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The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM

Abstract

In addition to triggering the activation of B- or T-cell antigen receptors, the binding of a ligand to its receptor at the cell surface can sometimes determine the physiological outcome of interactions between antigen-presenting cells, T and B lymphocytes. The protein SLAM (also known as CDw150), which is present on the surface of B and T cells, forms such a receptor–ligand pair as it is a self-ligand. We now show that a T-cell-specific, SLAM-associated protein (SAP), which contains an SH2 domain and a short tail, acts as an inhibitor by blocking recruitment of the SH2-domain-containing signal-transduction molecule SHP-2 to a docking site in the SLAM cytoplasmic region. The gene encoding SAP maps to the same area of the X chromosome as the locus for X-linked lymphoproliferative disease (XLP) and we found mutations in the SAP gene in three XLP patients. Absence of the inhibitor SAP in XLP patients affects T/B-cell interactions induced by SLAM, leading to an inability to control B-cell proliferation caused by Epstein–Barr virus infections.

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Figure 1: Comparison of deduced amino-acid sequences of human SAP, murine SAP and other SH2-domain-containing proteins.
Figure 2: Characterization of the human and murine SAP proteins and their interactions with SLAM.
Figure 3: SAP expression.
Figure 4: mRNA analysis of XLP patients.
Figure 5: Nucleotide and amino-acid sequences of SAP isolated from a patient with XLP.
Figure 6: Genomic analysis of patients with XLP.
Figure 7: The SAP SH2 domain binds to a specific sequence in the cytoplasmic domain of SLAM.
Figure 8: SAP blocks recruitment of the tyrosine phosphatase SHP-2 to the phosphorylated cytoplasmic domain of SLAM.
Figure 9: SAP has a positive effect in the SLAM co-stimulatory pathway.

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Acknowledgements

We thank J. David, J. Fingeroth and N. Letvin for critically reviewing the manuscript; J. Sumegi for sharing unpublished data; N. van Orsouw and J. Vijg for guidance in analysing PCR products; and E. Wang, M. Comiskey, A. Bywater and A. Hren for technical assistance. This work was supported by a grant from the NIH. J.S. is supported by a fellowship from the Ministerio de Educacion y Cultura de España.

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Correspondence to J. Sayos or C. Terhorst.

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Sayos, J., Wu, C., Morra, M. et al. The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM. Nature 395, 462–469 (1998). https://doi.org/10.1038/26683

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