Affinage

SH2D1A

SH2 domain-containing protein 1A · UniProt O60880

Round 2 corrected
Length
128 aa
Mass
14.2 kDa
Annotated
2026-04-28
130 papers in source corpus 31 papers cited in narrative 28 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SH2D1A encodes SAP, a small lymphocyte-specific adaptor protein composed almost entirely of a single SH2 domain that serves as a master regulator of SLAM-family receptor signaling in T, NK, and NKT cells. SAP binds the immunoreceptor tyrosine-based switch motifs (ITSMs) of SLAM-family receptors (SLAM/CD150, 2B4/CD244, NTB-A, CD84, Ly-9) via a unique three-pronged mechanism that recognizes both phosphorylated and non-phosphorylated TIpYXX(V/I) peptides, simultaneously blocking recruitment of the inhibitory phosphatases SHP-1/SHP-2 and recruiting the Src-family kinase FynT through a non-canonical SH2–SH3 surface interaction that promotes kinase activation (PMID:9774102, PMID:10549287, PMID:11477403, PMID:12545174). This dual adaptor/inhibitor function is essential for NKT cell development, germinal center formation, T-dependent humoral immunity, NK/CTL cytotoxicity against EBV-infected B cells, and TCR restimulation-induced cell death (RICD), with RICD requiring SAP-dependent suppression of diacylglycerol kinase α to sustain DAG-Ras signaling (PMID:15711562, PMID:15774582, PMID:15677558, PMID:19759517, PMID:26764158). Loss-of-function mutations in SH2D1A cause X-linked lymphoproliferative disease (XLP), in which SLAM-family receptors acquire inappropriate inhibitory signaling due to unopposed SHP recruitment, leading to fatal EBV-driven immunopathology, dysgammaglobulinemia, and lymphoma (PMID:9774102, PMID:22069374).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1998 High

    Positional cloning of SH2D1A as the gene mutated in X-linked lymphoproliferative disease established that a single-SH2-domain adaptor protein controls SLAM signaling by competing with SHP-2 for binding to SLAM's cytoplasmic tail — defining the molecular basis of XLP.

    Evidence Positional cloning, mutation analysis in XLP families, co-immunoprecipitation and SHP-2 competition assays

    PMID:9771704 PMID:9774102 PMID:9811875

    Open questions at the time
    • Mechanism by which SAP loss causes the diverse clinical manifestations of XLP was unknown
    • Whether SAP interacts with receptors beyond SLAM was not addressed
  2. 1999 High

    Structural studies revealed that SAP employs a unique three-pronged binding mode recognizing residues N-terminal and C-terminal to the tyrosine — explaining how SAP engages both phosphorylated and non-phosphorylated SLAM peptides and why XLP mutations disrupt these contacts.

    Evidence X-ray crystallography and NMR of SAP–SLAM peptide complexes, phosphopeptide library screening, quantitative fluorescence binding

    PMID:10549287 PMID:10607564

    Open questions at the time
    • How this binding mode translated into downstream signaling beyond SHP-2 blocking was unknown
    • Whether non-canonical binding extended to other SLAM-family receptors was untested
  3. 1999 High

    Discovery that SAP associates with 2B4 (CD244) on NK cells and blocks SHP-2 recruitment extended the SAP-controlled signaling network beyond SLAM to other SLAM-family receptors, broadening the molecular explanation for NK cell dysfunction in XLP.

    Evidence Co-immunoprecipitation in activated primary NK cells and transfectants

    PMID:10358138

    Open questions at the time
    • Full repertoire of SLAM-family receptors engaging SAP was not yet defined
    • The positive signaling arm downstream of SAP at 2B4 was uncharacterized
  4. 2001 High

    Reconstitution experiments overturned the purely inhibitory model of SAP by showing it actively recruits and activates FynT to SLAM, enabling downstream phosphorylation cascades involving SHIP, Dok1/2, Shc, and RasGAP — redefining SAP as a dual adaptor/blocker.

