title: 2B4 utilizes ITAM-containing receptor complexes to initiate intracellular signaling and cytolysis.
abstract: 2B4 is a member of the SLAM receptor family capable of activating NK cell cytotoxicity in the context of EBV infection. SAP (SLAM Associated Protein) deficiency causes defective signaling downstream of SLAM family receptors and high susceptibility to EBV. 2B4 costimulates natural cytotoxicity receptor (NCR) and TCR initiated signals to induce cellular cytotoxicity and cytokine release. The 2B4-SAP signal transduction pathway is not predicted to overlap with the TCR-ITAM pathway, although SAP is required for some TCR-induced signals. We therefore examined the functional relationship between SLAM family receptor 2B4 and ITAM-containing adaptor complexes. Removal of FcɛRIγ or CD3ζ-containing complexes, using genetically manipulated cell lines or siRNA specific suppression, significantly reduces 2B4-initiated functions in NK and T cells, respectively. Consistent with this relationship, Syk and ZAP-70 are capable of transducing 2B4 signals for calcium mobilization and cytolysis. Furthermore, ITAM-containing molecules constitutively associate with SAP. These results suggest a potential physical association between 2B4 and the ITAM receptor complexes that is required for 2B4-initiated signaling and cell-mediated killing.
authors: Department of Immunology, College of Medicine, Mayo Clinic, Rochester, MN 55905, United States.
authors: Anya T
authors: AT
authors: Bida
authors: Jadee L
authors: JL
authors: Upshaw Neff
authors: Christopher J
authors: CJ
authors: Dick
authors: Renee A
authors: RA
authors: Schoon
authors: Adipong
authors: A
authors: Brickshawana
authors: Claudia C
authors: CC
authors: Chini
authors: Daniel D
authors: DD
authors: Billadeau
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D004789:Enzyme Activation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D042541:Intracellular Space / Q000276:immunology*; D007694:Killer Cells, Natural / Q000166:cytology / Q000201:enzymology; D051379:Mice; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000378:metabolism; D051966:Phospholipase C gamma / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D011971:Receptors, Immunologic / Q000737:chemistry* / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D000071176:Signaling Lymphocytic Activation Molecule Family; D000072377:Syk Kinase
chemical_list: D015703:Antigens, CD; C084093:CD244 protein, human; D047908:Intracellular Signaling Peptides and Proteins; C112260:NCR1 protein, human; D055627:Natural Cytotoxicity Triggering Receptor 1; D011948:Receptors, Antigen, T-Cell; D011971:Receptors, Immunologic; D011994:Recombinant Proteins; C114953:SH2D1A protein, human; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D000071176:Signaling Lymphocytic Activation Molecule Family; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D051966:Phospholipase C gamma; D002118:Calcium