{"gene":"SLAMF7","run_date":"2026-04-28T20:42:07","timeline":{"discoveries":[{"year":2002,"finding":"CS1 (SLAMF7) is a self-ligand (homophilic receptor); recombinant CS1-Ig fusion protein bound cells transfected with CS1 but not cells expressing other CD2 family members, and soluble CS1-Ig enhanced NK cell cytolytic activity, demonstrating that homophilic CS1-CS1 interaction activates NK cell cytotoxicity.","method":"Recombinant fusion protein binding assay, redirected cytotoxicity assay with human NK cell line YT","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 — direct binding assay with recombinant protein plus functional NK cytotoxicity readout; single lab","pmids":["12213321"],"is_preprint":false},{"year":2004,"finding":"Two CS1 (SLAMF7) splice isoforms exist: CS1-L (containing ITSMs) and CS1-S (lacking ITSMs). CS1-L mediates activating signals (redirected cytotoxicity and calcium flux) in NK cells, whereas CS1-S does not. SAP associates with unstimulated CS1-L and dissociates upon pervanadate stimulation, linking ITSM phosphorylation state to SAP binding.","method":"cDNA transfection into rat NK cell line RNK-16, redirected cytotoxicity assay, calcium flux measurement, co-immunoprecipitation of SAP with CS1-L","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — functional reconstitution in NK cell line with two isoforms compared; single lab","pmids":["15368295"],"is_preprint":false},{"year":2007,"finding":"CS1 (SLAMF7) localizes to adhesion-promoting uropod membranes of polarized MM cells and mediates MM cell adhesion to bone marrow stromal cells (BMSCs); siRNA knockdown of CS1 inhibited MM cell adhesion to BMSCs.","method":"siRNA knockdown, cell adhesion assay, immunofluorescence localization","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 — siRNA loss-of-function with specific adhesion phenotype; single lab","pmids":["17906076"],"is_preprint":false},{"year":2007,"finding":"CS1 (SLAMF7) engagement on human B lymphocytes induces proliferation through an autocrine cytokine loop involving flt3 ligand, lymphotoxin A, TNF, and IL-14; neutralizing antibodies against these cytokines abolished CS1-induced B cell proliferation. Only the CS1-L isoform is expressed on B cells.","method":"Anti-CS1 mAb stimulation of isolated B cells, cytokine microarray, quantitative RT-PCR, neutralizing antibody blockade experiments","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple cytokine neutralization experiments confirm mechanism; single lab","pmids":["17878365"],"is_preprint":false},{"year":2009,"finding":"CRACC/SLAMF7 positively regulates NK cell function via the adaptor 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. Established using CRACC-deficient mice.","method":"CRACC-deficient mouse generation, NK cell functional assays, comparison of EAT-2-expressing vs. EAT-2-deficient contexts","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 1-2 — genetic knockout mouse combined with multiple functional assays; strong evidence for EAT-2-dependent vs. -independent signaling","pmids":["19151721"],"is_preprint":false},{"year":2009,"finding":"CS1 (SLAMF7) knockdown in MM cells decreased phosphorylation of ERK1/2, AKT, and STAT3, and accelerated apoptosis under serum deprivation. CS1 overexpression increased c-maf-targeted cyclin D2-dependent proliferation, integrin β7/αE-mediated adhesion to BMSCs, and VEGF-induced angiogenesis in vivo.","method":"Lentiviral siRNA knockdown, phospho-protein western blot, caspase activation assay, overexpression studies, murine xenograft model","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (KD and OE) with defined signaling and phenotypic readouts; single lab but comprehensive","pmids":["19196658"],"is_preprint":false},{"year":2014,"finding":"SLAMF7-mediated inhibition in EAT-2-negative NK cells is mediated by SHIP-1, which is recruited via tyrosine 261 of SLAMF7. This coupling requires Src kinases, which phosphorylate SLAMF7, and CD45, which activates Src kinases. MM cells lack EAT-2 and CD45, so SLAMF7 cannot trigger inhibitory SHIP-1 signaling in them, explaining why elotuzumab kills MM cells via indirect NK activation.","method":"Mutagenesis of SLAMF7 tyrosine 261, co-immunoprecipitation of SHIP-1 with SLAMF7, Src kinase inhibitor studies, CD45-deficient NK cell analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 — site-directed mutagenesis combined with co-IP and genetic models (CD45-deficient cells); mechanistic pathway thoroughly delineated","pmids":["25312647"],"is_preprint":false},{"year":2017,"finding":"Elotuzumab activates NK cells through two mechanisms: (1) CD16 (FcγRIIIa)-dependent ADCC and (2) direct SLAMF7 ligation-dependent costimulation of calcium signaling triggered by NKp46 and NKG2D, independent of CD16. The direct costimulation requires the full cytoplasmic domain of SLAMF7 on NK cells.","method":"F(ab')2 and Fc-mutant antibody forms, CD16-negative NK-92 cell assays, calcium mobilization assays with NKp46/NKG2D co-engagement, cytoplasmic domain-deleted SLAMF7 