)(2),
- Richard J. Ulevitch(1) and
- Gary M. Bokoch(1)(2)(§)
- From the (1)Departments of Immunology and
- (2) Cell Biology, Scripps Research Institute, La Jolla, California 92037 and the ‖Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111
- § To whom correspondence should be addressed: Depts. of Immunology and Cell Biology, IMM14, Scripps Research Inst., 10666 N. Torrey Pines Rd., La Jolla, CA 92037.
Abstract
The stress-activated p38 mitogen-activated protein (MAP) kinase defines a subgroup of the mammalian MAP kinases that appear to play a key role in regulating inflammatory responses. Co-expression of constitutively active forms of Rac and Cdc42 leads to activation of p38 while dominant negative Rac and Cdc42 inhibit the ability of interleukin-1 to increase p38 activity. p21-activated kinase 1 (Pak1) is a potential mediator of Rac/Cdc42 signaling, and we observe that Pak1 stimulates p38 activity. A dominant negative Pak1 suppresses both interleukin-1- and Rac/Cdc42-induced p38 activity. Rac and Cdc42 appear to regulate a protein kinase cascade initiated at the level of Pak and leading to activation of p38 and JNK.
Footnotes
-
↵* This work was supported by National Institutes of Health Grants HL48008 and GM39434 (to G. M. B.), AI35947 (to U. G. K.), AI15136 and GM37696 (to R. J. U.), GM51471 (to J. H.), and CA58836 (to J. C.), by University of California Breast Cancer Research Program Grant 1IB-0491 (to U. G. K.), and by a grant from the W. W. Smith Foundation (to J. 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.
-
↵1 The abbreviations used are:
- JNK
-
c-Jun amino-terminal kinase
- ERK
-
extracellular signal-regulated kinase
- MAP
-
mitogen-activated protein
- IL
-
interleukin
- Pak
-
p21-activated kinase
- HA
-
hemagglutinin.
-
↵2S. Zhang and G. M. Bokoch, unpublished observations.
-
↵3M. A. Sells, U. G. Knaus, D. Ambrose, S. Bagrodia, G. M. Bokoch, and J. Chernoff, submitted for publication.
-
↵4G. M. Bokoch and C. J. Der, unpublished observations.
-
5G. M. Bokoch, unpublished observations.
-
- Received July 25, 1995.
- Revision received August 17, 1995.
- © 1995 by The American Society for Biochemistry and Molecular Biology, Inc.