    Evidence SAP-deficient T cell reconstitution, dominant-negative FynT, co-immunoprecipitation, kinase assays

    PMID:11477403 PMID:12458214

    Open questions at the time
    • Structural basis for the non-canonical SAP SH2–FynT SH3 interaction was not yet resolved
    • Whether FynT recruitment was required for all SLAM-family receptor signaling was unknown
  5. 2001 High

    Identification of NTB-A, CD84, and Ly-9 as additional SAP-binding SLAM-family receptors, together with the ITSM molecular switch concept (SAP presence directing SHIP recruitment at SLAM instead of SHP-2), established SAP as a global regulator of an entire receptor family.

    Evidence Co-immunoprecipitation, yeast two-hybrid, GST-pulldown with Y→F mutants, XLP patient B cell lines

    PMID:11313386 PMID:11389028 PMID:11489943

    Open questions at the time
    • Relative functional importance of individual SLAM-family receptors in XLP pathology was unclear
    • B cell-intrinsic SAP functions had not been tested in vivo
  6. 2001 High

    Systematic characterization of XLP missense mutations identified two pathogenic mechanisms — reduced protein stability and impaired receptor binding — and showed that mutation T53I selectively ablates phosphorylation-independent binding, dissecting distinct SAP interaction modes.

    Evidence Ten disease alleles analyzed by site-directed mutagenesis, protein half-life assays, GST-pulldown with four SLAM-family receptors

    PMID:11477068

    Open questions at the time
    • Genotype–phenotype correlations in XLP patients were not addressed
    • Whether stability-reducing mutations could be pharmacologically rescued was unknown
  7. 2003 High

    The ternary SLAM–SAP–FynT crystal structure revealed a non-canonical SH2–SH3 surface interaction that directly couples FynT to the receptor and is predicted to relieve Fyn autoinhibition, providing the structural mechanism for SAP-mediated kinase activation.

    Evidence X-ray crystallography of ternary complex, biochemical binding validation

    PMID:12545174

    Open questions at the time
    • Direct demonstration that the ternary complex relieves Fyn autoinhibition in cells was lacking
    • Whether other SH3-domain proteins (e.g. NCK1) compete for the same SAP surface was untested
  8. 2004 High

    In vivo studies in SAP-deficient mice demonstrated that SAP is indispensable for germinal center formation and T-dependent humoral immunity, with adoptive transfer experiments revealing a B cell-intrinsic role for SAP, while protection from lupus models identified the SLAM–SAP axis as a specific checkpoint for autoimmune humoral responses.

    Evidence Sh2d1a−/− mice, adoptive co-transfer of SAP-KO vs. WT B and T cells, germinal center histology, lupus and EAE models

    PMID:15263031 PMID:15774582

    Open questions at the time
    • Molecular mechanism of SAP function within B cells during germinal center reactions was undefined
    • Whether SAP loss in T follicular helper cells was the dominant defect was debated
  9. 2004 High

    FynT Arg78-dependent reconstitution of 2B4 signaling in NK cells confirmed that SAP promotes activating 2B4 signals by recruiting FynT, and revealed SLAM and 2B4 trigger distinct downstream phosphorylation profiles despite sharing SAP/FynT dependency.

    Evidence NK cell line reconstitution with SAP R78A mutant, co-immunoprecipitation, phosphorylation assays

    PMID:15169881 PMID:15713798

    Open questions at the time
    • Receptor-specific downstream signaling pathways were incompletely mapped
    • How SLAM-family receptors cooperate or compete for limited SAP was unknown
  10. 2005 High

    SAP was shown to be absolutely required for NKT cell development in both mice and humans, with XLP carriers showing complete X-inactivation skewing in the NKT compartment — demonstrating a non-redundant developmental checkpoint controlled by SAP.

    Evidence Sh2d1a−/− mice, XLP patient lymphocyte subsets, bone marrow reconstitution, X-inactivation analysis in female carriers

    PMID:15711562 PMID:15738056

    Open questions at the time
    • Stage of NKT cell development blocked by SAP deficiency was not precisely defined
    • Which SLAM-family receptor(s) mediate SAP-dependent NKT selection was unknown
  11. 2005 High

    SAP-deficient CTLs from XLP patients showed defective polarization of perforin, 2B4, and lipid rafts toward EBV-infected B cells, with 2B4 blockade phenocopying this defect — establishing SAP/2B4 as directors of lytic synapse formation against EBV-positive targets.

