Affinage

SH2D1B

SH2 domain-containing protein 1B · UniProt O14796

Length
132 aa
Mass
15.3 kDa
Annotated
2026-06-10
21 papers in source corpus 11 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SH2D1B (EAT-2) is a free SH2 domain-containing intracellular adaptor that couples SLAM family immune receptors to downstream signaling, governing the activation threshold of innate immune effector cells (PMID:11689425, PMID:24687958). Its SH2 domain binds phosphotyrosine motifs in the cytoplasmic tails of SLAM family receptors including CD150, CD84, CD229, CD244/2B4, CRACC, and NTB-A, with a binding mode crystallographically similar to the related adaptor SAP but specific for the phosphorylated receptor; in doing so EAT-2 can compete with the recruitment of the phosphatase SHP-2 (PMID:11689425, PMID:16920955, PMID:12115647). In NK cells, EAT-2 acts through one or two tyrosines in its C-terminal tail — features absent from SAP — to link these receptors to PLCγ, calcium flux, and Erk signaling, accelerating polarization and exocytosis of cytotoxic granules toward target cells rather than enhancing conjugate formation (PMID:24687958, PMID:16339536). EAT-2 is a decisive switch in receptor outcome: it converts CRACC from an inhibitory to an activating receptor, and in its absence the same SLAM receptors signal inhibition (PMID:19151721). All of these activating functions require an intact SH2 domain, as the R31Q mutant abolishes EAT-2-dependent NK, DC, and monocyte responses (PMID:24374770). In dendritic cells EAT-2 instead acts as a negative regulator, suppressing SLAM-triggered IL-12 production by blocking p38 MAPK and JNK signaling and thereby limiting Th1 differentiation (PMID:26432891).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1996 Low

    Established EAT-2 as a distinct gene encoding a biochemically functional SH2 domain, placing it in the SH2 adaptor landscape before any immune function was known.

    Evidence RDA cloning, SH2 domain functional assay, and chromosomal mapping in the context of EWS/FLI1-driven transformation

    PMID:9000139

    Open questions at the time
    • Limited mechanistic follow-up; immune role not yet defined
    • Functional relationship of EWS/FLI1 upregulation to physiological EAT-2 function unclear
  2. 2001 High

    Defined the structural basis for EAT-2 recognition of SLAM family receptors and showed it binds phosphorylated, not unphosphorylated, receptor tails — answering how EAT-2 engages its receptors and how it differs from SAP.

    Evidence X-ray crystallography of the EAT-2–CD150 phosphopeptide complex with binding and SHP-2 competition assays

    PMID:11689425

    Open questions at the time
    • Functional consequence in living immune cells not directly tested
    • Whether SHP-2 displacement is the dominant in vivo mechanism not resolved
  3. 2002 Medium

    Identified CD84 as a SLAM family receptor that recruits both SAP and EAT-2 upon ligation, extending the EAT-2 receptor repertoire into B cells.

    Evidence Co-immunoprecipitation and tyrosine phosphorylation assay following CD84 ligation

    PMID:12115647

    Open questions at the time
    • Downstream signaling consequences in B cells not defined
    • No functional readout beyond receptor association
  4. 2005 High

    Demonstrated that EAT-2 associates with 2B4 and CRACC and identified PLCγ and PI3K as downstream mediators, while revealing that EAT-2 and SAP have opposing functions on NK cells.

    Evidence Reciprocal Co-IP, EAT-2 KO and overexpression mouse models, Src kinase inhibition, and functional NK cytotoxicity/cytokine assays

    PMID:16127454 PMID:16339536

    Open questions at the time
    • Apparent contradiction between inhibitory (2B4) and activating signaling readouts not reconciled
    • Role of EAT-2 C-terminal tyrosines not yet mapped
  5. 2006 High

    Showed EAT-2 is recruited to a specific tyrosine of NTB-A required for cytotoxicity, establishing that EAT-2 can mediate receptor function independently of SAP.

    Evidence Co-IP, reconstitution of NTB-A-null NK cells with tyrosine mutants, and SAP siRNA knockdown with functional assays

    PMID:16920955

    Open questions at the time
    • Mechanism linking the NTB-A tyrosine to EAT-2 effector signaling not detailed
    • Division of labor between SAP (cytokine) and EAT-2 (cytotoxicity) mechanistically incomplete
  6. 2009 High

    Established EAT-2 as a molecular switch that converts CRACC from inhibitory to activating, defining the principle that receptor outcome depends on adaptor availability.

