Affinage

SH2D1B

SH2 domain-containing protein 1B · UniProt O14796

Length
132 aa
Mass
15.3 kDa
Annotated
2026-04-28
21 papers in source corpus 11 papers cited in narrative 11 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SH2D1B (EAT-2) is a free SH2 domain adaptor protein that transduces signals from SLAM family receptors to control innate immune cell activation and inhibition. EAT-2 binds phosphorylated ITSM motifs in the cytoplasmic tails of SLAM family receptors (CD150, CD84, CD229, CD244/2B4, CRACC, NTB-A), competing with the phosphatase SHP-2 for receptor access and thereby modulating downstream signaling outcomes (PMID:11689425, PMID:12115647, PMID:16920955). In NK cells, EAT-2 couples SLAM family receptors to PLCγ, calcium flux, and Erk activation through tyrosine residues in its unique C-terminal tail, promoting cytotoxic granule polarization and exocytosis toward hematopoietic targets; in the absence of EAT-2, receptors such as CRACC switch from activating to inhibitory (PMID:24687958, PMID:19151721, PMID:16339536). In dendritic cells, EAT-2 instead functions as a negative regulator by suppressing p38 MAPK and JNK signaling downstream of SLAM engagement, restraining IL-12 production, and a promoter polymorphism reducing EAT-2 expression in NZB mice promotes lupus-like autoimmunity (PMID:26432891).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1996 Medium

    Before its immune function was recognized, EAT-2 was identified as a novel SH2-domain-containing gene upregulated by the EWS/FLI1 oncogene, establishing that it encodes a functional SH2 domain protein.

    Evidence Representational difference analysis and SH2 domain functional assays in NIH3T3 cells transformed by EWS/FLI1

    PMID:9000139

    Open questions at the time
    • No immune cell context examined
    • Physiological target ligands unknown
    • Transformation correlation not mechanistically resolved
  2. 2001 High

    Structural and biochemical work revealed that EAT-2 binds phosphorylated (but not unphosphorylated) SLAM family receptor ITSMs and competes with SHP-2, establishing its mechanism as a natural inhibitor of phosphatase-mediated signaling at these receptors.

    Evidence Crystal structure of EAT-2 bound to phosphotyrosine peptide from CD150; competition assays with SHP-2

    PMID:11689425

    Open questions at the time
    • Functional consequence of SHP-2 displacement not tested in living immune cells
    • Whether EAT-2 also transmits positive signals was unknown
  3. 2002 Medium

    Demonstration that CD84 ligation recruits EAT-2 in primary B cells extended the receptor repertoire for EAT-2 beyond CD150.

    Evidence Co-immunoprecipitation of EAT-2 with tyrosine-phosphorylated CD84 in human B cells

    PMID:12115647

    Open questions at the time
    • No reciprocal IP or mutagenesis
    • Downstream signaling not characterized
    • Functional consequence in B cells not tested
  4. 2005 High

    Genetic studies in mice and human NK cells showed that EAT-2 both inhibits 2B4-mediated NK cytotoxicity (via its C-terminal tyrosines) and activates CRACC-dependent NK killing (via PLCγ/PI3K), revealing that EAT-2 is not a simple inhibitor but a context-dependent signaling switch.

    Evidence EAT-2-knockout and overexpression mouse models; co-IP; cytotoxicity and IFN-γ assays; Src kinase inhibition; tyrosine-to-phenylalanine mutants

    PMID:16127454 PMID:16339536

    Open questions at the time
    • How EAT-2 exerts opposite effects through different SLAM receptors was unresolved
    • Downstream signaling cascade beyond PLCγ/PI3K not fully mapped
  5. 2006 High

    Mapping of EAT-2 recruitment to the second ITSM tyrosine of NTB-A showed receptor-site specificity and demonstrated that EAT-2 selectively mediates cytotoxicity but not IFN-γ production through NTB-A, establishing functional compartmentalization between EAT-2 and SAP.

    Evidence NTB-A tyrosine mutants in an NTB-A-negative NK line; SAP siRNA knockdown; cytotoxicity and cytokine assays

    PMID:16920955

    Open questions at the time
    • Structural basis for ITSM selectivity not resolved
    • Mechanism coupling EAT-2 to granule release versus cytokine pathways unknown
  6. 2009 High

    Genetic epistasis between CRACC-KO and EAT-2-KO mice proved that EAT-2 availability is the molecular switch determining whether CRACC activates or inhibits NK cells, explaining why CRACC is inhibitory in T cells that lack EAT-2.