constructs","journal":"Oncoimmunology","confidence":"High","confidence_rationale":"Tier 1-2 — multiple antibody variants and genetic constructs used to dissect CD16-dependent vs. SLAMF7-direct signaling; strong mechanistic dissection","pmids":["28932638"],"is_preprint":false},{"year":2019,"finding":"Soluble SLAMF7 (sSLAMF7), shed from MM cells, promotes MM cell growth through homophilic interaction with surface SLAMF7 and subsequent activation of SHP-2 and ERK signaling pathways. IKZF1 (Ikaros) was identified as a transcriptional activator of the SLAMF7 gene; lenalidomide and pomalidomide downregulate SLAMF7 expression by targeting Ikaros.","method":"Recombinant sSLAMF7 treatment of MM cells, phospho-protein western blot (SHP-2, ERK), promoter analysis, lenalidomide/pomalidomide treatment with IKZF1 degradation, murine xenograft model","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods including recombinant protein, signaling analysis, promoter study, and in vivo model; single lab","pmids":["31358854"],"is_preprint":false},{"year":2019,"finding":"Elotuzumab enhances SLAMF7-SLAMF7 homotypic interactions between NK cells and MM target cells in a CD16-independent manner, requiring the full cytoplasmic domain of SLAMF7 on NK cells. This costimulation is associated with upregulation of NKG2D and activated LFA-1 on NK cells, and enhanced cytotoxicity is partially reduced by NKG2D blocking.","method":"CD16-negative NK-92 cells, cytoplasmic domain-deleted SLAMF7 constructs, NKG2D blocking antibodies, degranulation/cytotoxicity assays","journal":"Cancer immunology research","confidence":"Medium","confidence_rationale":"Tier 2 — genetic constructs and receptor blocking; single lab; replicates and extends prior findings","pmids":["31431433"],"is_preprint":false},{"year":2022,"finding":"SLAMF7 engagement on macrophages drives a superactivated inflammatory state characterized by strong cytokine expression; IFN-γ is a key regulator of SLAMF7 expression on macrophages; SLAMF7 engagement induces TNF-α production which amplifies inflammation through an autocrine signaling loop.","method":"RNA-seq of synovial macrophages, SLAMF7 antibody engagement experiments, cytokine expression profiling, IFN-γ stimulation assays","journal":"Science immunology","confidence":"Medium","confidence_rationale":"Tier 2 — direct SLAMF7 engagement experiments with defined cytokine readouts; replicated across multiple disease contexts (RA, Crohn's, COVID-19)","pmids":["35148199"],"is_preprint":false},{"year":2023,"finding":"SLAMF7 attenuates TLR-dependent MAPK and NF-κB signaling in macrophages by cooperating with SHIP1; SLAMF7 interacts with SHIP1 and TRAF6 to inhibit K63 ubiquitination of TRAF6. Tyrosine phosphorylation sites within the SLAMF7 intracellular domain and the phosphatase domain of SHIP1 are required for the SLAMF7-SHIP1-TRAF6 interaction.","method":"Co-immunoprecipitation of SLAMF7/SHIP1/TRAF6 complex, ubiquitination assay (K63-linkage), SLAMF7 tyrosine mutants, SHIP1 phosphatase-dead mutants, sepsis mouse models","journal":"Journal of Clinical Investigation","confidence":"High","confidence_rationale":"Tier 1-2 — co-IP of trimolecular complex, ubiquitination assay, site-specific mutagenesis, and in vivo model; comprehensive mechanistic dissection","pmids":["36749634"],"is_preprint":false},{"year":2024,"finding":"In hepatocellular carcinoma cells, SLAMF7 associates with SHB adaptor protein through its cytoplasmic tyrosine 304 site to recruit SHIP1 to SLAMF7, which then inhibits TRAF6 ubiquitination and suppresses MAPK pathway activation and CCL2 transcription, thereby regulating macrophage migration and polarization.","method":"Co-immunoprecipitation of SLAMF7-SHB-SHIP1 complex, SLAMF7 Y304 mutant, TRAF6 ubiquitination assay, CCL2 promoter/MAPK/ATF2 signaling analysis, liver-specific Slamf7 knockout mice","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1-2 — site-specific mutagenesis, co-IP of trimolecular complex, ubiquitination assay, liver-specific KO mouse model; multiple orthogonal approaches","pmids":["38484085"],"is_preprint":false},{"year":2006,"finding":"CRACC (CS1/SLAMF7) engagement by its physiological self-ligand on MHC class I-negative target cells induces potent NK cell cytotoxicity; blocking CRACC engagement had no effect on NK cell proliferation or cytotoxic potential development, but CRACC-mediated killing contributes to NK cell autologous killing when inhibitory MHC class I signals are removed.","method":"Blocking antibodies against CRACC, NK cell cytotoxicity assays with MHC class I-negative targets, NK cell proliferation assays","journal":"International immunology","confidence":"Medium","confidence_rationale":"Tier 2 — direct blocking experiments with physiological ligand engagement; single lab","pmids":["16410313"],"is_preprint":false},{"year":2013,"finding":"Elotuzumab activates NK cells by binding to CS1/SLAMF7 on NK cells, promoting cytotoxicity against CS1+ MM target cells but not autologous CS1+ NK cells. NK cell activation by