    Evidence CRACC- and EAT-2-deficient mice with genetic epistasis and functional NK and T cell assays

    PMID:19151721

    Open questions at the time
    • Biochemical basis of the inhibitory-to-activating switch not resolved
    • Whether the switch applies uniformly to all SLAM receptors unknown
  7. 2013 Medium

    Confirmed that EAT-2 immune activation strictly requires SH2-domain receptor engagement across multiple cell types.

    Evidence Overexpression of wild-type versus R31Q SH2 mutant EAT-2 in human PBMCs with NK, DC, monocyte, and cytokine readouts

    PMID:24374770

    Open questions at the time
    • Single lab; effects shown via overexpression rather than endogenous editing
    • Which receptors mediate each cell-type effect not dissected
  8. 2014 High

    Resolved the activating mechanism in NK cells, mapping it to C-terminal tyrosines that couple receptors to PLCγ/Ca2+/Erk and drive granule polarization and exocytosis rather than conjugate formation.

    Evidence EAT-2 KO and tyrosine knock-in mice, biochemical PLCγ/Ca2+/Erk assays, and live-cell imaging of granule polarization

    PMID:24687958

    Open questions at the time
    • Identity of effectors recruited to the C-terminal tyrosines not fully defined
    • How the same receptors yield inhibition without EAT-2 not biochemically resolved
  9. 2015 Medium

    Revealed a contrasting negative-regulatory role in dendritic cells, where EAT-2 suppresses IL-12 by blocking p38/JNK, linking EAT-2 dosage to Th1 outcomes.

    Evidence EAT-2 silencing in DCs, CD40/SLAM cross-linking, p38/JNK signaling assays, T cell co-culture, and subcongenic NZB mouse mapping

    PMID:26432891

    Open questions at the time
    • Mechanism by which EAT-2 inhibits p38/JNK not defined
    • Reconciliation of activating (NK) versus inhibitory (DC) roles not established
  10. 2016 Medium

    Provided an unliganded human EAT-2 structure, exposing conformational flexibility in ligand-binding loops and a discrepancy with prior binding affinity data.

    Evidence X-ray crystallography of unliganded human EAT-2 with computational binding energy comparison

    PMID:27586300

    Open questions at the time
    • Contradicts prior biochemical affinity data; additional factors beyond SH2 domain inferred but not identified
    • Functional relevance of unliganded conformation untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How EAT-2 mediates opposite signaling outcomes — activating in NK cells versus inhibitory in dendritic cells — through the same SLAM receptor engagements remains unresolved.
  • Effectors bound by the C-terminal tyrosines not identified
  • Cell-type-specific signaling determinants unknown
  • Quantitative role of EAT-2 dosage versus SAP competition not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005829 cytosol 2
Pathway
R-HSA-168256 Immune System 4 R-HSA-162582 Signal Transduction 2
Partners
CD150CD229CD244CD84CRACCNTB-ASHP-2

