SEARCH:   Advanced

Blood, 1 April 2008, Vol. 111, No. 7, pp. 3607-3614. Prepublished online as a Blood First Edition Paper on January 31, 2008; DOI 10.1182/blood-2007-07-103077. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2007-07-103077v1 111/7/3607    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 Choi, E. Y. Articles by Chavakis, T. PubMed PubMed Citation Articles by Choi, E. Y. Articles by Chavakis, T. Related Collections Cell Adhesion and Motility Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Regulation of LFA-1–dependent inflammatory cell recruitment by Cbl-b and 14-3-3 proteins Eun Young Choi1, Valeria V. Orlova1, Susanna C. Fagerholm2,3, Susanna M. Nurmi2, Li Zhang4, Christie M. Ballantyne5, Carl G. Gahmberg2, and Triantafyllos Chavakis1 1 Experimental Immunology Branch (EIB), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD; 2 Division of Biochemistry, Faculty of Biosciences, University of Helsinki, Helsinki, Finland; 3 Division of Pathology and Neuroscience, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom; 4 Department of Physiology, University of Maryland School of Medicine, Baltimore; and 5 Department of Medicine, Baylor College of Medicine and Center for Cardiovascular Disease Prevention, Methodist DeBakey Heart Center, Houston, TX Inside-out signaling regulation of the β2-integrin leukocyte function–associated antigen-1 (LFA-1) by different cytoplasmic proteins, including 14-3-3 proteins, is essential for adhesion and migration of immune cells. Here, we identify a new pathway for the regulation of LFA-1 activity by Cbl-b, an adapter molecule and ubiquitin ligase that modulates several signaling pathways. Cbl-b–/– mice displayed increased macrophage recruitment in thioglycollate-induced peritonitis, which was attributed to Cbl-b deficiency in macrophages, as assessed by bone marrow chimera experiments. In vitro, Cbl-b–/– bone marrow–derived mononuclear phagocytes (BMDMs) displayed increased adhesion to endothelial cells. Activation of LFA-1 in Cbl-b–deficient cells was responsible for their increased endothelial adhesion in vitro and peritoneal recruitment in vivo, as the phenotype of Cbl-b deficiency was reversed in Cbl-b–/–LFA-1–/– mice. Consistently, LFA-1–mediated adhesion of BMDM to ICAM-1 but not VLA-4–mediated adhesion to VCAM-1 was enhanced by Cbl-b deficiency. Cbl-b deficiency resulted in increased phosphorylation of T758 in the β2-chain of LFA-1 and thereby in enhanced association of 14-3-3β protein with the β2-chain, leading to activation of LFA-1. Consistently, disruption of the 14-3-3/β2-integrin interaction abrogated the enhanced ICAM-1 adhesion of Cbl-b–/– BMDMs. In conclusion, Cbl-b deficiency activates LFA-1 and LFA-1–mediated inflammatory cell recruitment by stimulating the interaction between the LFA-1 β-chain and 14-3-3 proteins. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

	Blood Online is supported in part by Genentech BioOncology and Biogen Idec
	Copyright © 2008 by American Society of Hematology         Online ISSN: 1528-0020