elotuzumab is dependent on differential expression of EAT-2, which is present in NK cells but absent in primary MM cells.","method":"NK cell activation assays, ADCC assays, EAT-2 expression analysis in NK cells vs. MM cells, CS1-CS1 interaction studies","journal":"Cancer immunology, immunotherapy","confidence":"Medium","confidence_rationale":"Tier 2 — functional assays with mechanistic link to EAT-2 adaptor; single lab","pmids":["24162108"],"is_preprint":false},{"year":2019,"finding":"Cancer cell-expressed SLAMF7 is not required for CD47 antibody-mediated phagocytosis; SLAMF7 expression on cancer cells does not impact CD47 antibody therapy or CD20 antibody rituximab-mediated phagocytosis.","method":"SLAMF7 knockdown/knockout in cancer cells, phagocytosis assays with anti-CD47 and anti-CD20 antibodies, macrophage co-culture assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — genetic loss-of-function with specific functional readout; single lab","pmids":["30710089"],"is_preprint":false},{"year":2022,"finding":"SLAMF7 modulates B cell function to regulate CNS autoimmunity; SLAMF7-/- mice are more susceptible to EAE, and SLAMF7-/- B cells induce exaggerated T cell activation in co-culture. Adoptive transfer of SLAMF7-/- B cells into B cell-deficient mice increases EAE susceptibility, demonstrating B cell-dependent regulation by SLAMF7.","method":"SLAMF7 knockout mice, EAE model, adoptive transfer of B cells, B-T cell co-culture assays, spectral cytometry, scRNA-seq interactome analysis","journal":"Journal of neuroinflammation","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO, adoptive transfer (epistasis), and co-culture functional assays; single lab but multiple orthogonal approaches","pmids":["36199066"],"is_preprint":false},{"year":2023,"finding":"ALKBH5 promotes m6A modification of Slamf7 mRNA, which decreases Slamf7 mRNA stability in an m6A-dependent manner; specific inhibition of ALKBH5 increases Slamf7 expression in macrophages, and increased SLAMF7 expression promotes autophagy and reduces pro-inflammatory cytokine secretion.","method":"MeRIP assay, ALKBH5 inhibition experiments, mRNA stability assays, autophagy and cytokine secretion assays","journal":"Journal of hazardous materials","confidence":"Medium","confidence_rationale":"Tier 2 — MeRIP (epitranscriptomic mapping) combined with functional assays; single lab","pmids":["37827106"],"is_preprint":false}],"current_model":"SLAMF7 is a self-ligand, homophilic SLAM-family receptor that exerts context-dependent activating or inhibitory effects on immune cells: in EAT-2-expressing NK cells, SLAMF7 engagement drives activation of PLCγ/ERK/calcium signaling and enhances cytotoxicity against SLAMF7+ targets, while in EAT-2-negative cells (T cells, MM cells) it recruits SHIP1 via phosphorylated tyrosine 261/304—facilitated by CD45-activated Src kinases—to form a complex with TRAF6, suppressing K63 ubiquitination of TRAF6 and attenuating MAPK/NF-κB signaling; on MM cells SLAMF7 promotes adhesion to bone marrow stroma and activates ERK/AKT/STAT3 survival pathways partly through c-maf, and soluble SLAMF7 shed from MM cells signals back through surface SLAMF7 via SHP-2/ERK; on macrophages, SLAMF7 engagement can drive superactivation with TNF-α autocrine amplification, and its expression is regulated by IFN-γ and m6A modification via ALKBH5/METTL14."},"narrative":{"teleology":[{"year":2002,"claim":"Establishing that SLAMF7 is a homophilic receptor answered the fundamental question of ligand identity: SLAMF7 binds itself rather than a heterologous ligand, and this self-interaction activates NK cell cytotoxicity.","evidence":"Recombinant CS1-Ig fusion binding to CS1-transfected cells and redirected NK cytotoxicity assay","pmids":["12213321"],"confidence":"Medium","gaps":["Binding affinity not quantified","Homophilic interaction not confirmed in vivo","Downstream signaling pathway not identified"]},{"year":2004,"claim":"Identification of two splice isoforms (CS1-L with ITSMs, CS1-S without) resolved how SLAMF7 can couple to different signaling outcomes, and the finding that SAP associates with CS1-L linked SLAMF7 to the canonical SLAM-family adaptor machinery.","evidence":"Isoform reconstitution in RNK-16 NK cells with redirected cytotoxicity, calcium flux, and SAP co-immunoprecipitation","pmids":["15368295"],"confidence":"Medium","gaps":["EAT-2 role not yet tested","ITSM phosphorylation sites not individually mapped","Physiological ratio of isoforms unclear"]},{"year":2006,"claim":"Demonstrating that SLAMF7 homophilic engagement drives NK killing of MHC-I-negative targets established SLAMF7 as an activating receptor participating in 'missing-self' recognition.","evidence":"Anti-CRACC blocking antibodies in NK cytotoxicity assays against MHC-I-negative targets","pmids":["16410313"],"confidence":"Medium","gaps":["Relative contribution vs. NKG2D/NKp46 not quantified","In vivo relevance not tested"]},{"year":2007,"claim":"Two studies expanded SLAMF7 function beyond NK cells: on myeloma cells, SLAMF7 