    Evidence XLP patient CTL cytotoxicity, immunofluorescence of immunological synapse, 2B4 antibody blockade

    PMID:15677558

    Open questions at the time
    • Whether NTB-A cooperates with 2B4 at the lytic synapse was not resolved
    • The signaling cascade linking SAP/2B4 to cytoskeletal polarization machinery was unknown
  12. 2008 Medium

    Identification of NCK1 as a novel SAP SH2-domain partner competing with FynT for the same non-canonical surface expanded the adaptor network through which SAP modulates TCR-proximal signaling (LAT, SLP-76, ERK pathway).

    Evidence SH3 domain panel screen, NMR binding, siRNA knockdown with phospho-signaling readouts

    PMID:18951976

    Open questions at the time
    • Relative in vivo contribution of NCK1 vs. FynT binding to SAP function was unclear
    • Whether NCK1–SAP interaction operates in NK cells or only in T cells was untested
  13. 2009 High

    SAP and NTB-A were shown to cooperate in promoting TCR restimulation-induced cell death (RICD), with SAP progressively displacing SHP-1 from NTB-A to amplify TCR signal strength above the apoptotic threshold — explaining why SAP-deficient T cells resist RICD and accumulate during viral infections.

    Evidence XLP patient T cells, siRNA knockdown, antibody blockade, co-immunoprecipitation time-course, apoptosis assays

    PMID:19759517

    Open questions at the time
    • Downstream effector pathway linking amplified TCR signaling to the apoptotic program was not delineated
    • Whether other SLAM-family receptors contribute to RICD was untested
  14. 2011 High

    Natural chimera analysis in female XLP carriers demonstrated that SLAM-family receptors (NTB-A, 2B4) on B cells actively inhibit SAP-negative CTLs — proving that EBV susceptibility in XLP reflects inhibitory SLAM signaling against B cell targets, not a virus-specific defect.

    Evidence X-inactivation mosaicism in XLP carriers, SLAM receptor blockade restoring SAP− CTL killing, ectopic NTB-A on fibroblasts

    PMID:22069374

    Open questions at the time
    • Whether therapeutic SLAM receptor blockade could benefit XLP patients was not tested clinically
    • Contribution of each individual SLAM-family receptor to inhibitory signaling was not quantified
  15. 2016 High

    Mechanistic dissection revealed that SAP promotes RICD by enabling TCR-induced inhibition of diacylglycerol kinase α (DGKα), sustaining DAG–Ras–PKCθ signaling; pharmacological DGKα inhibition rescued RICD in SAP-deficient cells and prevented lethal CD8+ T cell expansion in SAP-deficient mice after LCMV infection — identifying a druggable node downstream of SAP.

    Evidence XLP patient T cells, DGKα inhibitors/genetic approaches, LCMV infection in Sh2d1a−/− mice, immune synapse imaging

    PMID:26764158

    Open questions at the time
    • How SAP mechanistically suppresses DGKα enzymatic activity was not defined
    • Clinical translation of DGKα inhibition in XLP patients has not been tested
    • Whether DGKα inhibition also rescues germinal center or NKT cell defects in SAP deficiency is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • The precise mechanism by which SAP controls NKT cell development, the SLAM-family receptor(s) mediating this checkpoint, the structural basis for SAP-dependent DGKα regulation, and whether therapeutic targeting of DGKα or SLAM receptors can benefit XLP patients remain unresolved.
  • Stage-specific SLAM-family receptor requirement for NKT cell selection is undefined
  • Molecular mechanism linking SAP to DGKα suppression is unknown
  • No clinical trial data exist for DGKα inhibition or SLAM receptor blockade in XLP

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 5 GO:0098772 molecular function regulator activity 4
Localization
GO:0005886 plasma membrane 3 GO:0005829 cytosol 2
Pathway
R-HSA-168256 Immune System 8 R-HSA-162582 Signal Transduction 6 R-HSA-5357801 Programmed Cell Death 2
Partners
CD244CD84FYNLY9NCK1PTPN6SLAMF1SLAMF6
Complex memberships
SLAM-SAP-FynT ternary complex

