Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q00604 (X-linked)
 16,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

2B4 was initially discovered on murine NK cells and T cells displaying non-MHC dependent cytotoxicity. Human 2B4 was cloned based on sequence homology with mouse 2B4. Recent evidence suggests that the function of this receptor might be different in the two species. Human 2B4 activates NK cell cytotoxicity and interferon gamma production when engaged by CD48, its ligand, on target cells. This activating function of human 2B4 requires recruitment of the SH2 domain containing molecule, SLAM-associated protein or SAP. In the absence of SAP in human NK cells, as occurs in immature NK cells or NK cells from X-linked lymphoproliferative disorder (XLPD) patients, human 2B4 acts as an inhibitory receptor. In contrast, in vitro and in vivo studies using 2B4-deficient mice suggest that the major function of mouse 2B4 is to inhibit murine NK cell functions when triggered by CD48 on target cells, although there are reports of activating function of murine 2B4. This inhibitory function of murine 2B4 is mediated by EAT-2, ERT and possibly other phosphatases like SHP-1 and SHIP. 2B4-SAP interaction in mouse NK cells might be a low affinity one and might not be physiologically relevant considering the inhibitory function of 2B4. This suggests that mouse and human 2B4 diverged functionally with the evolution of greater affinity between 2B4 and SAP in the human species. We speculate that evolutionary pressure from viral infections, possibly EBV, might have led to the emergence of this association and activating function of 2B4 in humans.
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PMID:Of mice and men: different functions of the murine and human 2B4 (CD244) receptor on NK cells. 1662 Oct 32

X-linked lymphoproliferative disease (XLP) is an immunodeficiency resulting from mutations in SH2D1A, which encodes signalling lymphocytic activation molecule (SLAM)-associated protein (SAP). In addition to SLAM, SAP associates with several other cell-surface receptors including 2B4 (CD244), Ly9 (CD229), CD84 and NTB-A. SAP contains a single src-homology-2 domain and acts as an intracellular adaptor protein by recruiting the protein tyrosine kinase FynT to the cytoplasmic domains of some of these receptors, which results in the initiation of specific downstream signal transduction pathways. XLP is likely to result from perturbed signalling through one or more of these SAP-associating receptors. In this study, we identified missense (Y54C, I84T and F87S) and insertion (fs82 --> X103) mutations in four different kindreds affected by XLP. Each mutation dramatically reduced the half-life of SAP, thus diminishing its expression in primary lymphocytes as well as in transfected cell lines. Interestingly, although the Y54C and F87S mutations compromised the ability of SAP to associate with different receptors, the I84T mutation had no effect on the ability of SAP to bind SLAM, CD84 or 2B4. However, signalling downstream of SLAM was reduced in the presence of SAP bearing the I84T mutation. These findings indicate that, irrespective of the type of mutation, signalling through SAP-associating receptors in XLP can be impaired by reducing the expression of SAP, the ability of SAP to bind surface receptors and/or its ability to activate signal transduction downstream of the SLAM-SAP complex.
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PMID:Missense mutations in SH2D1A identified in patients with X-linked lymphoproliferative disease differentially affect the expression and function of SAP. 1672 Jun 17

SAP is an intracellular adaptor molecule composed almost exclusively of an SH2 domain. It is mutated in patients with X-linked lymphoproliferative disease, a human immunodeficiency. Several immune abnormalities were also identified in SAP-deficient mice. By way of its SH2 domain, SAP interacts with tyrosine-based motifs in the cytoplasmic domain of SLAM family receptors. SAP promotes SLAM family receptor-induced protein tyrosine phosphorylation, due to its capacity to recruit the Src-related kinase FynT. This unusual property relies on the existence of a second binding surface in the SAP SH2 domain, centered on arginine 78 of SAP, that binds directly to the FynT SH3 domain. Herein, we wanted to further understand the mechanisms controlling the interaction between SLAM-SAP and FynT. Our experiments showed that, unlike conventional associations mediated by SH3 domains, the interaction of the FynT SH3 domain with SLAM-SAP was strictly inducible. It was absolutely dependent on engagement of SLAM by extracellular ligands. We obtained evidence that this inducibility was not due to increased binding of SLAM to SAP following SLAM engagement. Furthermore, it could occur independently of any appreciable SLAM-dependent biochemical signal. In fact, our data indicated that the induced association of the FynT SH3 domain with SLAM-SAP was triggered by a change in the conformation of SLAM-associated SAP caused by SLAM engagement. Together, these data elucidate further the events initiating SLAM-SAP signaling in immune cells. Moreover, they identify a strictly inducible interaction mediated by an SH3 domain.
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PMID:Association between SAP and FynT: Inducible SH3 domain-mediated interaction controlled by engagement of the SLAM receptor. 1684 11