localized to uropods and mediated adhesion to bone marrow stroma; on B cells, SLAMF7 ligation induced proliferation through an autocrine cytokine loop involving TNF, lymphotoxin-α, and IL-14.","evidence":"siRNA knockdown adhesion assays in MM cells; anti-CS1 mAb stimulation with cytokine neutralization in primary B cells","pmids":["17906076","17878365"],"confidence":"Medium","gaps":["Adhesion receptor partners on stroma not identified","Autocrine cytokine loop not confirmed in vivo","Signaling cascade in B cells not mapped"]},{"year":2009,"claim":"Genetic ablation of SLAMF7 in mice revealed that EAT-2, not SAP, is the critical adaptor for activating signaling, and in cells lacking EAT-2 SLAMF7 is inhibitory — a pivotal switch mechanism explaining cell-type-specific outcomes. Concurrently, SLAMF7 was shown to promote myeloma cell survival via ERK/AKT/STAT3 and c-maf.","evidence":"CRACC-knockout mouse NK/T cell assays; lentiviral knockdown/overexpression in MM cells with signaling analysis and xenograft models","pmids":["19151721","19196658"],"confidence":"High","gaps":["Structure of EAT-2–SLAMF7 complex unknown","Identity of inhibitory effector in EAT-2-negative cells not yet determined"]},{"year":2013,"claim":"The EAT-2-dependent activation model was validated in the therapeutic context of elotuzumab: differential EAT-2 expression (present in NK cells, absent in MM cells) explains why elotuzumab activates NK cells against MM without triggering fratricidal killing of NK cells.","evidence":"NK activation and ADCC assays comparing EAT-2-expressing NK cells with EAT-2-negative MM cells","pmids":["24162108"],"confidence":"Medium","gaps":["Other inhibitory adaptors in MM cells not examined","Patient heterogeneity in EAT-2 expression not addressed"]},{"year":2014,"claim":"SHIP1 was identified as the inhibitory effector recruited to SLAMF7 tyrosine 261, requiring CD45-activated Src kinases for SLAMF7 phosphorylation — explaining why MM cells (which lack CD45) cannot engage this inhibitory circuit and are therefore vulnerable to elotuzumab-mediated NK attack.","evidence":"Y261 mutagenesis, SHIP1 co-immunoprecipitation, Src kinase inhibitors, CD45-deficient NK cells","pmids":["25312647"],"confidence":"High","gaps":["Crystal structure of SLAMF7–SHIP1 interface not resolved","Role of Y304 not yet examined"]},{"year":2017,"claim":"Elotuzumab was shown to costimulate NK cells through a CD16-independent mechanism requiring the SLAMF7 cytoplasmic domain, demonstrating that SLAMF7 provides a direct activating signal synergizing with NKp46/NKG2D co-engagement.","evidence":"F(ab')2 and Fc-mutant antibodies, CD16-negative NK-92 cells, cytoplasmic domain deletion constructs, calcium mobilization","pmids":["28932638"],"confidence":"High","gaps":["Proximal signaling intermediates downstream of SLAMF7 cytoplasmic domain in this costimulatory mode not identified"]},{"year":2019,"claim":"Soluble SLAMF7 shed from MM cells was found to signal back through surface SLAMF7 via SHP-2/ERK, establishing an autocrine growth loop; additionally, IKZF1 (Ikaros) was identified as a transcriptional activator of SLAMF7, explaining how lenalidomide downregulates SLAMF7 through Ikaros degradation.","evidence":"Recombinant sSLAMF7 treatment, phospho-SHP-2/ERK analysis, SLAMF7 promoter analysis, IMiD treatment with IKZF1 degradation readout","pmids":["31358854"],"confidence":"Medium","gaps":["Protease responsible for SLAMF7 shedding not identified","sSLAMF7 levels as clinical biomarker not validated"]},{"year":2022,"claim":"Two studies broadened SLAMF7's physiological scope: on macrophages, SLAMF7 engagement drives a superactivated inflammatory state with TNF-α autocrine amplification regulated by IFN-γ; on B cells, SLAMF7 knockout increases susceptibility to EAE via exaggerated T cell activation, indicating a B cell-intrinsic regulatory role in CNS autoimmunity.","evidence":"RNA-seq and antibody engagement of synovial macrophages; SLAMF7-KO mice with EAE, adoptive B cell transfer, B-T co-culture","pmids":["35148199","36199066"],"confidence":"Medium","gaps":["Signaling pathway downstream of SLAMF7 in B cell regulation of T cells not mapped","Whether macrophage superactivation uses EAT-2 or SHIP1 pathway unclear"]},{"year":2023,"claim":"The SLAMF7–SHIP1 inhibitory axis was extended to macrophage innate signaling: SLAMF7 forms a trimolecular complex with SHIP1 and TRAF6, suppressing K63 ubiquitination of TRAF6 to attenuate TLR-dependent MAPK/NF-κB activation, establishing SLAMF7 as a negative regulator of innate inflammation.","evidence":"Co-IP of SLAMF7/SHIP1/TRAF6, K63-ubiquitination assays, tyrosine and phosphatase-dead mutants, sepsis mouse models","pmids":["36749634"],"confidence":"High","gaps":["How SLAMF7 superactivation (pro-inflammatory) and SHIP1/TRAF6 inhibition (anti-inflammatory) are balanced in the same macrophage not resolved"]},{"year":2023,"claim":"Epitranscriptomic regulation of SLAMF7 was discovered: ALKBH5-mediated m6A demethylation destabilizes Slamf7 mRNA, and