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Blood, 15 November 2006, Vol. 108, No. 10, pp. 3379-3386. Prepublished online as a Blood First Edition Paper on July 20, 2006; DOI 10.1182/blood-2006-03-013557. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2006-03-013557v1 108/10/3379    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 HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Fagerholm, S. C. Articles by Gahmberg, C. G. Search for Related Content PubMed PubMed Citation Articles by Fagerholm, S. C. Articles by Gahmberg, C. G. Related Collections Immunobiology Phagocytes Cell Adhesion and Motility Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY -Chain phosphorylation of the human leukocyte CD11b/CD18 (Mac-1) integrin is pivotal for integrin activation to bind ICAMs and leukocyte extravasation Susanna C. Fagerholm, Minna Varis, Michael Stefanidakis, Tiina J. Hilden, and Carl G. Gahmberg From the Division of Biochemistry, Faculty of Biosciences, University of Helsinki, Finland. The promiscuous CD11b/CD18 (Mac-1) integrin has important roles in regulating many immunologic functions such as leukocyte adhesion and emigration from the bloodstream via interactions with the endothelial ligands ICAM-1 and ICAM-2, iC3b-mediated phagocytosis, and apoptosis. However, the mechanisms for Mac-1 inside-out activation have remained poorly understood. Phosphorylation of integrin cytoplasmic domains is emerging as an important mechanism of regulating integrin functions. Here, we have studied phosphorylation of human CD11b, which takes place on the cytoplasmic Ser1126 in neutrophils. We show that mutation of the serine phosphorylation site leads to inability of Mac-1 to become activated to bind the cellular ligands ICAM-1 and ICAM-2. However, CD11b-mutant cells are fully capable of binding other studied CD11b ligands (ie, iC3b and denatured BSA). Activation epitopes expressed in the extracellular domain of the integrin and affinity for soluble ICAM ligands were decreased for the mutated integrin. Additionally, the mutation resulted in inhibition of chemokine-induced migration in a transendothelial assay in vitro and significantly reduced the accumulation of intravenously administered cells in the spleen and lungs of Balb/c mice. These results characterize a novel selective mechanism of Mac-1–integrin activation, which mediates leukocyte emigration from the bloodstream to the tissues. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. Han, X. Kim-Howard, H. Deshmukh, Y. Kamatani, P. Viswanathan, J. M. Guthridge, K. Thomas, K. M. Kaufman, J. Ojwang, A. Rojas-Villarraga, et al. Evaluation of imputation-based association in and around the integrin-{alpha}-M (ITGAM) gene and replication of robust association between a non-synonymous functional variant within ITGAM and systemic lupus erythematosus (SLE) Hum. Mol. Genet., March 15, 2009; 18(6): 1171 - 1180. [Abstract] [Full Text] [PDF] H. Nakayama, F. Yoshizaki, A. Prinetti, S. Sonnino, L. Mauri, K. Takamori, H. Ogawa, and K. Iwabuchi Lyn-coupled LacCer-enriched lipid rafts are required for CD11b/CD18-mediated neutrophil phagocytosis of nonopsonized microorganisms J. Leukoc. Biol., March 1, 2008; 83(3): 728 - 741. [Abstract] [Full Text] [PDF] S. Yona, H.-H. Lin, P. Dri, J. Q. Davies, R. P. G. Hayhoe, S. M. Lewis, S. E. M. Heinsbroek, K. A. Brown, M. Perretti, J. Hamann, et al. Ligation of the adhesion-GPCR EMR2 regulates human neutrophil function FASEB J, March 1, 2008; 22(3): 741 - 751. [Abstract] [Full Text] [PDF] G. Zauli, F. Corallini, F. Bossi, F. Fischetti, P. Durigutto, C. Celeghini, F. Tedesco, and P. Secchiero Osteoprotegerin increases leukocyte adhesion to endothelial cells both in vitro and in vivo Blood, July 15, 2007; 110(2): 536 - 543. [Abstract] [Full Text] [PDF]

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