Regular Article
Distinct Interactions of the X-Linked Lymphoproliferative Syndrome Gene Product SAP with Cytoplasmic Domains of Members of the CD2 Receptor Family

https://doi.org/10.1006/clim.2001.5035Get rights and content

Abstract

X-linked lymphoproliferative syndrome (XLP; Duncan's disease) is a primary immunodeficiency disease that manifests as an inability to regulate the immune response to Epstein–Barr virus (EBV) infection. Here we examine the ability of the product of the gene defective in XLP, SAP (DSHP/SH2D1A), to associate with the cytoplasmic domains of several members of the CD2 subfamily of cell surface receptors, including SLAM, 2B4, and CD84. While recruitment of SAP to SLAM occurred in a phosphorylation-independent manner, SAP was found to bind preferentially to tyrosine-phosphorylated cytoplasmic domains within 2B4 and CD84. Missense or nonsense mutations in the SAP open reading frame were identified in five of seven clinically diagnosed XLP patients from different kindreds. Four of these variants retained the ability to bind to the cytoplasmic tails of SLAM and CD84. While ectopic expression of wild-type SAP was observed to block the binding of SHP-2 to SLAM, mutant SAP derivatives that retained the ability to bind SLAM did not inhibit recruitment of SHP-2 to SLAM. In contrast, SAP binding to CD84 had no effect on the ability of CD84 to recruit SHP-2, but instead displaced SHP-1 from the cytoplasmic tail of CD84. These results suggest that mutations in the gene encoding the XLP protein SAP lead to functional defects in the protein that include receptor binding and SHP-1 and SHP-2 displacement and that SAP utilizes different mechanisms to regulate signaling through the CD2 family of receptors.

References (39)

  • D. Howie et al.

    The gene defective in X-linked lymphoproliferative disease controls T cell dependent immune surveillance against Epstein–Barr virus

    Curr. Opin. Immunol.

    (2000)
  • S.G. Tangye et al.

    The CD2-subset of the Ig superfamily of cell surface molecules: Receptor–ligand pairs expressed by NK cells and other immune cells

    Semin. Immunol.

    (2000)
  • D.T. Purtilo et al.

    X-linked recessive progressive combined variable immunodeficiency (Duncan's disease)

    Lancet

    (1975)
  • D.T. Purtilo et al.

    The X-linked lymphoproliferative disease: From autopsy toward cloning the gene 1975–1990

    Pediatr. Pathol.

    (1991)
  • T.A. Seemayer et al.

    X-linked lymphoproliferative disease: Twenty-five years after the discovery

    Pediatr. Res.

    (1995)
  • S. Harada et al.

    Immune deficiency in the X-linked lymphoproliferative syndrome

    J. Immunol.

    (1982)
  • T. Lindsten et al.

    Immune deficiency in the X-linked lymphoproliferative syndrome

    J. Immunol.

    (1982)
  • S. Harada et al.

    Cell-mediated immunity to Epstein–Barr virus (EBV) and natural killer (NK)-cell activity in the X-linked lymphoproliferative syndrome

    Int. J. Cancer

    (1982)
  • J. Sayos et al.

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

    Nature

    (1998)
  • Cited by (38)

    • Phenotypic differences between mice deficient in XIAP and SAP, two factors targeted in X-linked lymphoproliferative syndrome (XLP)

      2009, Cellular Immunology
      Citation Excerpt :

      The discovery that human X-linked lymphoproliferative syndrome can be caused by mutations in the genes encoding either SAP and XIAP led us to determine whether the two proteins might interact. We have previously described a system in which the association of SAP with the cytoplasmic tails of several members of the CD2 family, including SLAM and 2B4, can be readily evaluated [7]. Using this system, the cytoplasmic signaling domain of SLAM fused in-frame with glutathione-S-transferase (SLAM–GST) was expressed with FLAG-epitope-tagged SAP (SAP–FLAG) and XIAP.

    • The SLAM and SAP Gene Families Control Innate and Adaptive Immune Responses

      2008, Advances in Immunology
      Citation Excerpt :

      Thus, in principle, SAP should have the capacity to out‐compete SH2‐domain proteins that bind to the same phosphotyrosine motif with lesser affinity. Although there is a modicum of support for the concept of SAP as an inhibitor of the recruitment of the protein tyrosine phosphatase (SHP‐2) to the cytoplasmic tail of SLAM, CD244, CD84, and CD229 (Howie et al., 2002a; Lewis, 2001; Sayos et al., 1998), further experiments are required. SH2 domains are typically found in multidomain signaling enzymes or in adapter proteins, where they mediate protein–protein interactions and regulate associated catalytic subunits (Kuriyan and Cowburn, 1997; Machida and Mayer, 2005; Pawson, 2004).

    • NTB-A, a New Activating Receptor in T Cells That Regulates Autoimmune Disease

      2004, Journal of Biological Chemistry
      Citation Excerpt :

      A hallmark of CD2 family members is the presence of two to four SAP-binding motifs (TXYXX(V/I)) in the intracellular domain; SAP can bind to the both the phosphorylated and non-phosphorylated forms of CD150, although SAP has a higher affinity for the phosphorylated form (31, 32). In addition to binding SAP, CD150 has also been reported to bind SHP-2 (22, 24, 33–35). Both human and mouse NTB-A have two SAP-binding motifs in the intracellular domain.

    • SLAM-associated protein deficiency causes imbalanced early signal transduction and blocks downstream activation in T cells from X-linked lymphoproliferative disease patients

      2003, Journal of Biological Chemistry
      Citation Excerpt :

      Three days later, cells were harvested for scintillation counting after pulsing with 1 μCi of 3H-labeled tritiated thymidine during the last 16 h of culture. SH2D1A Retroviral Vector Generation, Transfections, and Transductions—The SH2D1A cDNA (31) and the MND-IRES-EGFP retroviral vector were generous gifts of Drs. C. S. Duckett (University of Michigan) and D. B. Kohn (Children's Hospital Los Angeles), respectively. The full-length SH2D1A cDNA was blunt-ended and ligated into the SfoI site of MND-IRES-EGFP (M-IE), upstream of the IRES sequence, thus generating MND-SH2D1A-IRES-EGFP (M-SAP-IE), a bicistronic retroviral vector expressing both SH2D1A and EGFP under the control of the myeloproliferative sarcoma virus LTR.

    View all citing articles on Scopus
    1

    To whom correspondence may be addressed at the Metabolism Branch, Division of Clinical Sciences, National Cancer Institute, National Institutes of Health, 10 Center Drive, Room 6B-05, Bethesda, MD 20892-1578. E-mail: [email protected].

    View full text