ALKBH5 inhibition increases SLAMF7 expression in macrophages, promoting autophagy and reducing pro-inflammatory cytokine secretion.","evidence":"MeRIP assay, ALKBH5 inhibition, mRNA stability and autophagy/cytokine assays in macrophages","pmids":["37827106"],"confidence":"Medium","gaps":["Specific m6A sites on SLAMF7 mRNA not mapped","METTL14 writer contribution not fully delineated","In vivo relevance of epitranscriptomic regulation not tested"]},{"year":2024,"claim":"A second ITSM tyrosine (Y304) was shown to recruit SHIP1 via the SHB adaptor in hepatocellular carcinoma cells, inhibiting TRAF6 ubiquitination, MAPK/ATF2 signaling, and CCL2 transcription, thereby controlling macrophage recruitment and polarization in the tumor microenvironment.","evidence":"Y304 mutagenesis, co-IP of SLAMF7-SHB-SHIP1 complex, TRAF6 ubiquitination assay, liver-specific Slamf7 KO mice","pmids":["38484085"],"confidence":"High","gaps":["Relative contributions of Y261 vs. Y304 in different cell types not compared","Structural basis of SHB vs. direct SHIP1 recruitment not resolved"]},{"year":null,"claim":"Key unresolved questions include how the opposing pro-inflammatory (superactivation) and anti-inflammatory (SHIP1/TRAF6) functions of SLAMF7 are coordinated within the same macrophage, the structural basis of the SLAMF7-EAT-2 vs. SLAMF7-SHIP1 signaling switch, and whether epitranscriptomic regulation of SLAMF7 is relevant in vivo.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural data for any SLAMF7 signaling complex","Mechanism integrating activating vs. inhibitory outcomes in a single cell type unknown","In vivo significance of m6A regulation of SLAMF7 untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,2,13]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,4,7,11]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,6,11,12]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2,7,9,13]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,6,7,10,11]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,6,8,11,12]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[0,2,9,13]}],"complexes":[],"partners":["EAT-2","SHIP1","TRAF6","SHB","SHP-2","SAP"],"other_free_text":[]},"mechanistic_narrative":"SLAMF7 is a homophilic, self-ligand SLAM-family immunoreceptor that functions as a context-dependent activating or inhibitory receptor on NK cells, macrophages, B cells, and myeloma cells, with signaling outcome determined by the availability of the adaptor EAT-2. In EAT-2-expressing NK cells, SLAMF7 ligation costimulates cytotoxicity via calcium signaling and NKG2D upregulation, whereas in EAT-2-negative cells (T cells, macrophages, myeloma cells) SLAMF7 recruits SHIP1 through phosphorylated tyrosine residues (Y261, Y304) — dependent on CD45-activated Src kinases — and forms a trimolecular complex with TRAF6, suppressing K63 ubiquitination of TRAF6 and thereby attenuating MAPK/NF-κB signaling [PMID:19151721, PMID:25312647, PMID:36749634, PMID:38484085]. On myeloma cells, SLAMF7 promotes adhesion to bone marrow stroma, activates ERK/AKT/STAT3 survival pathways partly through c-maf, and its soluble ectodomain signals back via SHP-2/ERK; on macrophages, SLAMF7 engagement can drive a superactivated inflammatory state with TNF-α autocrine amplification regulated by IFN-γ and m6A epitranscriptomic modification [PMID:19196658, PMID:31358854, PMID:35148199, PMID:37827106]."},"prefetch_data":{"uniprot":{"accession":"Q9NQ25","full_name":"SLAM family member 7","aliases":["CD2 subset 1","CD2-like receptor-activating cytotoxic cells","CRACC","Membrane protein FOAP-12","Novel Ly9","Protein 19A"],"length_aa":335,"mass_kda":37.4,"function":"Self-ligand receptor of the signaling lymphocytic activation molecule (SLAM) family. SLAM receptors triggered by homo- or heterotypic cell-cell interactions are modulating the activation and differentiation of a wide variety of immune cells and thus are involved in the regulation and interconnection of both innate and adaptive immune response. Activities are controlled by presence or absence of small cytoplasmic adapter proteins, SH2D1A/SAP and/or SH2D1B/EAT-2. Isoform 1 mediates NK cell activation through a SH2D1A-independent extracellular signal-regulated ERK-mediated pathway (PubMed:11698418). Positively regulates NK cell functions by a mechanism dependent on phosphorylated SH2D1B. Downstream signaling implicates PLCG1, PLCG2 and PI3K (PubMed:16339536). In addition to heterotypic NK cells-target cells interactions also homotypic interactions between NK cells may contribute to activation. However, in the absence of SH2D1B, inhibits NK cell function. Also acts inhibitory in T-cells (By similarity). May play a role in lymphocyte adhesion (PubMed:11802771). In LPS-activated monocytes negatively regulates production of pro-inflammatory cytokines (PubMed:23695528) Isoform 3 does not mediate any NK cell activation","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q9NQ25/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SLAMF7","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SLAMF7","total_profiled":1310},"omim":[{"mim_id":"606625","title":"SLAM