    Evidence CRACC-deficient and EAT-2-deficient mouse crosses; NK functional assays

    PMID:19151721

    Open questions at the time
    • Identity of the inhibitory effector recruited in the absence of EAT-2 not defined
    • Whether this switch operates for all SLAM receptors was untested
  7. 2013 Medium

    An SH2-domain-disrupting R31Q mutation abolished EAT-2-mediated enhancement of NK cytotoxicity, DC maturation, and monocyte phagocytosis, confirming that SLAM receptor binding through the SH2 domain is essential for all tested immunomodulatory functions.

    Evidence EAT-2 and R31Q mutant overexpression in human PBMCs; NK, DC, and phagocytosis functional assays

    PMID:24374770

    Open questions at the time
    • Overexpression system; endogenous levels not tested
    • Precise receptor targets mediating DC and monocyte effects not identified
  8. 2014 High

    Detailed dissection showed that C-terminal tail tyrosines of EAT-2 couple SLAM receptors to PLCγ, calcium, and Erk to drive cytotoxic granule polarization and exocytosis — a mechanism distinct from SAP, which promotes conjugate formation — thereby defining the unique effector arm of EAT-2 in NK cell killing.

    Evidence EAT-2 tyrosine mutants; calcium flux; Erk activation; live imaging of granule polarization

    PMID:24687958

    Open questions at the time
    • Whether EAT-2 directly recruits PLCγ or acts through an intermediate kinase not resolved
    • Contribution of individual tail tyrosines not fully dissected
  9. 2015 Medium

    EAT-2 was shown to function as a negative regulator in dendritic cells by suppressing p38 and JNK downstream of SLAM/CD40, restraining IL-12; a natural NZB promoter polymorphism reducing EAT-2 expression leads to enhanced DC activation and lupus-like autoimmunity.

    Evidence Gene silencing in DCs; signaling analysis; T cell–DC co-culture; subcongenic NZB mouse mapping

    PMID:26432891

    Open questions at the time
    • Mechanism by which EAT-2 blocks p38/JNK not defined
    • Whether the NZB polymorphism is causal or linked requires further genetic dissection
    • Inhibitory versus activating function in DCs vs NK cells not mechanistically reconciled

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular basis for how EAT-2 switches between activating (NK cell) and inhibitory (DC, T cell) outputs at different SLAM receptors remains unresolved, and no direct structural view of the EAT-2 C-terminal tail engaged with PLCγ or other effectors exists.
  • No structure of EAT-2 tail bound to PLCγ or downstream effectors
  • Whether EAT-2 recruits PLCγ directly or via an adaptor is unknown
  • Cell-type-specific co-factors that determine activating versus inhibitory outcome not identified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 5
Localization
GO:0005829 cytosol 2
Pathway
R-HSA-168256 Immune System 7 R-HSA-162582 Signal Transduction 4
Partners
CD244CD84PLCG1PTPN11SLAMF1SLAMF3SLAMF6SLAMF7

