Details for: SH2D1A

Gene ID: 4068

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: SH2D1A

Ensembl ID: ENSG00000183918

Description: SH2 domain containing 1A

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • central memory CD8-positive, alpha-beta T cell CL0000907
    CSI 26.87
    rCSI 18.1%
    PRS 76.29
  • CD8-positive, CD28-negative, alpha-beta regulatory T cell CL0000920
    CSI 19.39
    rCSI 38.65%
    PRS 79.97
  • CD8-positive, alpha-beta cytotoxic T cell CL0000794
    CSI 15.57
    rCSI 18.59%
    PRS 82.17
  • naive T cell CL0000898
    CSI 15.13
    rCSI 10.53%
    PRS 78.25
  • thymocyte CL0000893
    CSI 12.73
    rCSI 45.23%
    PRS 91.09
  • activated CD4-positive, alpha-beta T cell CL0000896
    CSI 12.03
    rCSI 11.12%
    PRS 82.13
  • CD8-positive, alpha-beta memory T cell, CD45RO-positive CL0001203
    CSI 11.7
    rCSI 14.17%
    PRS 49.63
  • mononuclear phagocyte CL0000113
    CSI 10.27
    rCSI 22.61%
    PRS 67.43
  • memory T cell CL0000813
    CSI 9.94
    rCSI 19.15%
    PRS 87.89
  • mucosal invariant T cell CL0000940
    CSI 9.76
    rCSI 7.89%
    PRS 73.57
  • CD4-positive, CD25-positive, alpha-beta regulatory T cell CL0000792
    CSI 9.63
    rCSI 9.46%
    PRS 78.68
  • T-helper 1 cell CL0000545
    CSI 9.34
    rCSI 16.86%
    PRS 84.12
  • double-positive, alpha-beta thymocyte CL0000809
    CSI 8.57
    rCSI 8.73%
    PRS 75.63
  • effector CD4-positive, alpha-beta T cell CL0001044
    CSI 8.12
    rCSI 23.3%
    PRS 82.56
  • CD4-positive, alpha-beta cytotoxic T cell CL0000934
    CSI 7.61
    rCSI 10.46%
    PRS 82.15
  • alpha-beta T cell CL0000789
    CSI 5.83
    rCSI 6.84%
    PRS 79.4
  • CD16-negative, CD56-bright natural killer cell, human CL0000938
    CSI 5.43
    rCSI 4.08%
    PRS 88.1
  • activated CD8-positive, alpha-beta T cell, human CL0001049
    CSI 5.39
    rCSI 9.21%
    PRS 80.63
  • innate lymphoid cell CL0001065
    CSI 5.31
    rCSI 10.95%
    PRS 64.34
  • CD4-positive, alpha-beta thymocyte CL0000810
    CSI 5.03
    rCSI 4.03%
    PRS 82.76
  • activated CD8-positive, alpha-beta T cell CL0000906
    CSI 4.25
    rCSI 4.17%
    PRS 83.77
  • double negative thymocyte CL0002489
    CSI 3.86
    rCSI 2.69%
    PRS 74.28
  • CD8-positive, alpha-beta thymocyte CL0000811
    CSI 3.78
    rCSI 5.89%
    PRS 85.89
  • CD4-positive, alpha-beta memory T cell CL0000897
    CSI 3.78
    rCSI 2.71%
    PRS 77.26
  • effector memory CD8-positive, alpha-beta T cell, terminally differentiated CL0001062
    CSI 3.74
    rCSI 18.75%
    PRS 75.58
  • mature T cell CL0002419
    CSI 3.53
    rCSI 2.74%
    PRS 80.62
  • effector CD8-positive, alpha-beta T cell CL0001050
    CSI 3.51
    rCSI 2.67%
    PRS 76.12
  • central memory CD4-positive, alpha-beta T cell CL0000904
    CSI 3.3
    rCSI 1.95%
    PRS 80.31
  • effector memory CD8-positive, alpha-beta T cell CL0000913
    CSI 3.11
    rCSI 2.83%
    PRS 77.6
  • natural T-regulatory cell CL0000903
    CSI 2.95
    rCSI 5.58%
    PRS 90.09
  • regulatory T cell CL0000815
    CSI 2.9
    rCSI 3.36%
    PRS 73.26
  • T follicular helper cell CL0002038
    CSI 2.25
    rCSI 1.69%
    PRS 78.28
  • activated type II NK T cell CL0000931
    CSI 2.02
    rCSI 2.28%
    PRS 79.27
  • T-helper 17 cell CL0000899
    CSI 1.76
    rCSI 1.4%
    PRS 83.88
  • CD8-alpha-alpha-positive, alpha-beta intraepithelial T cell CL0000915
    CSI 1.3
    rCSI 5.91%
    PRS 89.04
  • effector memory CD4-positive, alpha-beta T cell CL0000905
    CSI 1.23
    rCSI 1.67%
    PRS 86.65
  • CD4-positive helper T cell CL0000492
    CSI 1.2
    rCSI 0.91%
    PRS 76.95
  • lung resident memory CD8-positive, alpha-beta T cell CL4033039
    CSI 1.18
    rCSI 3.07%
    PRS 86.97
  • cytotoxic T cell CL0000910
    CSI 0.88
    rCSI 5.03%
    PRS 72.17
  • mature alpha-beta T cell CL0000791
    CSI 0.8
    rCSI 2.89%
    PRS 82.3
  • double negative T regulatory cell CL0011024
    CSI 0.68
    rCSI 12.96%
    PRS 90.13
  • helper T cell CL0000912
    CSI 0.45
    rCSI 0.63%
    PRS 67.85

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

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  • Node Color (Target Cell CSI, relative to current network):
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    • High
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    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [SH2D1A](/details-gene/4068) (SH2 Domain Containing 1A) is a protein-coding gene located on the X chromosome that encodes the signaling adaptor protein SAP (SLAM-associated protein). This protein plays a critical role in the regulation of the adaptive immune system, functioning as a key intracellular mediator for the SLAM (Signaling Lymphocytic Activation Molecule) family of receptors. Expression data reveals that [SH2D1A](/details-gene/4068) is a defining marker of the T cell lineage, with particularly high significance in cytotoxic and memory T lymphocytes. Mutations in this gene are the cause of X-linked lymphoproliferative disease (XLP) ([300490](https://omim.org/entry/300490)), a severe immunodeficiency characterized by an inadequate response to Epstein-Barr virus infection, highlighting its essential function in maintaining immune homeostasis ([Link](https://doi.org/10.1038/2424)). ## Cellular Roles and Expression Landscape The **Overall** expression profile of [SH2D1A](/details-gene/4068) demonstrates its highly specialized role within the immune system, particularly in T lymphocytes. The gene shows the highest significance in various subsets of CD8-positive T cells, including [central memory CD8-positive, alpha-beta T cell](/details-cell/CL0000907) (CSI: 26.87), [CD8-positive, CD28-negative, alpha-beta regulatory T cell](/details-cell/CL0000920) (CSI: 19.39), and [CD8-positive, alpha-beta cytotoxic T cell](/details-cell/CL0000794) (CSI: 15.57). This suggests a pivotal function in the cytotoxic arm of the adaptive immune response, from differentiation to memory formation. Furthermore, its high significance extends across the T cell lineage, including in developing [thymocyte](/details-cell/CL0000893) populations and multiple CD4-positive T cell subsets such as [activated CD4-positive, alpha-beta T cell](/details-cell/CL0000896) and [CD4-positive, CD25-positive, alpha-beta regulatory T cell](/details-cell/CL0000792). This broad expression across both cytotoxic and helper/regulatory T cells indicates that [SH2D1A](/details-gene/4068) is a fundamental component of T cell signaling architecture, rather than a marker for a specific terminal fate. Its role appears to be central to T cell biology, influencing activation, differentiation, and effector functions. ## Pathways and Molecular Function Functionally, [SH2D1A](/details-gene/4068) acts as an adaptor protein, consistent with its annotated molecular function of '[Protein-macromolecule adaptor activity](/details-cell/GO:0030674)'. It contains an SH2 domain that, unlike canonical SH2 domains, can bind to unphosphorylated tyrosine motifs within the cytoplasmic tails of SLAM family receptors such as CD150 (SLAMF1) and CD84 ([Link](https://doi.org/10.1016/s1097-2765(00)80206-3), [Link](https://doi.org/10.1093/emboj/21.3.314)). Upon binding, SAP recruits and activates the Src-family kinase Fyn, thereby transducing signals that regulate lymphocyte function ([Link](https://doi.org/10.1038/26683), [Link](https://doi.org/10.1038/ncb919)). This mechanism is central to its involvement in numerous biological processes. The gene is integral to the '[Adaptive immune response](/details-cell/GO:0002250)' and the overarching '[Immune system](/details-cell/R-HSA-168256)' pathway. Its roles are pleiotropic; it is involved in '[Positive regulation of natural killer cell mediated cytotoxicity](/details-cell/GO:0045954)' and also the '[Negative regulation of t cell receptor signaling pathway](/details-cell/GO:0050860)'. This dual functionality highlights SAP's role as a molecular switch that can either promote or inhibit immune responses depending on the specific cellular and signaling context ([Link](https://doi.org/10.1074/jbc.m206649200)). These functions support its high expression in cytotoxic lymphocytes and regulatory T cells, where it orchestrates cell-cell interactions and modulates activation thresholds. ## Research Directions The functional dichotomy of [SH2D1A](/details-gene/4068), promoting cytotoxicity in some contexts while inhibiting T cell activation in others, suggests a highly regulated signaling node. While its role in the monogenic disorder XLP is well-established ([Link](https://doi.org/10.1038/2424)), its contribution to more complex immunological diseases is an area of active investigation, as evidenced by reports of its altered expression in T cells from patients with rheumatoid arthritis ([Link](https://doi.org/10.1093/intimm/13.4.559)). **Proposed Hypotheses:** 1. Given its high expression in functionally opposing cell types like [CD8-positive, alpha-beta cytotoxic T cell](/details-cell/CL0000794) and [CD4-positive, CD25-positive, alpha-beta regulatory T cell](/details-cell/CL0000792), the signaling output of the SH2D1A/SAP protein may be determined by cell-type-specific post-translational modifications. These modifications could alter its protein-protein interactions, thereby switching its function from pro-cytotoxic to pro-regulatory. 2. The high significance of [SH2D1A](/details-gene/4068) in [central memory CD8-positive, alpha-beta T cell](/details-cell/CL0000907) suggests it is critical for the maintenance and recall function of immunological memory. We hypothesize that continuous, low-level signaling through the SLAM-SAP axis is a requisite survival signal for long-lived memory T cells. **Experimental Approach:** To test the first hypothesis, a combination of proteomics and functional immunology could be employed. SH2D1A protein would be immunoprecipitated from primary human cytotoxic T lymphocytes and regulatory T cells under both resting and activated conditions. Post-translational modifications, such as phosphorylation and acetylation, would be mapped using mass spectrometry. Site-directed mutagenesis could then be used to generate SH2D1A variants that either mimic or block key identified modifications. Expressing these mutants in a SH2D1A-deficient Jurkat T cell line would allow for assessment of their differential ability to recruit downstream effectors (e.g., Fyn kinase) and modulate T cell receptor signaling outputs. **Therapeutic Potential:** As an intracellular adaptor protein, [SH2D1A](/details-gene/4068) is not a conventional drug target for small molecules or antibodies. However, its monogenic link to XLP makes it a prime candidate for gene therapy. The therapeutic strategy would focus on **activation** or functional restoration, likely via ex vivo lentiviral or retroviral transduction of a correct [SH2D1A](/details-gene/4068) copy into autologous hematopoietic stem cells, followed by re-infusion. In the context of autoimmunity, where its signaling may be dysregulated, targeting the downstream kinases (e.g., Fyn) or upstream SLAM receptors that it modulates could offer a more tractable therapeutic avenue than attempting to inhibit the SH2D1A protein itself.