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 EAT-2 (SH2D1B) encodes a free SH2 domain that binds phosphorylated tyrosine motifs in the cytoplasmic tails of SLAM family receptors CD84, CD150, CD229, and CD244. Crystal structure of EAT-2 in complex with a phosphotyrosine peptide from CD150 (Tyr281) is very similar to SAP/SH2D1A bound to the same peptide, explaining high affinity for pTyr motifs. Unlike SAP, EAT-2 does not bind non-phosphorylated CD150. EAT-2 acts as a natural inhibitor by interfering with recruitment of the tyrosine phosphatase SHP-2 to these receptors. X-ray crystallography (EAT-2–phosphopeptide complex), binding assays, competition/inhibition assays with SHP-2 recruitment The EMBO journal High 11689425
2005 EAT-2 associates with the SLAM-related receptor 2B4 in NK cells and inhibits natural cytotoxicity and IFN-γ secretion. This inhibitory mechanism requires tyrosine phosphorylation of the C-terminal tail of EAT-2. The related adaptor ERT shares this inhibitory function in mouse NK cells. EAT-2 and SAP have distinct and opposing functions: SAP activates while EAT-2 inhibits NK cell function. Co-immunoprecipitation, EAT-2 knockout and overexpression mouse models, functional NK cell assays (cytotoxicity, cytokine secretion), phosphorylation-site mutagenesis Nature immunology High 16127454
2005 Upon activation, CRACC (CS-1) associates with EAT-2 in human NK cells. EAT-2 association induces phosphorylation of CRACC (partially reduced by Src kinase inhibitor). PLCγ1, PLCγ2, and PI3K are the major downstream signaling mediators of the CRACC/EAT-2 complex in NK cell cytotoxicity. EAT-2 also associates with 2B4 predominantly in resting NK cells, whereas SAP preferentially binds 2B4 upon activation. Co-immunoprecipitation, pharmacological Src kinase inhibition, signaling pathway analysis (PI3K, PLCγ) in human NK cells Journal of immunology Medium 16339536
2006 NTB-A is tyrosine-phosphorylated in resting human NK cells by Src family kinases and associates with both SAP and EAT-2. EAT-2 (but not SAP) is recruited specifically to the second tyrosine of NTB-A's cytoplasmic tail, and this tyrosine is sufficient and essential for NTB-A-mediated cytotoxicity. NTB-A can mediate cytotoxicity in the absence of SAP, likely via EAT-2, whereas NTB-A-mediated IFN-γ production depends on SAP. Co-immunoprecipitation, NTB-A-negative NK cell line reconstitution with tyrosine mutants, SAP siRNA knockdown, functional cytotoxicity and cytokine assays Journal of immunology High 16920955
2009 CRACC positively regulates NK cell function by a mechanism dependent on EAT-2 (but not SAP). In the absence of EAT-2, CRACC potently inhibits NK cell function. In T cells, which lack EAT-2, CRACC is inhibitory. Thus EAT-2 switches CRACC from an inhibitory to an activating receptor. CRACC-deficient mouse, EAT-2-deficient mouse, functional NK and T cell assays, genetic epistasis Nature immunology High 19151721
2002 CD84 undergoes rapid tyrosine phosphorylation upon ligation and recruits the SH2 domain-containing adaptors SAP and EAT-2, identifying CD84 as a SLAM family receptor that engages EAT-2 signaling in B cells. Co-immunoprecipitation, anti-CD84 ligation, tyrosine phosphorylation assay European journal of immunology Medium 12115647
2014 EAT-2 mediates NK cell activation by coupling SLAM family receptors to PLCγ, calcium fluxes, and Erk kinase. This signaling is triggered by one or two tyrosines in the C-terminal tail of EAT-2 (absent in SAP). Unlike SAP, EAT-2 does not enhance NK–target conjugate formation; instead it accelerates polarization and exocytosis of cytotoxic granules toward hematopoietic target cells. Genetic (EAT-2 KO and tyrosine mutant knock-in), biochemical (PLCγ, Ca2+, Erk assays), live-cell imaging of granule polarization The Journal of experimental medicine High 24687958
2015 EAT-2 negatively regulates cytokine (IL-12) production in dendritic cells downstream of SLAM engagement. A promoter polymorphism in the NZB mouse reduces EAT-2 expression ~70% in DCs. SLAM co-engagement blocks p38 MAPK and JNK signaling in DCs, an effect reversed in DCs with low EAT-2 (NZB allele). EAT-2 knockdown in normal DCs increases IL-12 production and enhances Th1 differentiation. EAT-2 gene silencing in DCs, CD40/SLAM cross-linking, downstream signaling assays (p38 MAPK, JNK), T cell co-culture cytokine assays, subcongenic mouse mapping Journal of immunology Medium 26432891
2016 X-ray crystallographic structure of human EAT-2 (SH2D1B) was determined in an unliganded form. Conformational differences were observed in ligand-binding loops compared to mouse EAT-2–peptide complex. EAT-2 shows similar binding energies to unphosphorylated ligands as SAP, which is inconsistent with prior biochemical data showing EAT-2 has lower affinity for unphosphorylated peptides than SAP, suggesting additional factors beyond the SH2 domain contribute to this difference. X-ray crystallography, computational binding energy comparison Protein and peptide letters Medium 27586300
2013 EAT-2-mediated immune activation requires an intact SH2 domain: an R31Q SH2 domain mutant form of EAT-2 failed to enhance NK cell anti-tumor activity, DC maturation, monocyte phagocytosis, or pro-inflammatory cytokine kinetics in human cells, indicating that EAT-2 interaction with SLAM receptors via its SH2 domain is required for these functions. EAT-2 overexpression vs. R31Q SH2 mutant in human PBMCs; functional assays (NK cytotoxicity, DC maturation, cytokine measurement) International immunology Medium 24374770
1996 EAT-2 (SH2D1B) was identified as a novel gene containing a unique but biochemically functional SH2 domain, upregulated by the EWS/FLI1 fusion oncogene in Ewing's sarcoma. Expression correlated with NIH3T3 transformation by EWS/FLI1-related chimeric proteins. Human EAT-2 was mapped to chromosome 1q22. Representational difference analysis (RDA) cloning, SH2 domain functional assay, chromosomal mapping Oncogene Low 9000139