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 SH2D1A (SAP) was identified as the gene mutated in X-linked lymphoproliferative syndrome (XLP); it encodes a 128-amino-acid protein composed almost entirely of a single SH2 domain, expressed in T and NK cells, that acts as an inhibitor by blocking recruitment of the SH2-domain-containing signal-transduction molecule SHP-2 to a docking site in the SLAM (CD150) cytoplasmic region. Positional cloning, mutation analysis in XLP patients, co-immunoprecipitation, functional blocking assay Nature High 9771704 9774102 9811875
1999 Crystal structures of SAP revealed it binds both phosphorylated and non-phosphorylated SLAM peptides using a mode that involves specific interactions with residues N-terminal to the tyrosine in addition to C-terminal contacts ('extended, phosphotyrosine-independent sequence recognition'), recognizing the motif TIpYXX(V/I). XLP-causing mutations were shown to disrupt these interactions. X-ray crystallography, phosphopeptide library screen, mutagenesis Molecular cell High 10549287
1999 The SAP SH2 domain binds SLAM peptides in a phosphorylation-independent manner with Kd ~330 nM (non-phospho) and ~150 nM (phospho), and NMR studies demonstrated a 'three-pronged' binding mechanism engaging both N-terminal and C-terminal residues flanking the tyrosine, distinct from canonical SH2 'two-pronged' binding. NMR spectroscopy (15N/13C-labeled SAP), fluorescence binding assays Current biology High 10607564
2001 SAP regulates SLAM-mediated signaling in T cells by facilitating selective recruitment and activation of the Src-family kinase FynT to SLAM; in the absence of SAP, SLAM fails to trigger protein tyrosine phosphorylation and downstream signals involving SHIP, Dok2, Dok1, Shc, and RasGAP. SAP is thus an adaptor for FynT rather than merely an inhibitor of SHP-2. Reconstitution in T cell lines, co-immunoprecipitation, dominant-negative/knockout approaches, signaling assays in SAP-deficient cells Nature immunology High 11477403
2001 SAP associates with the novel SLAM-family receptor NTB-A (a 60-kD glycoprotein on NK, T, and B cells). In XLP-NK cells lacking SAP, NTB-A delivers inhibitory rather than activating signals, contributing to the inability of XLP-NK cells to kill EBV-infected B cells. SAP prevents NTB-A from recruiting inhibitory SHPs. Molecular cloning, co-immunoprecipitation, NK cell cytotoxicity assays with XLP patient cells, antibody-blocking experiments The Journal of experimental medicine High 11489943
2001 In B cells, SAP (SH2D1A) determines which phosphatase associates with CD150 (SLAM): when SAP is present, SHIP is recruited to phosphorylated Y281 and Y327 of CD150; when SAP is absent (as in XLP B cell lines), SHP-2 associates instead. SAP thus functions as a molecular switch (via the TxYxxV/I 'immunoreceptor tyrosine-based switch motif') regulating alternative downstream signaling. Co-immunoprecipitation, GST-fusion pulldowns with Y→F mutants of CD150, comparison of SAP-positive vs. SAP-negative B cell lines Journal of immunology High 11313386
2001 SAP (SH2D1A) binds the SH3 domain of FynT directly, an interaction mediated through the surface of the SAP SH2 domain. In cells, FynT is indispensable for SLAM tyrosine phosphorylation and SAP dramatically enhances this phosphorylation while blocking SHP-2 recruitment. Disease-causing SAP mutants show significantly reduced affinity for both FynT and SLAM, confirming the dual adaptor/inhibitor role. In vitro peptide array binding, in vivo co-immunoprecipitation, kinase assays, site-directed mutagenesis of disease mutants The Journal of biological chemistry High 12458214
