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Mol. Cell. Biol. 23 (4): 1316-1333

Copyright © 2003 by the American Society for Microbiology. All rights reserved.

Rho Family GTPases Are Required for Activation of Jak/STAT Signaling by G Protein-Coupled Receptors

Stéphane Pelletier,1,2 François Duhamel,1,2 Philippe Coulombe,1,3 Michel R. Popoff,4 and Sylvain Meloche1,2,3*

Institut de recherches cliniques de Montréal,1 Departments of Pharmacology,2 Molecular Biology, Université de Montréal, Montréal, Québec, Canada,3 Unité des Toxines Microbiennes, Institut Pasteur, Paris, France4

Received for publication 15 April 2002. Revision received 17 June 2002. Accepted for publication 29 October 2002.

Abstract: As do cytokine receptors and receptor tyrosine kinases, G protein-coupled receptors (GPCRs) signal to Janus kinases (Jaks) and signal transducers and activators of transcription (STATs). However, the early biochemical events linking GPCRs to this signaling pathway have been unclear. Here we show that GPCR-stimulated Rac activity and the subsequent generation of reactive oxygen species are necessary for activating tyrosine phosphorylation of Jaks and STAT-dependent transcription. The requirement for Rac activity can be overcome by addition of hydrogen peroxide. Expression of activated mutants of Rac1 is sufficient to activate Jak2 and STAT-dependent transcription, and the activation of Jak2 correlates with the ability of Rac1 to bind to NADPH oxidase subunit p67phox. We further show that GPCR agonists stimulate tyrosine phosphorylation of STAT1 and STAT3 proteins in a Rac-dependent manner. The tyrosine phosphorylation of STAT3 is biphasic; the first peak of phosphorylation is weak and correlates with rapid activation of Jaks by GPCRs, whereas the second peak is stronger and requires the synthesis of an autocrine factor. Rho also plays an essential role in the induction of STAT transcriptional activity. Our results highlight a novel role for Rho GTPases in mediating the regulatory effects of GPCRs on STAT-dependent gene expression.

* Corresponding author. Mailing address: Institut de recherches cliniques de Montréal, 110 Pine Ave. W., Montreal, Quebec H2W 1R7, Canada. Phone: (514) 987-5783. Fax: (514) 987-5536. E-mail: melochs{at}ircm.qc.ca.

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