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Blood, 30 July 2009, Vol. 114, No. 5, pp. 1073-1082. Prepublished online as a Blood First Edition Paper on May 8, 2009; DOI 10.1182/blood-2008-10-183699. This Article Full Text Full Text (PDF) Supplemental Methods, Table, and Figures All Versions of this Article: blood-2008-10-183699v1 114/5/1073    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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 CrossRef Google Scholar Articles by Molteni, R. Articles by Pardi, R. PubMed PubMed Citation Articles by Molteni, R. Articles by Pardi, R. Related Collections Immunobiology Phagocytes, Granulocytes, and Myelopoiesis Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  PHAGOCYTES, GRANULOCYTES, AND MYELOPOIESIS β-Arrestin 2 is required for the induction and strengthening of integrin-mediated leukocyte adhesion during CXCR2-driven extravasation Raffaella Molteni1,2, Carolina Lage Crespo1,2, Sara Feigelson3, Christian Moser4, Monica Fabbri1,2, Valentin Grabovsky3, Fritz Krombach4, Carlo Laudanna5, Ronen Alon3, and Ruggero Pardi1,2 1 San Raffaele University School of Medicine and 2 Scientific Institute San Raffaele, Milano, Italy; 3 Department of Immunology, Weizmann Institute of Science, Rehovot, Israel; 4 Walter Brendel Center of Experimental Medicine, Ludwig-Maximilians-Universität München, Munich, Germany; and 5 Division of General Pathology, Department of Pathology, School of Medicine, and the Center for Biomedical Computing (CBMC), University of Verona, Verona, Italy Leukocyte extravasation involves interdependent signaling pathways underlying the complex dynamics of firm adhesion, crawling, and diapedesis. While signal transduction by agonist-bound chemokine receptors plays a central role in the above responses, it is unclear how it contributes to the sustained and concurrent nature of such responses, given the rapid kinetics of chemokine-induced trimeric G protein coupling and homologous desensitization. Our findings unveil a novel role of β-arrestins in regulating the activation of signaling pathways underlying discrete integrin-mediated steps in CXCR2-driven leukocyte extravasation. By combining in vivo approaches in β-arrestin knockout mice with in vitro studies in engineered cellular models, we show that membrane-recruited β-arrestin 2 is required for the onset and maintenance of shear stress-resistant leukocyte adhesion mediated by both β1 and β2 integrins. While both β-arrestin isoforms are required for rapid keratinocyte-derived chemokine (KC)–induced arrest onto limiting amounts of vascular cell adhesion molecule-1 (VCAM-1), adhesion strengthening under shear is selectively dependent on β-arrestin 2. The latter synergizes with phospholipase C in promoting activation of Rap1A and B, both of which co-operatively control subsecond adhesion as well as postarrest adhesion stabilization. Thus, receptor-induced Gi and β-arrestins act sequentially and in spatially distinct compartments to promote optimal KC-induced integrin-dependent adhesion during leukocyte extravasation. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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