2002 NMR structures of the SAP SH2 domain in complex with SLAM-derived peptides (with and without phosphotyrosine) provided direct structural evidence for the 'three-pronged' binding mechanism. The consensus binding sequence T/S-x-x-x-x-V/I (lacking Tyr or pTyr) is recognized via a surface distinct from canonical SH2 engagement. Structural mapping explained binding defects in XLP-causing SAP mutants. NMR structure determination, hydrogen exchange, synthetic peptide repertoire screening, disease mutant structural analysis The EMBO journal High 11823424
2001 Analysis of XLP missense mutations identified two classes: (i) mutations reducing SAP protein half-life (Y7C, S28R, Q99P, P101L, V102G, X129R) and (ii) mutations that structurally impair binding to SLAM-family receptors (CD150, CD84, CD229, CD244). Mutant T53I selectively abolishes phosphorylation-independent interactions while preserving phosphotyrosine-dependent binding, and abrogates binding to CD229/CD224, demonstrating that SAP controls multiple distinct signaling pathways. Site-directed mutagenesis, protein half-life assays, GST-pulldown and co-immunoprecipitation with four SLAM-family receptors The Journal of biological chemistry High 11477068
2003 Crystal structure of a ternary SLAM-SAP-Fyn-SH3 complex showed that the SAP SH2 domain binds the FynT SH3 domain through a non-canonical surface-surface interaction (not involving canonical SH3 or SH2 binding motifs), directly coupling FynT to SLAM. This binding mode is predicted to preclude Fyn's autoinhibited conformation, thereby promoting kinase activation upon recruitment. X-ray crystallography of ternary complex, biochemical binding assays Nature cell biology High 12545174
1999 SAP was shown to associate with 2B4 (CD244) on activated human NK cells and T cells, and this interaction prevented 2B4 from recruiting SHP-2. Loss of SAP in XLP leads to aberrant inhibitory signaling through 2B4, extending the pathological mechanism beyond SLAM to include other SLAM-family receptors. Co-immunoprecipitation in activated cells, functional assays with pervanadate-stimulated transfectants Journal of immunology High 10358138
2001 Cell surface receptors Ly-9 (CD229) and CD84 also recruit SAP through their cytoplasmic TxYxxV/I motifs, particularly when their tyrosine residues are phosphorylated, as shown by yeast two-hybrid, COS cell transfection, and lymphoid cell assays. SAP regulation of SLAM-family signaling therefore extends to at least four receptors (SLAM, 2B4, CD84, Ly-9). Yeast two-hybrid, COS cell co-transfection/co-immunoprecipitation, lymphoid cell co-immunoprecipitation Blood High 11389028
2000 SH2D1A (SAP) associates with Dok1 (p62dok) in a manner dependent on phosphorylation of Dok1 Y449; an XLP-associated SH2 domain mutant fails to associate with Dok1. Overexpression of SH2D1A activates NF-κB in 293T cells through a mechanism requiring IκB kinase β but independent of the SH2 domain. Co-immunoprecipitation, lane-shift SH2 domain mutant analysis, NF-κB reporter assays, dominant-negative IKKβ Proceedings of the National Academy of Sciences of the United States of America Medium 10852966
2002 SAP (SH2D1A) association with 2B4 in NK cells is dependent on PI3K activity: PI3K inhibitors (wortmannin, LY294002) prevent SAP recruitment to 2B4 after 2B4 ligation without altering the 2B4–p85 association, and PI3K inhibition significantly reduces NK cell cytotoxicity in a SAP-dependent manner. Co-immunoprecipitation with pharmacological PI3K inhibitors in primary NK cells, NK cell cytotoxicity assays, XLP patient NK cells as controls The Journal of biological chemistry Medium 11815622
2004 CD150 (SLAM)-mediated Akt phosphorylation in B cells requires Syk and SH2D1A (SAP), is negatively regulated by Lyn and Btk, and is SHIP-independent. CD150-mediated ERK activation requires SHIP but not SAP. SAP thus acts as a switch between CD150-initiated signaling pathways, directing signaling towards Akt rather than ERK. DT40 B cell sublines deficient in specific signaling molecules, stimulation assays, phospho-specific western blotting Blood Medium 15315965
