This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Pak, Y.
Right arrow Articles by Rotin, D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Pak, Y.
Right arrow Articles by Rotin, D.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, November 2002, p. 7942-7952, Vol. 22, No. 22
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.22.7942-7952.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Direct Binding of the ß1 Adrenergic Receptor to the Cyclic AMP-Dependent Guanine Nucleotide Exchange Factor CNrasGEF Leads to Ras Activation

Youngshil Pak, Nam Pham, and Daniela Rotin*

Program in Cell Biology, The Hospital for Sick Children, and Biochemistry Department, University of Toronto, Toronto, M5G 1X8 Ontario, Canada

Received 7 March 2002/ Returned for modification 12 April 2002/ Accepted 29 July 2002

G-protein-coupled receptors (GPCRs) can indirectly activate Ras primarily through the ß{gamma} subunits of G proteins, which recruit c-Src, phosphatidylinositol 3-kinase, and Grb2-SOS. However, a direct interaction between a Ras activator (guanine nucleotide exchange factor [GEF]) and GPCRs that leads to Ras activation has never been demonstrated. We report here a novel mechanism for a direct GPCR-mediated Ras activation. The ß1 adrenergic receptor (ß1-AR) binds to the PDZ domain of the cyclic AMP (cAMP)-dependent Ras exchange factor, CNrasGEF, via its C-terminal SkV motif. In cells heterologously expressing ß1-AR and CNrasGEF, Ras is activated by the ß1-AR agonist isoproterenol, and this activation is abolished in ß1-AR mutants that cannot bind CNrasGEF or in CNrasGEF mutants lacking the catalytic CDC25 domain or cAMP-binding domain. Moreover, the activation is transduced via Gs{alpha} and not via Gß{gamma}. In contrast to ß1-AR, the ß2-AR neither binds CNrasGEF nor activates Ras via CNrasGEF after agonist stimulation. These results suggest a model whereby the physical interaction between the ß1-AR and CNrasGEF facilitates the transduction of Gs{alpha}-induced cAMP signal into the activation of Ras. The present study provides the first demonstration of direct physical association between a Ras activator and a GPCR, leading to agonist-induced Ras activation

* Corresponding author. Mailing address: Program in Cell Biology, The Hospital for Sick Children, 555 University Ave., Toronto, M5G 1X8 Ontario, Canada. Phone: (416) 813-5098. Fax: (416) 813-5771. E-mail: drotin{at}sickkids.ca.

Molecular and Cellular Biology, November 2002, p. 7942-7952, Vol. 22, No. 22
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.22.7942-7952.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Vuchak, L. A., Tsygankova, O. M., Prendergast, G. V., Meinkoth, J. L. (2009). Protein Kinase A and B-Raf Mediate Extracellular Signal-Regulated Kinase Activation by Thyrotropin. Mol. Pharmacol. 76: 1123-1129 [Abstract] [Full Text]  
  • Lynch, G. S., Ryall, J. G. (2008). Role of {beta}-Adrenoceptor Signaling in Skeletal Muscle: Implications for Muscle Wasting and Disease. Physiol. Rev. 88: 729-767 [Abstract] [Full Text]  
  • He, J., Bellini, M., Inuzuka, H., Xu, J., Xiong, Y., Yang, X., Castleberry, A. M., Hall, R. A. (2006). Proteomic Analysis of beta1-Adrenergic Receptor Interactions with PDZ Scaffold Proteins. J. Biol. Chem. 281: 2820-2827 [Abstract] [Full Text]  
  • Amsen, E. M., Pham, N., Pak, Y., Rotin, D. (2006). The Guanine Nucleotide Exchange Factor CNrasGEF Regulates Melanogenesis and Cell Survival in Melanoma Cells. J. Biol. Chem. 281: 121-128 [Abstract] [Full Text]  
  • Maudsley, S., Martin, B., Luttrell, L. M. (2005). The Origins of Diversity and Specificity in G Protein-Coupled Receptor Signaling. J. Pharmacol. Exp. Ther. 314: 485-494 [Abstract] [Full Text]  
  • Berkel, W. P.-v., Verheijen, M.H.G., Cuppen, E., Asahina, M., de Rooij, J., Jansen, G., Plasterk, R.H.A., Bos, J. L., Zwartkruis, F.J.T. (2005). Requirement of the Caenorhabditis elegans RapGEF pxf-1 and rap-1 for Epithelial Integrity. Mol. Biol. Cell 16: 106-116 [Abstract] [Full Text]  
  • He, J., Bellini, M., Xu, J., Castleberry, A. M., Hall, R. A. (2004). Interaction with Cystic Fibrosis Transmembrane Conductance Regulator-associated Ligand (CAL) Inhibits {beta}1-Adrenergic Receptor Surface Expression. J. Biol. Chem. 279: 50190-50196 [Abstract] [Full Text]  
  • Wang, W., Zhu, W., Wang, S., Yang, D., Crow, M. T., Xiao, R.-P., Cheng, H. (2004). Sustained {beta}1-Adrenergic Stimulation Modulates Cardiac Contractility by Ca2+/Calmodulin Kinase Signaling Pathway. Circ. Res. 95: 798-806 [Abstract] [Full Text]  
  • Yang, H., Cooley, D., Legakis, J. E., Ge, Q., Andrade, R., Mattingly, R. R. (2003). Phosphorylation of the Ras-GRF1 Exchange Factor at Ser916/898 Reveals Activation of Ras Signaling in the Cerebral Cortex. J. Biol. Chem. 278: 13278-13285 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»