title: Direct and indirect interactions of the cytoplasmic region of CD244 (2B4) in mice and humans with FYN kinase.
abstract: 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.
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, United Kingdom.
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Clarkson
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Simmonds
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Puklavec
authors.forename: Marion H
authors.initials: MH
authors.lastname: Brown
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D000071178:CD48 Antigen; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007694:Killer Cells, Natural / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D011485:Protein Binding; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism*; D051381:Rats; D011971:Receptors, Immunologic / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D000071176:Signaling Lymphocytic Activation Molecule Family; D014157:Transcription Factors / Q000378:metabolism; D018909:src Homology Domains / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; C084093:CD244 protein, human; D000071178:CD48 Antigen; C000604065:CD48 protein, human; C490007:Cd244a protein, mouse; C000604066:Cd48 protein, mouse; C000604067:Cd48 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C114953:SH2D1A protein, human; C103572:SH2D1B protein, human; C499569:Sh2d1a protein, mouse; C491225:Sh2d1b1 protein, mouse; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D000071176:Signaling Lymphocytic Activation Molecule Family; D014157:Transcription Factors; C494957:FYN protein, human; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn