This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplemental material
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 Paing, M. M.
Right arrow Articles by Trejo, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Paing, M. M.
Right arrow Articles by Trejo, J.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, April 2006, p. 3231-3242, Vol. 26, No. 8
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.8.3231-3242.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Clathrin Adaptor AP2 Regulates Thrombin Receptor Constitutive Internalization and Endothelial Cell Resensitization{dagger}

May M. Paing,1 Christopher A. Johnston,1 David P. Siderovski,1 and JoAnn Trejo1,2*

Department of Pharmacology,1 Department of Cell and Developmental Biology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-73652

Received 18 August 2005/ Returned for modification 30 September 2005/ Accepted 17 January 2006

Protease-activated receptor 1 (PAR1), a G protein-coupled receptor for the coagulant protease thrombin, is irreversibly activated by proteolysis. Unactivated PAR1 cycles constitutively between the plasma membrane and intracellular stores, thereby providing a protected receptor pool that replenishes the cell surface after thrombin exposure and leads to rapid resensitization to thrombin signaling independent of de novo receptor synthesis. Here, we show that AP2, a clathrin adaptor, binds directly to a tyrosine-based motif in the cytoplasmic tail of PAR1 and is essential for constitutive receptor internalization and cellular recovery of thrombin signaling. Expression of a PAR1 tyrosine mutant or depletion of AP2 by RNA interference leads to significant inhibition of PAR1 constitutive internalization, loss of intracellular uncleaved PAR1, and failure of endothelial cells and other cell types to regain thrombin responsiveness. Our findings establish a novel role for AP2 in direct regulation of PAR1 trafficking, a process critically important to the temporal and spatial aspects of thrombin signaling.

* Corresponding author. Mailing address: Department of Pharmacology, University of North Carolina at Chapel Hill, 1106 Mary Ellen Jones Bldg., Chapel Hill, NC 27599-7365. Phone: (919) 843-7691. Fax: (919) 966-5640. E-mail: joann_trejo{at}med.unc.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, April 2006, p. 3231-3242, Vol. 26, No. 8
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.8.3231-3242.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Ricks, T. K., Trejo, J. (2009). Phosphorylation of Protease-activated Receptor-2 Differentially Regulates Desensitization and Internalization. J. Biol. Chem. 284: 34444-34457 [Abstract] [Full Text]  
  • Atzori, L., Lucattelli, M., Scotton, C. J., Laurent, G. J., Bartalesi, B., De Cunto, G., Lunghi, B., Chambers, R. C., Lungarella, G. (2009). Absence of Proteinase-Activated Receptor-1 Signaling in Mice Confers Protection from fMLP-Induced Goblet Cell Metaplasia. Am. J. Respir. Cell Mol. Bio. 41: 680-687 [Abstract] [Full Text]  
  • Baugher, P. J., Richmond, A. (2008). The Carboxyl-terminal PDZ Ligand Motif of Chemokine Receptor CXCR2 Modulates Post-endocytic Sorting and Cellular Chemotaxis. J. Biol. Chem. 283: 30868-30878 [Abstract] [Full Text]  
  • Meiser, A., Mueller, A., Wise, E. L., McDonagh, E. M., Petit, S. J., Saran, N., Clark, P. C., Williams, T. J., Pease, J. E. (2008). The Chemokine Receptor CXCR3 Is Degraded following Internalization and Is Replenished at the Cell Surface by De Novo Synthesis of Receptor. J. Immunol. 180: 6713-6724 [Abstract] [Full Text]  
  • Urs, N. M., Kowalczyk, A. P., Radhakrishna, H. (2008). Different Mechanisms Regulate Lysophosphatidic Acid (LPA)-dependent Versus Phorbol Ester-dependent Internalization of the LPA1 Receptor. J. Biol. Chem. 283: 5249-5257 [Abstract] [Full Text]  
  • Holliday, N. D., Holst, B., Rodionova, E. A., Schwartz, T. W., Cox, H. M. (2007). Importance of Constitutive Activity and Arrestin-Independent Mechanisms for Intracellular Trafficking of the Ghrelin Receptor. Mol. Endocrinol. 21: 3100-3112 [Abstract] [Full Text]  
  • Komarova, Y. A., Mehta, D., Malik, A. B. (2007). Dual Regulation of Endothelial Junctional Permeability. Sci Signal 2007: re8-re8 [Abstract] [Full Text]  
  • Hamdan, F. F., Rochdi, M. D., Breton, B., Fessart, D., Michaud, D. E., Charest, P. G., Laporte, S. A., Bouvier, M. (2007). Unraveling G Protein-coupled Receptor Endocytosis Pathways Using Real-time Monitoring of Agonist-promoted Interaction between beta-Arrestins and AP-2. J. Biol. Chem. 282: 29089-29100 [Abstract] [Full Text]  
  • Wolfe, B. L., Marchese, A., Trejo, J. (2007). Ubiquitination differentially regulates clathrin-dependent internalization of protease-activated receptor-1. JCB 177: 905-916 [Abstract] [Full Text]  
  • Fessart, D., Simaan, M., Zimmerman, B., Comeau, J., Hamdan, F. F., Wiseman, P. W., Bouvier, M., Laporte, S. A. (2007). Src-dependent phosphorylation of beta2-adaptin dissociates the beta-arrestin-AP-2 complex. J. Cell Sci. 120: 1723-1732 [Abstract] [Full Text]  
  • Mohammad, S., Baldini, G., Granell, S., Narducci, P., Martelli, A. M., Baldini, G. (2007). Constitutive Traffic of Melanocortin-4 Receptor in Neuro2A Cells and Immortalized Hypothalamic Neurons. J. Biol. Chem. 282: 4963-4974 [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»