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Binding of SAP SH2 domain to FynT SH3 domain reveals a novel mechanism of receptor signalling in immune regulation

Nature Cell Biology volume 5, pages 149–154 (2003)Cite this article

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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Figure 1: SAP is required for recruitment of FynT to SLAM in normal T cells.
Figure 2: Binding of SAP to the SH3 domain of FynT.
Figure 3: Mapping the site of interaction between SAP and the FynT SH3 domain.
Figure 4: Arg 78 of SAP is required for SLAM receptor-mediated signalling in T cells.
Figure 5: The SAP–FynT interaction is required for modulation of cytokine production in T cells.

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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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Authors and Affiliations

  1. Laboratory of Molecular Oncology, Clinical Research Institute of Montreal, Montréal, H2W 1R7, Québec, Canada

    Sylvain Latour, Romain Roncagalli, Riyan Chen, Marcin Bakinowski, Xiaochu Shi, Dominique Davidson & André Veillette

  2. Unité INSERM U429, Hôpital Necker Enfants-Malades, Paris, France

    Sylvain Latour

  3. Program in Molecular Biology, University of Montréal, Montréal, H2W 1R7, Québec, Canada

    Romain Roncagalli & André Veillette

  4. Department of Medicine, University of Montréal, Montréal, H2W 1R7, Québec, Canada

    André Veillette

  5. National Human Genome Research Institute, National Institutes of Health, Bethesda, 20892, MD, USA

    Pamela L. Schwartzberg

  6. Department of Biochemistry, McGill University, Montréal, H3G 1Y6, Québec, Canada

    André Veillette

  7. Departments of Microbiology and Immunology, McGill University, Montréal, H3G 1Y6, Québec, Canada

    André Veillette

  8. Department of Medicine, McGill University, Montréal, H3G 1Y6, Québec, Canada

    André Veillette

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Correspondence to André Veillette.

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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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