Source papers

Stage 0 corpus · 21 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Influence of CRACC, a SLAM family receptor coupled to the adaptor EAT-2, on natural killer cell function. Nature immunology 148 19151721
2004 eat-2 and eat-18 are required for nicotinic neurotransmission in the Caenorhabditis elegans pharynx. Genetics 139 15020415
2005 Negative regulation of natural killer cell function by EAT-2, a SAP-related adaptor. Nature immunology 117 16127454
2001 Structural basis for the interaction of the free SH2 domain EAT-2 with SLAM receptors in hematopoietic cells. The EMBO journal 116 11689425
2005 The cytotoxicity receptor CRACC (CS-1) recruits EAT-2 and activates the PI3K and phospholipase Cgamma signaling pathways in human NK cells. Journal of immunology (Baltimore, Md. : 1950) 106 16339536
1996 EAT-2 is a novel SH2 domain containing protein that is up regulated by Ewing's sarcoma EWS/FLI1 fusion gene. Oncogene 88 9000139
2014 EAT-2, a SAP-like adaptor, controls NK cell activation through phospholipase Cγ, Ca++, and Erk, leading to granule polarization. The Journal of experimental medicine 79 24687958
2002 CD84 is up-regulated on a major population of human memory B cells and recruits the SH2 domain containing proteins SAP and EAT-2. European journal of immunology 73 12115647
2006 Molecular analysis of NTB-A signaling: a role for EAT-2 in NTB-A-mediated activation of human NK cells. Journal of immunology (Baltimore, Md. : 1950) 43 16920955
2020 Lifespan and healthspan benefits of exogenous H2S in C. elegans are independent from effects downstream of eat-2 mutation. NPJ aging and mechanisms of disease 34 32566245
2010 Expression of the SLAM family of receptors adapter EAT-2 as a novel strategy for enhancing beneficial immune responses to vaccine antigens. Journal of immunology (Baltimore, Md. : 1950) 31 21149608
2020 EAT-18 is an essential auxiliary protein interacting with the non-alpha nAChR subunit EAT-2 to form a functional receptor. PLoS pathogens 14 32243475
2012 Vaccines expressing the innate immune modulator EAT-2 elicit potent effector memory T lymphocyte responses despite pre-existing vaccine immunity. Journal of immunology (Baltimore, Md. : 1950) 14 22745373
2013 Manipulation of EAT-2 expression promotes induction of multiple beneficial regulatory and effector functions of the human innate immune system as a novel immunomodulatory strategy. International immunology 13 24374770
2011 Vaccine platforms combining circumsporozoite protein and potent immune modulators, rEA or EAT-2, paradoxically result in opposing immune responses. PloS one 13 21912619
2013 Improved cytotoxic T-lymphocyte immune responses to a tumor antigen by vaccines co-expressing the SLAM-associated adaptor EAT-2. Cancer gene therapy 12 23949283
2019 Cross Talk with the GAR-3 Receptor Contributes to Feeding Defects in Caenorhabditis elegans eat-2 Mutants. Genetics 9 30898771
2015 Identification of the SLAM Adapter Molecule EAT-2 as a Lupus-Susceptibility Gene That Acts through Impaired Negative Regulation of Dendritic Cell Signaling. Journal of immunology (Baltimore, Md. : 1950) 5 26432891
2023 EAT-2 attenuates C. elegans development via metabolic remodeling in a chemically defined food environment. Cellular and molecular life sciences : CMLS 4 37450052
2016 The X-ray Crystallographic Structure of Human EAT2 (SH2D1B). Protein and peptide letters 1 27586300
2025 Optimizing a C. elegans whole organism screen biased for chemicals that target the nematode clade specific receptor EAT-2. microPublication biology 0 41142196

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