2004 SH2D1A-deficient mice cannot form germinal centers upon immunization, and both SAP-deficient T cells and B cells have functional defects impairing T-dependent IgG antibody responses. Adoptive co-transfer experiments demonstrated that SAP expression is required in B cells for antigen-specific IgG production, identifying a B cell-intrinsic role for SAP. Knockout mouse model, adoptive co-transfer experiments (KO B cells + WT T cells, and vice versa), germinal center histology Proceedings of the National Academy of Sciences of the United States of America High 15774582
2004 SH2D1A deficiency protects mice from T-dependent humoral autoimmunity (experimental lupus) by blocking germinal center formation and T-dependent antibody responses, while leaving T-independent responses intact. This identifies the SLAM-SH2D1A axis as specifically required for T-dependent humoral immunity. Sh2d1a−/− mouse lupus model, germinal center analysis, T-dependent vs. T-independent immunization, EAE susceptibility The Journal of experimental medicine High 15263031
2004 SAP and the SLAM-family receptor NTB-A cooperate to regulate TCR-induced restimulation-induced cell death (RICD) in activated T cells. SAP/NTB-A signaling augments proximal TCR signaling strength to reach the threshold for apoptosis; upon TCR restimulation, SAP is increasingly recruited to NTB-A while SHP-1 dissociates. SAP-deficient T cells (XLP) resist RICD, and blocking NTB-A in normal T cells recapitulates XLP-like RICD resistance. XLP patient T cells, siRNA knockdown, antibody blockade, co-immunoprecipitation time-course, apoptosis assays The Journal of clinical investigation High 19759517
2005 SAP is essential for NKT cell development in both mice and humans; Sh2d1a−/− mice and XLP patients (confirmed by germline SH2D1A mutations) completely lack NKT cells in thymus and periphery. The defect is hematopoietic cell-autonomous and rescued by reconstitution of SAP expression in bone marrow. Female XLP carriers show completely skewed X-chromosome inactivation within NKT cells but not T or B cells. Knock-out mouse analysis, analysis of XLP patient lymphocyte subsets, bone marrow reconstitution, X-inactivation skewing analysis in XLP carriers Nature medicine / The Journal of experimental medicine High 15711562 15738056
2005 SAP-deficient CTLs from XLP patients show specific lytic defects against EBV-positive B cells, associated with impaired polarization of 2B4, perforin, and lipid rafts to the contact zone. Blockade of 2B4 in normal CTLs reproduces the SAP-deficient polarization defect, demonstrating that the SAP/2B4 pathway directs lytic machinery polarization toward EBV-positive targets. XLP patient CTL cytotoxicity assays, immunofluorescence microscopy of immunological synapse, 2B4 antibody blockade Blood High 15677558
2005 2B4 signals activate NK cells through a mechanism strictly dependent on SAP: SAP binds all 4 ITSMs of 2B4 in a phosphorylation-dependent manner and acts as an inhibitor of negative regulators (SHP-1, SHP-2, SHIP, Csk) at the third ITSM. Fyn can also associate with phosphorylated 2B4, and both Fyn and Csk can phosphorylate 2B4. Structure-function mutagenesis of 2B4 ITSMs, co-immunoprecipitation, kinase phosphorylation assays in NK cell lines Blood High 15713798
2004 2B4-induced tyrosine phosphorylation signaling in NK cells (involving 2B4, Vav-1, and SHIP-1) is absolutely dependent on co-expression of SAP and requires Arg78 of SAP (the FynT-binding residue). This confirmed that SAP promotes 2B4 signaling by recruiting FynT, and established that SLAM and 2B4 trigger distinct tyrosine phosphorylation profiles despite both requiring SAP. NK cell line reconstitution, structure-function mutagenesis (R78 of SAP), co-immunoprecipitation, tyrosine phosphorylation assays Molecular and cellular biology High 15169881
