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Blood, 15 June 2005, Vol. 105, No. 12, pp. 4722-4729. Prepublished online as a Blood First Edition Paper on February 15, 2005; DOI 10.1182/blood-2004-09-3796. This Article Full Text (PDF) All Versions of this Article: 2004-09-3796v1 105/12/4722    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 Eissmann, P. Articles by Watzl, C. Search for Related Content PubMed PubMed Citation Articles by Eissmann, P. Articles by Watzl, C. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted September 30, 2004 Accepted February 11, 2005 Molecular basis for positive and negative signaling by the natural killer cell receptor 2B4 (CD244) Philipp Eissmann, Lisa Beauchamp, Joe Wooters, John C Tilton, Eric O Long, and Carsten Watzl* Institute for Immunology, University Heidelberg, Heidelberg, Germany Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA Protein Chemistry and Proteomics, Wyeth Research, Cambridge, MA, USA Institute for Immunology, University Heidelberg, Heidelberg, Germany; Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA * Corresponding author; email: carsten.watzl{at}urz.uni-heidelberg.de. Triggering of 2B4 (CD244) can induce NK cell activation, co-stimulation, or even inhibition of NK cell activity. Here we investigate the molecular basis for the different signals generated by 2B4. We show that the first immunoreceptor tyrosine-based switch motif (ITSM) within the cytoplasmic tail of 2B4 is sufficient for 2B4-mediated NK cell activation while the third ITSM can negatively influence 2B4 signaling. We further identify signaling molecules that associate with 2B4. SAP can bind to all four ITSM of 2B4 in a phosphorylation-dependent manner. The phosphorylated third ITSM can additionally recruit the phosphatases SHP-1, SHP-2, SHIP, and the inhibitory kinase Csk. SAP acts as an inhibitor of interactions between 2B4 and these negative-regulatory molecules, explaining how 2B4 inhibits NK cell activation in the absence of functional SAP, as occurs in cells from X-linked lymphoproliferative syndrome (XLP) patients. Recently, another function for SAP was proposed: SAP can recruit the kinase Fyn to the SLAM (CD150) immune receptor. We now show that Fyn can also associate with phosphorylated 2B4. Finally, we demonstrate that Fyn and Csk can both phosphorylate 2B4, suggesting a possible mechanism of 2B4 phosphorylation. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. El Firar, T. Voisin, C. Rouyer-Fessard, M. A. Ostuni, A. Couvineau, and M. Laburthe Discovery of a functional immunoreceptor tyrosine-based switch motif in a 7-transmembrane-spanning receptor: role in the orexin receptor OX1R-driven apoptosis FASEB J, December 1, 2009; 23(12): 4069 - 4080. [Abstract] [Full Text] [PDF] N. G. Clarkson and M. H. Brown Inhibition and Activation by CD244 Depends on CD2 and Phospholipase C-{gamma}1 J. Biol. Chem., September 11, 2009; 284(37): 24725 - 24734. [Abstract] [Full Text] [PDF] B. Altvater, S. Landmeier, S. Pscherer, J. Temme, K. Schweer, S. Kailayangiri, D. Campana, H. Juergens, M. Pule, and C. 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