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J. Biol. Chem., Vol. 282, Issue 35, 25385-25394, August 31, 2007

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Direct and Indirect Interactions of the Cytoplasmic Region of CD244 (2B4) in Mice and Humans with FYN Kinase^*

From the Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, United Kingdom

Engagement of the receptor CD244 (2B4) by its ligand CD48 has inhibitory and activating potential, and this differs depending on experimental systems in mouse and human. We show that, in both mouse and human upon engagement of its ligand CD48, CD244 can give a negative signal to natural killer cells, implying conservation of function between the two species. The signaling mechanisms used by CD244 in both human and mouse are conserved as shown by quantitative analyses of the direct molecular interactions of the SH2 domains of the adaptors SLAM-associated protein (SAP) and EAT-2 and of FYN kinase with CD244 together with the indirect interactions of the FYN SH2 domain with EAT-2. Functional experiments support the biochemical hierarchy of interactions and show that EAT-2 is not inhibitory per se. The data are consistent with a model in which the mechanism of signal transduction by CD244 is to regulate FYN kinase recruitment and/or activity and the outcome of CD48/CD244 interactions is determined by which other receptors are engaged.

Received for publication, May 31, 2007

^* This work was supported by the Medical Research Council and the Cellular Immunology Unit Hybridoma Fund. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 44-1865-275-595; Fax: 44-1865-275-591; E-mail: Marion.Brown{at}path.ox.ac.uk.

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This article has been cited by other articles:

				L. K. Chlewicki, C. A. Velikovsky, V. Balakrishnan, R. A. Mariuzza, and V. Kumar Molecular Basis of the Dual Functions of 2B4 (CD244) J. Immunol., June 15, 2008; 180(12): 8159 - 8167. [Abstract] [Full Text] [PDF]