FAMILY, MEMBER 7; SLAMF7","url":"https://www.omim.org/entry/606625"},{"mim_id":"600684","title":"T-LYMPHOCYTE SURFACE ANTIGEN LY-9; LY9","url":"https://www.omim.org/entry/600684"},{"mim_id":"120980","title":"INTEGRIN, ALPHA-M; ITGAM","url":"https://www.omim.org/entry/120980"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"intestine","ntpm":30.5},{"tissue":"lymphoid tissue","ntpm":58.0},{"tissue":"stomach 1","ntpm":32.1}],"url":"https://www.proteinatlas.org/search/SLAMF7"},"hgnc":{"alias_symbol":["CRACC","19A","CS1","CD319"],"prev_symbol":[]},"alphafold":{"accession":"Q9NQ25","domains":[{"cath_id":"2.60.40.10","chopping":"24-126","consensus_level":"high","plddt":91.4739,"start":24,"end":126},{"cath_id":"2.60.40.10","chopping":"133-216","consensus_level":"high","plddt":89.9946,"start":133,"end":216},{"cath_id":"1.20.5","chopping":"223-268","consensus_level":"medium","plddt":84.0109,"start":223,"end":268}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NQ25","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NQ25-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NQ25-F1-predicted_aligned_error_v6.png","plddt_mean":78.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SLAMF7","jax_strain_url":"https://www.jax.org/strain/search?query=SLAMF7"},"sequence":{"accession":"Q9NQ25","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NQ25.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NQ25/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NQ25"}},"corpus_meta":[{"pmid":"17906076","id":"PMC_17906076","title":"Anti-CS1 humanized monoclonal antibody HuLuc63 inhibits myeloma cell adhesion and induces antibody-dependent cellular cytotoxicity in the bone marrow milieu.","date":"2007","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/17906076","citation_count":405,"is_preprint":false},{"pmid":"24162108","id":"PMC_24162108","title":"Elotuzumab directly enhances NK cell cytotoxicity against myeloma via CS1 ligation: evidence for augmented NK cell function complementing ADCC.","date":"2013","source":"Cancer immunology, immunotherapy : CII","url":"https://pubmed.ncbi.nlm.nih.gov/24162108","citation_count":252,"is_preprint":false},{"pmid":"7677996","id":"PMC_7677996","title":"Multiple activation states of VLA-4. 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medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36193848","citation_count":18,"is_preprint":false},{"pmid":"32373944","id":"PMC_32373944","title":"LncRNA HAGLR accelerates femoral neck fracture healing through negatively regulating miRNA-19a-3p.","date":"2020","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32373944","citation_count":18,"is_preprint":false},{"pmid":"10954599","id":"PMC_10954599","title":"RNA-binding characteristics of the chloroplast S1-like ribosomal protein CS1.","date":"2000","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/10954599","citation_count":17,"is_preprint":false},{"pmid":"32201518","id":"PMC_32201518","title":"MicroRNA-19a-3p regulates cell growth through modulation of the PIK3IP1-AKT pathway in hepatocellular carcinoma.","date":"2020","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/32201518","citation_count":17,"is_preprint":false},{"pmid":"33842319","id":"PMC_33842319","title":"Osteosarcoma Cell-Derived Small Extracellular Vesicles Enhance Osteoclastogenesis and Bone Resorption Through Transferring MicroRNA-19a-3p.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33842319","citation_count":17,"is_preprint":false},{"pmid":"34680541","id":"PMC_34680541","title":"Novel CS1 CAR-T Cells and Bispecific CS1-BCMA CAR-T Cells Effectively Target Multiple Myeloma.","date":"2021","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/34680541","citation_count":16,"is_preprint":false},{"pmid":"10716877","id":"PMC_10716877","title":"Regulation of CS1 fibronectin expression and function by IL-1 in endothelial cells.","date":"2000","source":"Cellular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/10716877","citation_count":16,"is_preprint":false},{"pmid":"32487061","id":"PMC_32487061","title":"Association of circulating SLAMF7+Tfh1 cells with IgG4 levels in patients with IgG4-related disease.","date":"2020","source":"BMC immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32487061","citation_count":16,"is_preprint":false},{"pmid":"32096186","id":"PMC_32096186","title":"LncRNA NEAT1 promotes cardiac hypertrophy through microRNA-19a-3p/SMYD2 axis.","date":"2020","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32096186","citation_count":16,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50791,"output_tokens":4767,"usd":0.111939},"stage2":{"model":"claude-opus-4-6","input_tokens":8267,"output_tokens":3704,"usd":0.200903},"total_usd":0.312842,"stage1_batch_id":"msgbatch_011rkcQdVV1RaFq9XhcG6df6","stage2_batch_id":"msgbatch_01RzgrJafdF4EWHhj5mNi6dh","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"CS1 (SLAMF7) is a self-ligand (homophilic receptor); recombinant CS1-Ig fusion protein bound cells transfected with CS1 but not cells expressing other CD2 family members, and soluble CS1-Ig enhanced NK cell cytolytic activity, demonstrating that homophilic CS1-CS1 interaction activates NK cell cytotoxicity.