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Blood, 15 December 2008, Vol. 112, No. 13, pp. 5007-5015. Prepublished online as a Blood First Edition Paper on September 22, 2008; DOI 10.1182/blood-2008-03-144543. This Article Full Text (PDF) Supplemental Methods, Table, Figures, and Videos All Versions of this Article: blood-2008-03-144543v1 112/13/5007    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 Imai, Y. Articles by Shimaoka, M. Search for Related Content PubMed PubMed Citation Articles by Imai, Y. Articles by Shimaoka, M. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 12, 2008 Accepted August 26, 2008 Genetic perturbation of the putative cytoplasmic membrane-proximal salt bridge aberrantly activates 4 integrins Yoichi Imai, Eun Jeong Park, Dan Peer, Antonio Peixoto, Guiying Cheng, Ulrich H von Andrian, Christopher V Carman, and Motomu Shimaoka* Department of Anaesthesia, Harvard Medical School, Boston, MA, United States Department of Pathology, Harvard Medical School, Boston, MA, United States Immune Disease Institute, Harvard Medical School, Boston, MA, United States Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, MA, United States * Corresponding author; email: shimaoka{at}idi.harvard.edu. 4 integrins play a pivotal role in leukocyte migration and tissue-specific homing. The ability of integrins to bind ligand is dynamically regulated by activation-dependent conformational changes triggered in the cytoplasmic domain. An NMR solution structure defined a putative membrane-proximal salt bridge between the IIb3 integrin cytoplasmic tails, which restrains integrins in their low affinity state. However, the physiological importance of this salt bridge in 4 integrin regulation remains to be elucidated. To address this question, we disrupted the salt bridge in murine germline by mutating the conserved cytoplasmic arginine RGFFKR in 4 integrins. In lymphocytes from knock-in mice (4-R/AGFFKR), 41 and 47 integrins exhibited constitutively upregulated ligand binding. However, transmigration of these cells across VCAM-1 and MAdCAM-1 substrates, or across endothelial monolayers, was reduced. Perturbed detachment of the tail appeared to cause the reduced cell migration of 4-R/AGFFKR lymphocytes. In vivo, 4-R/AGFFKR cells exhibited increased firm adhesion to Peyer's patch venules but reduced homing to the gut. Our results demonstrate that the membrane-proximal salt bridge plays a critical role in supporting proper 4 integrin adhesive dynamics. Loss of this interaction destabilizes the non-adhesive conformation, and thereby perturbs the properly balanced cycles of adhesion and de-adhesion required for efficient cell migration. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: N. Huser, A. Fasan, M. Semmrich, P. Schmidbauer, B. Holzmann, and M. Laschinger Intact LFA-1 deactivation promotes T-cell activation and rejection of cardiac allograft Int. Immunol., November 27, 2009; (2009) dxp111v1. [Abstract] [Full Text] [PDF]

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