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Molecular and Cellular Biology, February 2001, p. 1173-1184, Vol. 21, No. 4
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.4.1173-1184.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Regulation of Mitogen-Activated Protein Kinases in Cardiac Myocytes through the Small G Protein Rac1

Angela Clerk,1,* Fong H. Pham,1 Stephen J. Fuller,2 Erik Sahai,3 Klaus Aktories,4 Richard Marais,3 Chris Marshall,3 and Peter H. Sugden2

Division of Biomedical Sciences (Molecular Pathology Section), Imperial College School of Medicine, London SW7 2AZ,1 National Heart and Lung Institute (NHLI) Division (Cardiac Medicine Section), Imperial College School of Medicine, London SW3 6LY,2 and Chester Beatty Laboratories, Institute of Cancer Research, London SW3 6JB,3 United Kingdom, and Institut für Pharmakologie und Toxikologie, Albert Ludwig Universität, D79104 Freiburg, Germany4

Received 12 June 2000/Returned for modification 26 July 2000/Accepted 22 November 2000

Small guanine nucleotide-binding proteins of the Ras and Rho (Rac, Cdc42, and Rho) families have been implicated in cardiac myocyte hypertrophy, and this may involve the extracellular signal-related kinase (ERK), c-Jun N-terminal kinase (JNK), and/or p38 mitogen-activated protein kinase (MAPK) cascades. In other systems, Rac and Cdc42 have been particularly implicated in the activation of JNKs and p38-MAPKs. We examined the activation of Rho family small G proteins and the regulation of MAPKs through Rac1 in cardiac myocytes. Endothelin 1 and phenylephrine (both hypertrophic agonists) induced rapid activation of endogenous Rac1, and endothelin 1 also promoted significant activation of RhoA. Toxin B (which inactivates Rho family proteins) attenuated the activation of JNKs by hyperosmotic shock or endothelin 1 but had no effect on p38-MAPK activation. Toxin B also inhibited the activation of the ERK cascade by these stimuli. In transfection experiments, dominant-negative N17Rac1 inhibited activation of ERK by endothelin 1, whereas activated V12Rac1 cooperated with c-Raf to activate ERK. Rac1 may stimulate the ERK cascade either by promoting the phosphorylation of c-Raf or by increasing MEK1 and/or -2 association with c-Raf to facilitate MEK1 and/or -2 activation. In cardiac myocytes, toxin B attenuated c-Raf(Ser-338) phosphorylation (50 to 70% inhibition), but this had no effect on c-Raf activity. However, toxin B decreased both the association of MEK1 and/or -2 with c-Raf and c-Raf-associated ERK-activating activity. V12Rac1 cooperated with c-Raf to increase expression of atrial natriuretic factor (ANF), whereas N17Rac1 inhibited endothelin 1-stimulated ANF expression, indicating that the synergy between Rac1 and c-Raf is potentially physiologically important. We conclude that activation of Rac1 by hypertrophic stimuli contributes to the hypertrophic response by modulating the ERK and/or possibly the JNK (but not the p38-MAPK) cascades.

* Corresponding author. Mailing address: Division of Biomedical Sciences (Molecular Pathology Section), Imperial College School of Medicine, Sir Alexander Fleming Building, South Kensington, London SW7 2AZ, United Kingdom. Phone: (44) 20 7594 3009. Fax: (44) 20 7594 3022. E-mail: a.clerk{at}ic.ac.uk.

Molecular and Cellular Biology, February 2001, p. 1173-1184, Vol. 21, No. 4
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.4.1173-1184.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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