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Blood, 1 September 2008, Vol. 112, No. 5, pp. 1853-1862. Prepublished online as a Blood First Edition Paper on June 12, 2008; DOI 10.1182/blood-2007-12-127795. This Article Full Text (PDF) All Versions of this Article: blood-2007-12-127795v1 112/5/1853    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 Takala, H. Articles by Fagerholm, S. C Search for Related Content PubMed PubMed Citation Articles by Takala, H. Articles by Fagerholm, S. C Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted December 12, 2007 Accepted April 22, 2008 Integrin 2 phosphorylation on THR758 acts as a molecular switch to regulate 14-3-3 and filamin binding Heikki Takala, Elisa Nurminen, Susanna M Nurmi, Maria Aatonen, Tomas Strandin, Maarit Takatalo, Tiila Kiema, Carl G Gahmberg, Jari Ylanne, and Susanna C Fagerholm* Department of Biological and Environmental Science and Nanoscience Center, University of Jyvaskyla, Jyvaskyla, Finland Faculty of Biosciences, Division of Biochemistry, University of Helsinki, Helsinki, Finland Peptide and Protein laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland Department of Biochemistry, University of Oulu, Oulu, Finland Division of Pathology and Neuroscience, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom * Corresponding author; email: s.c.fagerholm{at}dundee.ac.uk. Leukocyte integrins of the 2 family are essential for immune cell-cell adhesion. In activated cells, 2 integrins are phosphorylated on the cytoplasmic Thr758, leading to 14-3-3 protein recruitment to the 2 integrin. The mutation of this phosphorylation site impairs cell adhesion, actin reorganization and cell spreading. Thr758 is contained in a Thr-triplet of 2 that also mediates binding to filamin. Here, we investigated the binding of filamin, talin and 14-3-3 proteins to phosphorylated and unphosphorylated 2 integrins by biochemical methods and X-ray crystallography. 14-3-3 proteins bound only to the phosphorylated integrin cytoplasmic peptide, with a high affinity (Kd 261 nM), whereas filamin bound only the unphosphorylated integrin cytoplasmic peptide (Kd 0.5 mM). Phosphorylation did not regulate talin binding to 2 directly, but 14-3-3 was able to out-compete talin for the binding to phosphorylated 2-integrin. X-ray crystallographic data clearly explained how phosphorylation eliminated filamin binding and induced 14-3-3 protein binding. Filamin knockdown in T cells led to an increase in stimulated cell adhesion to ICAM-1-coated surfaces. Our results suggest that the phosphorylation of 2 integrins on Thr758 acts as a molecular switch to inhibit filamin binding and allow 14-3-3 protein binding to the integrin cytoplasmic domain, thereby modulating T cell adhesion. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: O. K. Heikkinen, S. Ruskamo, P. V. Konarev, D. I. Svergun, T. Iivanainen, S. M. Heikkinen, P. Permi, H. Koskela, I. Kilpelainen, and J. Ylanne Atomic Structures of Two Novel Immunoglobulin-like Domain Pairs in the Actin Cross-linking Protein Filamin J. Biol. Chem., September 11, 2009; 284(37): 25450 - 25458. [Abstract] [Full Text] [PDF] K. R. Legate, S. A. Wickstrom, and R. Fassler Genetic and cell biological analysis of integrin outside-in signaling Genes & Dev., February 15, 2009; 23(4): 397 - 418. [Abstract] [Full Text] [PDF] S. S. Ithychanda, M. Das, Y.-Q. Ma, K. Ding, X. Wang, S. Gupta, C. Wu, E. F. Plow, and J. Qin Migfilin, a Molecular Switch in Regulation of Integrin Activation J. Biol. Chem., February 13, 2009; 284(7): 4713 - 4722. [Abstract] [Full Text] [PDF] A. Bhunia, X.-Y. Tang, H. Mohanram, S.-M. Tan, and S. Bhattacharjya NMR Solution Conformations and Interactions of Integrin {alpha}L{beta}2 Cytoplasmic Tails J. Biol. Chem., February 6, 2009; 284(6): 3873 - 3884. [Abstract] [Full Text] [PDF] D. S. Harburger and D. A. Calderwood Integrin signalling at a glance J. Cell Sci., January 15, 2009; 122(2): 159 - 163. [Full Text] [PDF] K. R. Legate and R. Fassler Mechanisms that regulate adaptor binding to {beta}-integrin cytoplasmic tails J. Cell Sci., January 15, 2009; 122(2): 187 - 198. [Abstract] [Full Text] [PDF] Y. Lad, P. Jiang, S. Ruskamo, D. S. Harburger, J. Ylanne, I. D. Campbell, and D. A. Calderwood Structural Basis of the Migfilin-Filamin Interaction and Competition with Integrin {beta} Tails J. Biol. Chem., December 12, 2008; 283(50): 35154 - 35163. [Abstract] [Full Text] [PDF]

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