\",\n      \"method\": \"Recombinant fusion protein binding assay, redirected cytotoxicity assay with human NK cell line YT\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct binding assay with recombinant protein plus functional NK cytotoxicity readout; single lab\",\n      \"pmids\": [\"12213321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Two CS1 (SLAMF7) splice isoforms exist: CS1-L (containing ITSMs) and CS1-S (lacking ITSMs). CS1-L mediates activating signals (redirected cytotoxicity and calcium flux) in NK cells, whereas CS1-S does not. SAP associates with unstimulated CS1-L and dissociates upon pervanadate stimulation, linking ITSM phosphorylation state to SAP binding.\",\n      \"method\": \"cDNA transfection into rat NK cell line RNK-16, redirected cytotoxicity assay, calcium flux measurement, co-immunoprecipitation of SAP with CS1-L\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional reconstitution in NK cell line with two isoforms compared; single lab\",\n      \"pmids\": [\"15368295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CS1 (SLAMF7) localizes to adhesion-promoting uropod membranes of polarized MM cells and mediates MM cell adhesion to bone marrow stromal cells (BMSCs); siRNA knockdown of CS1 inhibited MM cell adhesion to BMSCs.\",\n      \"method\": \"siRNA knockdown, cell adhesion assay, immunofluorescence localization\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — siRNA loss-of-function with specific adhesion phenotype; single lab\",\n      \"pmids\": [\"17906076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CS1 (SLAMF7) engagement on human B lymphocytes induces proliferation through an autocrine cytokine loop involving flt3 ligand, lymphotoxin A, TNF, and IL-14; neutralizing antibodies against these cytokines abolished CS1-induced B cell proliferation. Only the CS1-L isoform is expressed on B cells.\",\n      \"method\": \"Anti-CS1 mAb stimulation of isolated B cells, cytokine microarray, quantitative RT-PCR, neutralizing antibody blockade experiments\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple cytokine neutralization experiments confirm mechanism; single lab\",\n      \"pmids\": [\"17878365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CRACC/SLAMF7 positively regulates NK cell function via the adaptor 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. Established using CRACC-deficient mice.\",\n      \"method\": \"CRACC-deficient mouse generation, NK cell functional assays, comparison of EAT-2-expressing vs. EAT-2-deficient contexts\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genetic knockout mouse combined with multiple functional assays; strong evidence for EAT-2-dependent vs. -independent signaling\",\n      \"pmids\": [\"19151721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CS1 (SLAMF7) knockdown in MM cells decreased phosphorylation of ERK1/2, AKT, and STAT3, and accelerated apoptosis under serum deprivation. CS1 overexpression increased c-maf-targeted cyclin D2-dependent proliferation, integrin β7/αE-mediated adhesion to BMSCs, and VEGF-induced angiogenesis in vivo.\",\n      \"method\": \"Lentiviral siRNA knockdown, phospho-protein western blot, caspase activation assay, overexpression studies, murine xenograft model\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (KD and OE) with defined signaling and phenotypic readouts; single lab but comprehensive\",\n      \"pmids\": [\"19196658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SLAMF7-mediated inhibition in EAT-2-negative NK cells is mediated by SHIP-1, which is recruited via tyrosine 261 of SLAMF7. This coupling requires Src kinases, which phosphorylate SLAMF7, and CD45, which activates Src kinases. MM cells lack EAT-2 and CD45, so SLAMF7 cannot trigger inhibitory SHIP-1 signaling in them, explaining why elotuzumab kills MM cells via indirect NK activation.\",\n      \"method\": \"Mutagenesis of SLAMF7 tyrosine 261, co-immunoprecipitation of SHIP-1 with SLAMF7, Src kinase inhibitor studies, CD45-deficient NK cell analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — site-directed mutagenesis combined with co-IP and genetic models (CD45-deficient cells); mechanistic pathway thoroughly delineated\",\n      \"pmids\": [\"25312647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Elotuzumab activates NK cells through two mechanisms: (1) CD16 (FcγRIIIa)-dependent ADCC and (2) direct SLAMF7 ligation-dependent costimulation of calcium signaling triggered by NKp46 and NKG2D, independent of CD16. The direct costimulation requires the full cytoplasmic domain of SLAMF7 on NK cells.