SLAM (signaling lymphocyte activation molecule)-associated protein (SAP) is a Src homology 2 (SH2) domain-containing adaptor expressed in T cells and natural killer cells. Its essential role in immune responses is underscored by the recent finding that mutations in SAP result in a rare but fatal X-linked lymphoproliferative disease (XLP). Although SAP is known to associate with SLAM-family receptors, the exact molecular mechanism by which SAP regulates lymphocyte signaling remains elusive. We here report that in T cells, SAP associates with the PAK-interacting exchange factor (PIX), a guanine nucleotide exchange factor (GEF) specific for Rac/Cdc42 GTPases. Moreover, SAP, PIX, and an activated form of Cdc42 form a complex in mammalian cells. We demonstrate that the SAP-PIX interaction is specific and is mediated by the C-terminal region of the SAP SH2 domain and the PIX SH3 domain. We further show that SAP is required for the recruitment of PIX to the SLAM-family receptors. Interestingly, overexpression of SAP, but not its homolog EAT-2, leads to a synergistic activation of nuclear factor of activating T cells (NFAT) in combination with a calcium signal in T cells. This SAP-mediated activation appears to be receptor-dependent and can be blocked by a dominant negative form of PIX. Taken together, our data strongly suggest that, in addition to the known SAP-interacting kinase Fyn, PIX may be another key player in SAP-mediated T cell activation.
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PMID:The X-linked lymphoproliferative disease gene product SAP associates with PAK-interacting exchange factor and participates in T cell activation. 1698 70

The homeostasis of the immune response requires tight regulation of the proliferation and apoptosis of activated lymphocytes. In humans, defects in immune homeostasis result in lymphoproliferation disorders including autoimmunity, haemophagocytic lymphohystiocytosis and lymphomas. The X-linked lymphoproliferative syndrome (XLP) is a rare, inherited immunodeficiency that is characterized by lymphohystiocytosis, hypogammaglobulinaemia and lymphomas, and that usually develops in response to infection with Epstein-Barr virus (EBV). Mutations in the signalling lymphocyte activation molecule (SLAM)-associated protein SAP, a signalling adaptor molecule, underlie 60% of cases of familial XLP. Here, we identify mutations in the gene that encodes the X-linked inhibitor-of-apoptosis XIAP (also termed BIRC4) in patients with XLP from three families without mutations in SAP. These mutations lead to defective expression of XIAP. We show that apoptosis of lymphocytes from XIAP-deficient patients is enhanced in response to various stimuli including the T-cell antigen receptor (TCR)-CD3 complex, the death receptor CD95 (also termed Fas or Apo-1) and the TNF-associated apoptosis-inducing ligand receptor (TRAIL-R). We also found that XIAP-deficient patients, like SAP-deficient patients, have low numbers of natural killer T-lymphocytes (NKT cells), indicating that XIAP is required for the survival and/or differentiation of NKT cells. The observation that XIAP-deficiency and SAP-deficiency are both associated with a defect in NKT cells strengthens the hypothesis that NKT cells have a key role in the immune response to EBV. Furthermore, by identifying an XLP immunodeficiency that is caused by mutations in XIAP, we show that XIAP is a potent regulator of lymphocyte homeostasis in vivo.
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PMID:XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome. 1708 92

The adapter protein SAP is important for the signal transduction of the family of SLAM-related receptors (SRR), which have important immune-modulating functions. The importance of SAP and SRR for a functional immune reaction becomes obvious in patients suffering from X-linked lymphoproliferative disease, which is characterized by non-functional SAP. Here we investigate the regulation of SAP expression in human NK cells. We demonstrate that SAP mRNA expression and protein levels are low in freshly isolated resting NK cells. IL-2 stimulation leads to an up-regulation of SAP expression, which can be enhanced by IL-12, the stimulation of TLR3 by polyinosinic-polycytidylic acid (poly(I:C))and to a lesser extent by IFN-alpha. EAT-2, a SAP-related adapter protein, is already detectable in resting NK cells and does not change its expression after IL-2 stimulation. The regulation of SAP has functional consequences for the stimulation of NK cell cytotoxicity by 2B4. In resting NK cells, 2B4 stimulation can only enhance NK cell lysis when co-triggered with other activating NK cell receptors. In IL-2-activated NK cells with high SAP expression the triggering of 2B4 alone is sufficient to induce NK cell cytotoxicity, demonstrating a correlation between the regulated SAP expression and the function of 2B4.
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PMID:Modulation of 2B4 (CD244) activity and regulated SAP expression in human NK cells. 1717 59

