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Regulation of SLAM-mediated signal transduction by SAP, the X-linked lymphoproliferative gene product

Nature Immunology volume 2, pages 681–690 (2001)Cite this article

Abstract

Signaling lymphocyte activation molecule (SLAM)-associated protein (SAP) is a short intracellular molecule that is mutated in humans with X-linked lymphoproliferative (XLP) disease. Although the exact role and mechanism of action of SAP are not known, it has the capacity to interact with the cytoplasmic region of SLAM and other related immune cell receptors. As SAP is composed almost exclusively of a Src homology 2 (SH2) domain, it has been proposed that it functions as a natural blocker of SH2 domain–mediated interactions. We report here that the SLAM receptor is capable of triggering a protein tyrosine phosphorylation signal in T cells via a mechanism that is strictly dependent on SAP expression. This signal involves the SH2 domain–containing inositol phosphatase (SHIP); the adaptor molecules Dok2, Dok1 and Shc; and Ras GTPase–activating protein RasGAP. SAP is essential for this pathway because it facilitates the selective recruitment and activation of the Src-related protein tyrosine kinase FynT. We also show that signaling via the SLAM-SAP pathway in an established T cell line can alter the profile of cytokine production during T cell activation. These findings identify a mechanism by which a putative adaptor molecule is required for receptor-mediated signaling events in the immune system. They also provide insights into the pathophysiology of a severe human lymphoproliferative disease.

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Figure 1: SAP is required for SLAM-induced intracellular protein tyrosine phosphorylation in T cells.
Figure 2: Molecular characterization of the SLAM-induced protein tyrosine phosphorylation signal.
Figure 3: The second and third tyrosines in the cytoplasmic region of SLAM are required for SAP-dependent intracellular protein tyrosine phosphorylation.
Figure 4: SAP functions by recruiting a putative protein tyrosine kinase, rather than displacing a protein tyrosine phosphatase activity.
Figure 5: SAP-dependent physical and functional association of SLAM with the Src-related protein tyrosine kinase FynT.
Figure 6: SLAM-SAP signaling inhibits antigen receptor–mediated production of IFN-γ, but not IL-2, in BI-141 T cells.

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Acknowledgements

We thank the members of the Veillette laboratory, M. Nemer and A. Fischer for critical comments on the manuscript and I. Gamache and X. Shi for technical help. Supported by grants from the National Cancer Institute of Canada, the CANVAC National Centre of Excellence 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.) and the National Cancer Institute of Canada (to R. K. H.).

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Authors and Affiliations

  1. Laboratory of Molecular Oncology, IRCM, 110 Pine Ave. West, Montréal, H2W 1R7, Québec, Canada

    Sylvain Latour & André Veillette

  2. McGill Cancer Centre, McGill University, Montréal, H3G 1Y6, Québec, Canada

    Sylvain Latour & André Veillette

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

    Sylvain Latour

  4. The Program in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, M5G 1X5, Ontario, Canada

    Gerald Gish & Tony Pawson

  5. Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, V5Z 1L3, British Columbia, Canada

    Cheryl D. Helgason & R. Keith Humphries

  6. Departments of Biochemistry, Medicine and Microbiology and Immunology, McGill University, Montréal, H3G 1Y6, Québec, Canada

    André Veillette

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Correspondence to André Veillette.

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Latour, S., Gish, G., Helgason, C. et al. Regulation of SLAM-mediated signal transduction by SAP, the X-linked lymphoproliferative gene product. Nat Immunol 2, 681–690 (2001). https://doi.org/10.1038/90615

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