Genular Protein ID: 777081637

Symbol: SH21A_HUMAN

Name: SH2 domain-containing protein 1A

UniProtKB Accession Codes:

O60880 A8MSW0 O95383 O95384 O95385 O95386 Q6FGS6 Q9UNR0

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BindingDB 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 2 CDD 1 CTD 1 ChEMBL 1 ChiTaRS 1 DIP 1 DNASU 1 DisGeNET 1 DisProt 1 EMBL 16 Ensembl 8 EvolutionaryTrace 1 ExpressionAtlas 1 GO 10 Gene3D 1 GeneCards 1 GeneReviews 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 HGNC 1 HOGENOM 1 HPA 1 IDEAL 1 InParanoid 1 IntAct 1 InterPro 4 KEGG 1 MANE-Select 1 MIM 3 MINT 1 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 1 OrthoDB 1 PANTHER 2 PDB 6 PDBsum 6 PIRSF 1 PRINTS 1 PRO 1 PROSITE 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 6 RNAct 1 Reactome 1 RefSeq 2 SMART 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 9771704

Title: Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene.

PubMed ID: 9771704

DOI: 10.1038/2424

PubMed ID: 9774102

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

PubMed ID: 9774102

DOI: 10.1038/26683

PubMed ID: 11282995

Title: Decreased expression of signaling lymphocytic-activation molecule-associated protein (SAP) transcripts in T cells from patients with rheumatoid arthritis.

PubMed ID: 11282995

DOI: 10.1093/intimm/13.4.559

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 15772651

Title: The DNA sequence of the human X chromosome.

PubMed ID: 15772651

DOI: 10.1038/nature03440

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 11389028

Title: Cell surface receptors Ly-9 and CD84 recruit the X-linked lymphoproliferative disease gene product SAP.

