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Molecular and Cellular Biology, June 2004, p. 5144-5156, Vol. 24, No. 12
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.12.5144-5156.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Molecular Dissection of 2B4 Signaling: Implications for Signal Transduction by SLAM-Related Receptors

Riyan Chen,1 Francis Relouzat,2 Romain Roncagalli,1,3 Ala Aoukaty,4 Rusung Tan,4 Sylvain Latour,2 and André Veillette1,3,5,6,7*

Laboratory of Molecular Oncology, Clinical Research Institute of Montreal,1 Program in Molecular Biology,3 Department of Medicine, University of Montréal,5 Departments of Microbiology and Immunology,6 Medicine, McGill University, Montréal, Québec,7 Department of Pathology and Laboratory Medicine, British Columbia's Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada,4 Unité INSERM U429, Hôpital Necker Enfants-Malades, Paris, France2

Received 3 January 2004/ Returned for modification 2 February 2004/ Accepted 19 March 2004

2B4 is a SLAM-related receptor expressed on natural killer (NK) cells and cytotoxic T cells. It can regulate killing and gamma interferon secretion by NK cells, as well as T-cell-mediated cytotoxicity. There are conflicting data regarding the mechanism of action of 2B4. In these studies, we attempted to understand better the nature and basis of 2B4 signaling. Our studies showed that engagement of 2B4 on NK cells triggered a tyrosine phosphorylation signal implicating 2B4, Vav-1, and, to a lesser extent, SHIP-1 and c-Cbl. Structure-function analyses demonstrated that this response was defined by a series of tyrosine-based motifs in the cytoplasmic region of 2B4 and was not influenced by the extracellular or transmembrane segment of 2B4. In addition, the 2B4-induced signal was absolutely dependent on coexpression of SAP, a Src homology 2 (SH2) domain-containing adaptor associating with SLAM-related receptors and mutated in X-linked lymphoproliferative disease. It was also observed that 2B4 was detectably associated with the Src-related protein tyrosine kinase FynT in an immortalized NK cell line. Mutation of arginine 78 of SAP, a residue critical for binding of SAP to FynT, eliminated 2B4-mediated protein tyrosine phosphorylation, implying that SAP promotes 2B4 signaling most probably by recruiting FynT. Finally, despite the similarities in the signaling modalities of 2B4 and its relative SLAM, the natures of the tyrosine phosphorylation signals induced by these two receptors were found to be different. These differences were not caused by variations in the extent of binding to SAP but rather were dictated by the tyrosine-based sequences in the cytoplasmic domain of the receptors. Taken together, these data lead to a better understanding of 2B4 signaling. Furthermore, they provide firm evidence that the signals transduced by the various SLAM-related receptors are unique and that the specificity of these signals is defined by the distinctive arrays of intracytoplasmic tyrosines in the receptors.

* Corresponding author. Mailing address: IRCM, 110 Pine Ave. West, Montreal, Quebec, Canada H2W 1R7. Phone: (514) 987-5561. Fax: (514) 987-5562. E-mail: veillea{at}ircm.qc.ca.

Molecular and Cellular Biology, June 2004, p. 5144-5156, Vol. 24, No. 12
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.12.5144-5156.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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