2008 SAP interacts with the SH3 domains of NCK1 (a novel binding partner) as well as FynT via the same surface on the SAP SH2 domain. NMR analysis showed NCK1-SH3 and Fyn-SH3 engage the same residues on SAP with comparable affinities. SAP depletion by siRNA reduces NCK1 tyrosine phosphorylation and downstream TCR signaling (LAT, SLP-76 phosphorylation) and impairs T cell proliferation via the MAP kinase Erk pathway. SH3 domain panel screen, NMR binding analysis, siRNA knockdown, phospho-western blotting, T cell proliferation assays Cellular signalling Medium 18951976
2004 SH2D1A gene expression is controlled by a combination of transcriptional and post-transcriptional mechanisms: the basal promoter contains an Ets consensus site bound by Ets-1 and Ets-2 (shown by gel mobility shift/supershift and dominant-negative overexpression). SH2D1A mRNA is rapidly degraded in T cells via its 3' UTR through a balance between destabilizing factor AUF1 and stabilizing factor HuR, though the degradation rate itself is not altered by TCR engagement. Promoter deletion analysis, gel mobility shift and supershift assays, dominant-negative transcription factor overexpression, RNA decay assays, RNA-gel mobility shift assays European journal of immunology Medium 15459902
2006 XLP missense mutations (Y54C, I84T, F87S) and an insertion (fs82→X103) each dramatically reduce SAP protein half-life. Y54C and F87S additionally impair receptor binding, while I84T does not affect binding to SLAM, CD84, or 2B4 but nonetheless reduces downstream SLAM signaling, demonstrating that reduced SAP stability is sufficient to impair signaling even when binding affinity is preserved. Patient-derived lymphocytes and transfected cell lines, protein stability assays, receptor co-immunoprecipitation, downstream signaling assays International immunology Medium 16720617
2011 In female XLP carriers (natural mixed SAP+/SAP- chimeras due to random X-inactivation), EBV-specific CD8+ T cells were exclusively SAP+, while CMV- and influenza-specific memory cells were distributed across both populations. Blocking SLAM receptors NTB-A and 2B4 (not EBV itself) restored cytotoxicity of SAP- CD8+ T cells against EBV-infected B cells; ectopic NTB-A expression on fibroblasts inhibited SAP- CTL cytotoxicity. This demonstrated that SLAM receptors acquire inhibitory function in the absence of SAP and that susceptibility to EBV in XLP reflects the nature of the antigen-presenting cell (B cells express SLAM receptors), not a direct effect of EBV. Human XLP carrier lymphocyte analysis, SLAM receptor blockade experiments, ectopic NTB-A expression on fibroblasts, antigen-specific T cell functional assays PLoS biology High 22069374
2016 SAP-deficient T cells exhibit impaired TCR restimulation-induced cell death (RICD) due to diminished TCR-induced inhibition of diacylglycerol kinase α (DGKα), leading to increased DAG metabolism and decreased Ras/PKCθ signaling. Pharmacological or genetic inhibition of DGKα in SAP-deficient T cells restores DAG signaling at the immune synapse and rescues RICD via NUR77 and NOR1 pro-apoptotic proteins. DGKα inhibition also prevents excessive CD8+ T cell expansion and IFN-γ in SAP-deficient mice after LCMV infection without impairing lytic activity. SAP-deficient T cells from XLP patients, DGKα inhibitors, in vivo LCMV mouse model, immune synapse imaging, apoptosis/signaling assays Science translational medicine High 26764158
2003 Differential methylation of CpG-rich regions in the 5' region and exon 1 of the SH2D1A gene correlates with cell lineage-specific transcription: the gene is hypomethylated in T/NK cells (which express it) and hypermethylated in B cells and granulocytes (which do not). Bisulfite sequencing, methylation-sensitive restriction enzyme digestion Immunogenetics Medium 12709835

