TY - JOUR
T1 - 2B4 utilizes ITAM-containing receptor complexes to initiate intracellular signaling and cytolysis
AU - Bida, Anya T.
AU - Upshaw Neff, Jadee L.
AU - Dick, Christopher J.
AU - Schoon, Renee A.
AU - Brickshawana, Adipong
AU - Chini, Claudia C.
AU - Billadeau, Daniel D.
N1 - Funding Information:
This work was supported by NCI grant CA47752 to D.D.B. and NIH grant F31-AI75632 to A.T.B. D.D.B. is a Leukemia and Lymphoma Society Scholar.
PY - 2011/5
Y1 - 2011/5
N2 - 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 Fce{open}RIγ 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.
AB - 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 Fce{open}RIγ 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.
KW - 2B4
KW - Cell activation
KW - Natural killer cells
KW - SAP
KW - Signal transduction
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U2 - 10.1016/j.molimm.2011.02.008
DO - 10.1016/j.molimm.2011.02.008
M3 - Article
C2 - 21439641
AN - SCOPUS:79954621871
SN - 0161-5890
VL - 48
SP - 1149
EP - 1159
JO - Molecular Immunology
JF - Molecular Immunology
IS - 9-10
ER -