PubMed ID: 11389028

DOI: 10.1182/blood.v97.12.3867

PubMed ID: 11806999

Title: Molecular dissection of the signaling and costimulatory functions of CD150 (SLAM): CD150/SAP binding and CD150-mediated costimulation.

PubMed ID: 11806999

DOI: 10.1182/blood.v99.3.957

PubMed ID: 12115647

Title: CD84 is up-regulated on a major population of human memory B cells and recruits the SH2 domain containing proteins SAP and EAT-2.

PubMed ID: 12115647

DOI: 10.1002/1521-4141(200206)32:6<1640::aid-immu1640>3.0.co;2-s

PubMed ID: 12458214

Title: Dual functional roles for the X-linked lymphoproliferative syndrome gene product SAP/SH2D1A in signaling through the signaling lymphocyte activation molecule (SLAM) family of immune receptors.

PubMed ID: 12458214

DOI: 10.1074/jbc.m206649200

PubMed ID: 12545173

Title: Binding of SAP SH2 domain to FynT SH3 domain reveals a novel mechanism of receptor signalling in immune regulation.

PubMed ID: 12545173

DOI: 10.1038/ncb919

PubMed ID: 19608861

Title: Lysine acetylation targets protein complexes and co-regulates major cellular functions.

PubMed ID: 19608861

DOI: 10.1126/science.1175371

PubMed ID: 21219180

Title: SLAM family receptors and SAP adaptors in immunity.

PubMed ID: 21219180

DOI: 10.1146/annurev-immunol-030409-101302

PubMed ID: 10549287

Title: Crystal structures of the XLP protein SAP reveal a class of SH2 domains with extended, phosphotyrosine-independent sequence recognition.

PubMed ID: 10549287

DOI: 10.1016/s1097-2765(00)80206-3

PubMed ID: 11823424

Title: A 'three-pronged' binding mechanism for the SAP/SH2D1A SH2 domain: structural basis and relevance to the XLP syndrome.

PubMed ID: 11823424

DOI: 10.1093/emboj/21.3.314

PubMed ID: 12545174

Title: SAP couples Fyn to SLAM immune receptors.

PubMed ID: 12545174

DOI: 10.1038/ncb920

PubMed ID: 10598819

Title: SH2D1A mutation analysis for diagnosis of XLP in typical and atypical patients.

PubMed ID: 10598819

DOI: 10.1007/s004390051137

PubMed ID: 11049992

Title: Correlation of mutations of the SH2D1A gene and Epstein-Barr virus infection with clinical phenotype and outcome in X-linked lymphoproliferative disease.

PubMed ID: 11049992

PubMed ID: 11034354

Title: Defective NK cell activation in X-linked lymphoproliferative disease.

PubMed ID: 11034354

DOI: 10.4049/jimmunol.165.7.3549

PubMed ID: 11493483

Title: SH2D1A mutations in Japanese males with severe Epstein-Barr virus-associated illnesses.

PubMed ID: 11493483

DOI: 10.1182/blood.v98.4.1268

PubMed ID: 11477068

Title: Characterization of SH2D1A missense mutations identified in X-linked lymphoproliferative disease patients.

PubMed ID: 11477068

DOI: 10.1074/jbc.m101305200

PubMed ID: 14674764

Title: Disease-causing SAP mutants are defective in ligand binding and protein folding.

PubMed ID: 14674764

DOI: 10.1021/bi034798l

PubMed ID: 14583885

Title: Fatal hemophagocytic lymphohistiocytosis associated with Epstein-Barr virus infection in a patient with a novel mutation in the signaling lymphocytic activation molecule-associated protein.

PubMed ID: 14583885

DOI: 10.1086/379126

PubMed ID: 15841490

Title: Characterization of a new disease-causing mutation of SH2D1A in a family with X-linked lymphoproliferative disease.

PubMed ID: 15841490

DOI: 10.1002/humu.9339

PubMed ID: 16720617

Title: Missense mutations in SH2D1A identified in patients with X-linked lymphoproliferative disease differentially affect the expression and function of SAP.

PubMed ID: 16720617

DOI: 10.1093/intimm/dxl039

PubMed ID: 21119115

Title: Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency).

PubMed ID: 21119115

DOI: 10.1182/blood-2010-07-298372

Sequence Information:

  • Length: 128
  • Mass: 14187
  • Checksum: 90234E7A6614EE3D
  • Sequence:
    • MDAVAVYHGK ISRETGEKLL LATGLDGSYL LRDSESVPGV YCLCVLYHGY IYTYRVSQTE 
TGSWSAETAP GVHKRYFRKI KNLISAFQKP DQGIVIPLQY PVEKKSSARS TQGTTGIRED 
PDVCLKAP