Abstract
SAP (or SH2D1A), an adaptor-like molecule expressed in immune cells, is composed almost exclusively of a Src homology 2 (SH2) domain1,2,3,4. In humans, SAP is mutated and either absent or non-functional in X-linked lymphoproliferative (XLP) syndrome, a disease characterized by an inappropriate response to Epstein-Barr virus (EBV) infection5. Through its SH2 domain, SAP associates with tyrosines in the cytoplasmic domain of the SLAM family of immune cell receptors, and is absolutely required for the function of these receptors1,6,7,8,9,10. This property results from the ability of SAP to promote the selective recruitment and activation of FynT, a cytoplasmic Src-related protein tyrosine kinase (PTK)8. Here, we demonstrate that SAP operates in this pathway by binding to the SH3 domain of FynT, through a second region in the SAP SH2 domain distinct from the phosphotyrosine-binding motif. We demonstrate that this interaction is essential for SAP-mediated signalling in T cells, and for the capacity of SAP to modulate immune cell function. These observations characterize a biologically important signalling mechanism in which an adaptor molecule composed only of an SH2 domain links a receptor devoid of intrinsic catalytic activity to the kinase required for its function.
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Acknowledgements
Supported by grants from the CANVAC National Centre of Excellence, the National Cancer Institute of Canada and the Canadian Institutes of Health Research (to A.V.), the Institut National de la Santé et de la Recherche Médicale and the Association pour la Recherche sur le Cancer (France) (to S.L.). S.L. held a Fellowship from the Medical Research Council of Canada. He is now a Scientist from the Centre National de la Recherche Scientifique (France). A.V. is a Senior Investigator of the Canadian Institutes of Health Research and holds a Canada Research Chair.
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Latour, S., Roncagalli, R., Chen, R. et al. Binding of SAP SH2 domain to FynT SH3 domain reveals a novel mechanism of receptor signalling in immune regulation. Nat Cell Biol 5, 149–154 (2003). https://doi.org/10.1038/ncb919
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DOI: https://doi.org/10.1038/ncb919
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