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2005 The DNA sequence of the human X chromosome. Nature 816 15772651
1998 The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM. Nature 706 9774102
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1998 Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene. Nature genetics 577 9771704
2005 A quantitative protein interaction network for the ErbB receptors using protein microarrays. Nature 568 16273093
2015 Widespread macromolecular interaction perturbations in human genetic disorders. Cell 454 25910212
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
1998 Inactivating mutations in an SH2 domain-encoding gene in X-linked lymphoproliferative syndrome. Proceedings of the National Academy of Sciences of the United States of America 406 9811875
2005 Regulation of NKT cell development by SAP, the protein defective in XLP. Nature medicine 301 15711562
2005 Defective NKT cell development in mice and humans lacking the adapter SAP, the X-linked lymphoproliferative syndrome gene product. The Journal of experimental medicine 269 15738056
2010 Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency). Blood 265 21119115
2001 NTB-A [correction of GNTB-A], a novel SH2D1A-associated surface molecule contributing to the inability of natural killer cells to kill Epstein-Barr virus-infected B cells in X-linked lymphoproliferative disease. The Journal of experimental medicine 256 11489943
2003 SAP couples Fyn to SLAM immune receptors. Nature cell biology 249 12545174
2003 The SAP and SLAM families in immune responses and X-linked lymphoproliferative disease. Nature reviews. Immunology 233 14523387
1999 Cutting edge: human 2B4, an activating NK cell receptor, recruits the protein tyrosine phosphatase SHP-2 and the adaptor signaling protein SAP. Journal of immunology (Baltimore, Md. : 1950) 232 10358138
2010 X-linked lymphoproliferative disease due to SAP/SH2D1A deficiency: a multicenter study on the manifestations, management and outcome of the disease. Blood 215 20926771
2001 Altered lymphocyte responses and cytokine production in mice deficient in the X-linked lymphoproliferative disease gene SH2D1A/DSHP/SAP. Proceedings of the National Academy of Sciences of the United States of America 210 11404475
2001 Regulation of SLAM-mediated signal transduction by SAP, the X-linked lymphoproliferative gene product. Nature immunology 205 11477403
1999 Crystal structures of the XLP protein SAP reveal a class of SH2 domains with extended, phosphotyrosine-independent sequence recognition. Molecular cell 202 10549287
1998 Identification and characterization of novel substrates of Trk receptors in developing neurons. Neuron 191 9856458
2000 Correlation of mutations of the SH2D1A gene and epstein-barr virus infection with clinical phenotype and outcome in X-linked lymphoproliferative disease. Blood 190 11049992
2009 SLAM receptors and SAP influence lymphocyte interactions, development and function. Nature reviews. Immunology 175 19079134
2012 TGF-β1 down-regulation of NKG2D/DAP10 and 2B4/SAP expression on human NK cells contributes to HBV persistence. PLoS pathogens 170 22438812
2001 CD150 association with either the SH2-containing inositol phosphatase or the SH2-containing protein tyrosine phosphatase is regulated by the adaptor protein SH2D1A. Journal of immunology (Baltimore, Md. : 1950) 169 11313386
2007 The coupling of synthesis and partitioning of EBV's plasmid replicon is revealed in live cells. The EMBO journal 165 17853891
2005 Molecular basis for positive and negative signaling by the natural killer cell receptor 2B4 (CD244). Blood 164 15713798
1982 Epstein-Barr virus-induced diseases in boys with the X-linked lymphoproliferative syndrome (XLP): update on studies of the registry. The American journal of medicine 160 6283885
2005 SAP controls the cytolytic activity of CD8+ T cells against EBV-infected cells. Blood 149 15677558
1997 p38-2, a novel mitogen-activated protein kinase with distinct properties. The Journal of biological chemistry 148 9235954
2009 Ubiquitin-mediated proteolysis of HuR by heat shock. The EMBO journal 142 19322201
1993 MTCP-1: a novel gene on the human chromosome Xq28 translocated to the T cell receptor alpha/delta locus in mature T cell proliferations. Oncogene 138 8361760
2009 Restimulation-induced apoptosis of T cells is impaired in patients with X-linked lymphoproliferative disease caused by SAP deficiency. The Journal of clinical investigation 134 19759517
2001 Hemophagocytic lymphohistiocytosis due to germline mutations in SH2D1A, the X-linked lymphoproliferative disease gene. Blood 118 11159547
2000 Defective NK cell activation in X-linked lymphoproliferative disease. Journal of immunology (Baltimore, Md. : 1950) 116 11034354
2006 Transcriptional activation by EBV nuclear antigen 1 is essential for the expression of EBV's transforming genes. Proceedings of the National Academy of Sciences of the United States of America 115 16966603
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