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Blood, 1 July 2008, Vol. 112, No. 1, pp. 34-44. Prepublished online as a Blood First Edition Paper on April 24, 2008; DOI 10.1182/blood-2007-07-102103. This Article Full Text (PDF) All Versions of this Article: blood-2007-07-102103v1 112/1/34    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Lagane, B. Articles by Bachelerie, F. Search for Related Content PubMed PubMed Citation Articles by Lagane, B. Articles by Bachelerie, F. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 18, 2007 Accepted March 27, 2008 CXCR4 dimerization and -arrestin-mediated signaling account for the enhanced chemotaxis to CXCL12 in WHIM syndrome Bernard Lagane*, Ken Y. C. Chow, Karl Balabanian, Angelique Levoye, Julie Harriague, Thierry Planchenault, Francoise Baleux, Nathalie Gunera-saad, Fernando Arenzana-Seisdedos, and Francoise Bachelerie Unite de Pathogenie Virale Moleculaire, INSERM U819, Institut Pasteur, Paris, France Unite de Chimie Organique, Institut Pasteur, Paris, France URCI-LS CH Lyon-sud, Universite Lyon 1, Lyon, France * Corresponding author; email: lagane{at}pasteur.fr. WHIM syndrome is an immune deficiency linked in many cases to heterozygous mutations causing truncations in the cytoplasmic tail of the chemokine receptor CXCR4. Leukocytes expressing truncated CXCR4 display enhanced responses to the receptor ligand CXCL12, including chemotaxis, which likely impair their trafficking and contribute to the immuno-hematological clinical manifestations of the syndrome. CXCR4 desensitization and endocytosis are dependent on -arrestin recruitment to the cytoplasmic tail, so that the truncated CXCR4 are refractory to these processes and so have enhanced G-protein-dependent signaling. Here, we show that the augmented responsiveness of WHIM leukocytes is also accounted for by enhanced -arrestin2-dependent signaling downstream of the truncated CXCR4 receptor. Indeed, the WHIM-associated receptor CXCR41013 maintains association with -arrestin2 and triggers augmented and prolonged -arrestin2-dependent signaling, as revealed by ERK1/2 phosphorylation kinetics. Evidence is also provided that CXCR41013-mediated chemotaxis critically requires -arrestin2, and disrupting the SHSK motif in the third intracellular loop of CXCR41013 abrogates -arrestin2-mediated signaling, but not coupling to G-proteins, and normalizes chemotaxis. We also demonstrate that CXCR41013 spontaneously forms heterodimers with wild-type CXCR4. Accordingly, we propose a model where enhanced functional interactions between -arrestin2 and receptor dimers account for the altered responsiveness of WHIM leukocytes to CXCL12. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. Levoye, K. Balabanian, F. Baleux, F. Bachelerie, and B. Lagane CXCR7 heterodimerizes with CXCR4 and regulates CXCL12-mediated G protein signaling Blood, June 11, 2009; 113(24): 6085 - 6093. [Abstract] [Full Text] [PDF] O. D. Schneider, A. A. Weiss, and W. E. Miller Pertussis Toxin Signals through the TCR to Initiate Cross-Desensitization of the Chemokine Receptor CXCR4 J. Immunol., May 1, 2009; 182(9): 5730 - 5739. [Abstract] [Full Text] [PDF] J. Kim, S. Ahn, K. Rajagopal, and R. J. Lefkowitz Independent {beta}-Arrestin2 and Gq/Protein Kinase C{zeta} Pathways for ERK Stimulated by Angiotensin Type 1A Receptors in Vascular Smooth Muscle Cells Converge on Transactivation of the Epidermal Growth Factor Receptor J. Biol. Chem., May 1, 2009; 284(18): 11953 - 11962. [Abstract] [Full Text] [PDF] L. D. Notarangelo and R. Badolato Leukocyte trafficking in primary immunodeficiencies J. Leukoc. Biol., March 1, 2009; 85(3): 335 - 343. [Abstract] [Full Text] [PDF] K. E. Luker, M. Gupta, and G. D. Luker Imaging chemokine receptor dimerization with firefly luciferase complementation FASEB J, March 1, 2009; 23(3): 823 - 834. [Abstract] [Full Text] [PDF] S. von Vietinghoff and K. Ley Homeostatic Regulation of Blood Neutrophil Counts J. Immunol., October 15, 2008; 181(8): 5183 - 5188. [Abstract] [Full Text] [PDF]

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