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 EAT-2 (SH2D1B) is a free SH2 domain protein expressed in macrophages and B lymphocytes that binds phosphorylated SLAM family receptors (CD84, CD150/SLAM, CD229, CD244) via a pTyr motif, and acts as a natural inhibitor by interfering with recruitment of the tyrosine phosphatase SHP-2 to these receptors. Unlike SAP, EAT-2 does not bind non-phosphorylated CD150. Crystal structure of EAT-2 in complex with phosphotyrosine peptide from CD150 cytoplasmic tail; biochemical binding assays; competition assays with SHP-2 The EMBO journal High 11689425
2005 EAT-2 associates with the SLAM-related receptor 2B4 in NK cells and inhibits NK cell natural cytotoxicity and IFN-γ secretion by a mechanism requiring tyrosine phosphorylation of its C-terminal tail. The related adaptor ERT shares this inhibitory function. EAT-2-deficient and EAT-2-overexpressing mouse models; co-immunoprecipitation; functional cytotoxicity and cytokine assays; phosphorylation studies with tyrosine mutants Nature immunology High 16127454
2005 Upon activation, CRACC associates with EAT-2 in human NK cells; EAT-2 association induces CRACC tyrosine phosphorylation partially dependent on Src kinases, and downstream signals include PLCγ1, PLCγ2, and PI3K activation leading to NK cell cytotoxicity. EAT-2 also associates with 2B4 predominantly in resting NK cells. Co-immunoprecipitation; pharmacological Src kinase inhibition; functional cytotoxicity assays; signaling pathway analysis Journal of immunology High 16339536
2006 EAT-2 is recruited specifically to the second tyrosine (in an ITSM motif) of NTB-A in human NK cells; this recruitment mediates NTB-A-dependent cytotoxicity but not IFN-γ production, demonstrating differential dependence on EAT-2 versus SAP for distinct NK cell effector functions. NTB-A tyrosine mutants expressed in NTB-A-negative NK cell line; SAP silencing by siRNA; functional cytotoxicity and cytokine assays Journal of immunology High 16920955
2009 CRACC positively regulates NK cell function through EAT-2 (but not SAP); in the absence of EAT-2, CRACC becomes inhibitory. In T cells, which lack EAT-2, CRACC is inhibitory. Thus EAT-2 availability determines the activating vs. inhibitory outcome of CRACC signaling. CRACC-deficient mouse; EAT-2-deficient mouse; genetic epistasis; NK cell functional assays (cytotoxicity, cytokine production) Nature immunology High 19151721
2014 EAT-2 mediates NK cell activation by linking SLAM family receptors to PLCγ, calcium flux, and Erk kinase signaling via one or two tyrosines in its C-terminal tail (not found in SAP). Unlike SAP, EAT-2 does not enhance NK–target conjugate formation but instead accelerates polarization and exocytosis of cytotoxic granules toward hematopoietic target cells. Genetic, biochemical (phosphorylation, co-IP), and live-imaging approaches; EAT-2 tyrosine mutants; calcium flux assays; Erk activation assays; granule polarization imaging The Journal of experimental medicine High 24687958
2002 CD84, upon ligation, undergoes rapid tyrosine phosphorylation and recruits both SAP and EAT-2, suggesting EAT-2 participates in signal transduction through this SLAM family receptor on B cells. Co-immunoprecipitation of SAP and EAT-2 with phosphorylated CD84; anti-CD84 antibody ligation assays on primary human B cells European journal of immunology Medium 12115647
2015 EAT-2 negatively regulates cytokine (IL-12) production in dendritic cells downstream of SLAM engagement by blocking activation of p38 MAPK and JNK signaling pathways following CD40 cross-linking; a NZB mouse promoter polymorphism reducing EAT-2 expression by ~70% in DCs disrupts this inhibition and promotes lupus-like autoimmunity. EAT-2 gene silencing in DCs; downstream signaling analysis (p38, JNK); T cell–DC co-culture assays; subcongenic mouse mapping Journal of immunology Medium 26432891
2016 The crystal structure of human EAT-2 (SH2D1B) in unliganded form reveals conformational differences in ligand-binding loops compared with mouse EAT-2–peptide complex structure, and shows similar calculated binding energies to unphosphorylated ligands as SAP, suggesting additional factors beyond the SH2 domain contribute to the differential phosphotyrosine specificity of EAT-2 versus SAP. X-ray crystallography of human EAT-2; structural comparison with mouse EAT-2 and SAP Protein and peptide letters Medium 27586300
1996 EAT-2 (SH2D1B) was identified as a novel gene upregulated by the EWS/FLI1 fusion oncogene; it encodes a protein containing a biochemically functional SH2 domain and its expression correlates with EWS/FLI1-mediated transformation of NIH3T3 cells. Representational difference analysis (RDA); RT-PCR; SH2 domain functional assessment; NIH3T3 transformation assay Oncogene Medium 9000139
2013 EAT-2 overexpression enhances human NK cell anti-tumor activity, DC maturation, and monocyte phagocytosis; these effects are abolished by an R31Q mutation in the SH2 domain, indicating the interaction between EAT-2 and SLAM receptors (via its SH2 domain) is required for these immunomodulatory functions. EAT-2 overexpression in human PBMCs; R31Q SH2 mutant as negative control; NK cytotoxicity assays; DC maturation assays; phagocytosis assays International immunology Medium 24374770

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 147 19151721
2004 eat-2 and eat-18 are required for nicotinic neurotransmission in the Caenorhabditis elegans pharynx. Genetics 138 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) 105 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
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
2011 Vaccine platforms combining circumsporozoite protein and potent immune modulators, rEA or EAT-2, paradoxically result in opposing immune responses. PloS one 12 21912619
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