SAP (SLAM-associated protein) was identified in 1998 as an adaptor molecule involved in the intracellular signaling pathways elicited through the cell surface receptor SLAM and as the protein defective in the human immunodeficiency X-linked lymphoproliferative disease (XLP). During the past eight years, it has been established that the SLAM family of cell surface receptors (SLAM, 2B4, NTB-A, Ly9, CD84) and the SAP family of adaptors (SAP, EAT-2, ERT) play critical roles in lymphocyte development, differentiation, and acquisition of effector functions. Studies of these proteins have shown unexpected roles in cytokine production by T cells and myeloid cells, T cell-dependent humoral immune responses, NK cell-mediated cytotoxicity, and NKT cell development. This review highlights recent findings that have improved our understanding of the roles of the SLAM and SAP families of molecules in immune regulation and discusses how perturbations in the signaling pathways involving these proteins can result in different disease states.
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PMID:Regulation of cellular and humoral immune responses by the SLAM and SAP families of molecules. 1720 83

Mouse CD229 (Ly9) is a cell surface molecule of the CD150 (signaling lymphocyte activation molecule) family. This family consists of nine leukocyte receptors of the immunoglobulin superfamily that are involved in leukocyte activation. CD229 binds to SAP, a protein encoded by the gene for X-linked lymphoproliferative disease. In this study, mouse CD229 expression was assessed with a new CD229-specific monoclonal antibody (mAb) (Ly9.ab3), raised using CD229-transfected cells. CD229 was expressed on Sca-1+c-kit+Lin- hematopoietic stem cells, and this expression increased during lymphocyte maturation. Virtually, all T and B cells expressed high levels of CD229. CD229 was absent on granulocytes, bone marrow-derived dendritic cells, platelets, and red blood cells (RBCs). However, it was expressed at significant levels on monocytes, indicating that it is also expressed on mouse myeloid cells. We also show that natural killer cells, natural killer T cells, and B1 cells express very high levels of this molecule. In vitro functional experiments showed that ligation of CD229 inhibited the expression of the activation markers CD69 and CD25 on T lymphocytes in response to anti-CD3 stimulation. Moreover, this reduced activation was concurrent with a reduction in cytokine production. Our results show that CD229 is a pan-lymphocyte marker and indicate that mAbs against CD229 are able to down-modulate T-cell activation.
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PMID:Characterization of mouse CD229 (Ly9), a leukocyte cell surface molecule of the CD150 (SLAM) family. 1791 64

SAP (also named SH2D1A) is an intracellular adaptor molecule expressed in T cells, natural killer (NK) cells, and some B cells. The SAP gene is mutated in X-linked lymphoproliferative (XLP) disease, a human immunodeficiency characterized by a faulty immune response to Epstein-Barr virus infection. Previous reports documented severe defects in antibody production and germinal center (GC) formation in SAP-deficient humans and mice genetically engineered to lack SAP expression. However, in vitro studies and adoptive transfer experiments provided conflicting data as to whether this phenotype is caused by a functional defect resulting from SAP deficiency in T cells, B cells, or both. Here, we ascertained which cell types are responsible for this humoral immunity defect by using a conditional gene targeting approach. We also thoroughly examined the expression pattern of SAP in normal immune cells by using intracellular flow cytometry. The results showed that expression of SAP in T cells, but not in B cells or NK cells, is required and sufficient for SAP-dependent antibody production and GC formation. These data provide a critical insight into the mechanism by which SAP regulates humoral immunity. They also help elucidate the basis of a severe human immunodeficiency.
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PMID:SAP expression in T cells, not in B cells, is required for humoral immunity. 1821 18

Natural killer (NK) cell cytotoxicity requires triggering of activation receptors over inhibitory receptors. CD244, a member of CD150 receptor family, positively regulates NK-mediated lyses by activating an intracellular multiproteic signaling network that involves the adaptors X-linked lymphoproliferative gene product SAP and 3BP2. However, the exact mechanisms used by 3BP2 to enhance CD244-mediated cytotoxicity are still not fully understood. Here using the human NK cell line YT-overexpressing 3BP2, we found that the adaptor increases CD244, PI3K, and Vav phosphorylation upon CD244 engagement. The use of enzymatic inhibitors revealed that 3BP2-dependent cytolysis enhancement was PKC-dependent and PI3K-ERK independent. Furthermore, 3BP2 overexpression enhanced PKC delta phosphorylation. SAP knockdown expression inhibited PKC delta activation, indicating that the activating role played by 3BP2 depends upon the presence of SAP. In conclusion, our data show that 3BP2 acts downstream of SAP, increases CD244 phosphorylation and links the receptor with PI3K, Vav, PLC gamma, and PKC downstream events in order to achieve maximum NK killing function.
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PMID:The adaptor 3BP2 activates CD244-mediated cytotoxicity in PKC- and SAP-dependent mechanisms. 1847 51


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