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Thrombin Protease-activated Receptor-1 Signals through Gq- and G13-initiated MAPK Cascades Regulating c-Jun Expression to Induce Cell Transformation

Marinissen, Maria Julia and Servitja, Joan-Marc and Offermanns, Stefan and Simon, Melvin I. and Gutkind, J. Silvio (2003) Thrombin Protease-activated Receptor-1 Signals through Gq- and G13-initiated MAPK Cascades Regulating c-Jun Expression to Induce Cell Transformation. Journal of Biological Chemistry, 278 (47). pp. 46814-46825. ISSN 0021-9258. http://resolver.caltech.edu/CaltechAUTHORS:MARjbc03

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Abstract

Although the ability of G protein-coupled receptors to stimulate normal and aberrant cell growth has been intensely investigated, the precise nature of the molecular mechanisms underlying their transforming potential are still not fully understood. In this study, we have taken advantage of the potent mitogenic effect of thrombin and the focus-forming activity of one of its receptors, protease-activated receptor-1, to dissect how this receptor coupled to Gi, Gq/11, and G12/13 transduces signals from the membrane to the nucleus to initiate transcriptional events involved in cell transformation. Using endogenous and transfected thrombin receptors in NIH 3T3 cells, ectopic expression of muscarinic receptors coupled to Gq and Gi, and chimeric G protein subunits and murine fibroblasts deficient in Gq/11, and G12/13, we show here that, although coupling to Gi is sufficient to induce ERK activation, the ability to couple to Gq and/or G13 is necessary to induce c-jun expression and cell transformation. Furthermore, we show that Gq and G13 can initiate the activation of MAPK cascades, including JNK, p38, and ERK5, which in turn regulate the activity of transcription factors controlling expression from the c-jun promoter. We also present evidence that c-Jun and the kinases regulating its expression are integral components of the transforming pathway initiated by protease-activated receptor-1.


Item Type:Article
Additional Information:Copyright © 2003 by the American Society for Biochemistry and Molecular Biology. Received for publication, June 2, 2003, and in revised form, August 29, 2003. Published, JBC Papers in Press, September 3, 2003, DOI 10.1074/jbc.M305709200 The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Subject Keywords:HETEROTRIMERIC G-PROTEINS; EARLY GENE-EXPRESSION; SMOOTH-MUSCLE-CELLS; NIH 3T3 CELLS; COUPLED RECEPTORS; ALPHA-SUBUNIT; BINDING PROTEINS; KINASE PATHWAY; MALIGNANT TRANSFORMATION; TYROSINE PHOSPHORYLATION
Record Number:CaltechAUTHORS:MARjbc03
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:MARjbc03
Alternative URL:http://www.jbc.org/cgi/content/abstract/278/47/46814
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:5748
Collection:CaltechAUTHORS
Deposited By: Lindsay Cleary
Deposited On:31 Oct 2006
Last Modified:26 Dec 2012 09:14

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