\",\n      \"method\": \"F(ab')2 and Fc-mutant antibody forms, CD16-negative NK-92 cell assays, calcium mobilization assays with NKp46/NKG2D co-engagement, cytoplasmic domain-deleted SLAMF7 constructs\",\n      \"journal\": \"Oncoimmunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple antibody variants and genetic constructs used to dissect CD16-dependent vs. SLAMF7-direct signaling; strong mechanistic dissection\",\n      \"pmids\": [\"28932638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Soluble SLAMF7 (sSLAMF7), shed from MM cells, promotes MM cell growth through homophilic interaction with surface SLAMF7 and subsequent activation of SHP-2 and ERK signaling pathways. IKZF1 (Ikaros) was identified as a transcriptional activator of the SLAMF7 gene; lenalidomide and pomalidomide downregulate SLAMF7 expression by targeting Ikaros.\",\n      \"method\": \"Recombinant sSLAMF7 treatment of MM cells, phospho-protein western blot (SHP-2, ERK), promoter analysis, lenalidomide/pomalidomide treatment with IKZF1 degradation, murine xenograft model\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including recombinant protein, signaling analysis, promoter study, and in vivo model; single lab\",\n      \"pmids\": [\"31358854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Elotuzumab enhances SLAMF7-SLAMF7 homotypic interactions between NK cells and MM target cells in a CD16-independent manner, requiring the full cytoplasmic domain of SLAMF7 on NK cells. This costimulation is associated with upregulation of NKG2D and activated LFA-1 on NK cells, and enhanced cytotoxicity is partially reduced by NKG2D blocking.\",\n      \"method\": \"CD16-negative NK-92 cells, cytoplasmic domain-deleted SLAMF7 constructs, NKG2D blocking antibodies, degranulation/cytotoxicity assays\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic constructs and receptor blocking; single lab; replicates and extends prior findings\",\n      \"pmids\": [\"31431433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SLAMF7 engagement on macrophages drives a superactivated inflammatory state characterized by strong cytokine expression; IFN-γ is a key regulator of SLAMF7 expression on macrophages; SLAMF7 engagement induces TNF-α production which amplifies inflammation through an autocrine signaling loop.\",\n      \"method\": \"RNA-seq of synovial macrophages, SLAMF7 antibody engagement experiments, cytokine expression profiling, IFN-γ stimulation assays\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct SLAMF7 engagement experiments with defined cytokine readouts; replicated across multiple disease contexts (RA, Crohn's, COVID-19)\",\n      \"pmids\": [\"35148199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SLAMF7 attenuates TLR-dependent MAPK and NF-κB signaling in macrophages by cooperating with SHIP1; SLAMF7 interacts with SHIP1 and TRAF6 to inhibit K63 ubiquitination of TRAF6. Tyrosine phosphorylation sites within the SLAMF7 intracellular domain and the phosphatase domain of SHIP1 are required for the SLAMF7-SHIP1-TRAF6 interaction.\",\n      \"method\": \"Co-immunoprecipitation of SLAMF7/SHIP1/TRAF6 complex, ubiquitination assay (K63-linkage), SLAMF7 tyrosine mutants, SHIP1 phosphatase-dead mutants, sepsis mouse models\",\n      \"journal\": \"Journal of Clinical Investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — co-IP of trimolecular complex, ubiquitination assay, site-specific mutagenesis, and in vivo model; comprehensive mechanistic dissection\",\n      \"pmids\": [\"36749634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In hepatocellular carcinoma cells, SLAMF7 associates with SHB adaptor protein through its cytoplasmic tyrosine 304 site to recruit SHIP1 to SLAMF7, which then inhibits TRAF6 ubiquitination and suppresses MAPK pathway activation and CCL2 transcription, thereby regulating macrophage migration and polarization.\",\n      \"method\": \"Co-immunoprecipitation of SLAMF7-SHB-SHIP1 complex, SLAMF7 Y304 mutant, TRAF6 ubiquitination assay, CCL2 promoter/MAPK/ATF2 signaling analysis, liver-specific Slamf7 knockout mice\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — site-specific mutagenesis, co-IP of trimolecular complex, ubiquitination assay, liver-specific KO mouse model; multiple orthogonal approaches\",\n      \"pmids\": [\"38484085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CRACC (CS1/SLAMF7) engagement by its physiological self-ligand on MHC class I-negative target cells induces potent NK cell cytotoxicity; blocking CRACC engagement had no effect on NK cell proliferation or cytotoxic potential development, but CRACC-mediated killing contributes to NK cell autologous killing when inhibitory MHC class I signals are removed.\",\n      \"method\": \"Blocking antibodies against CRACC, NK cell cytotoxicity assays with MHC class I-negative targets, NK cell proliferation assays\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct blocking experiments with physiological ligand engagement; single lab\",\n      \"pmids\": [\"16410313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Elotuzumab activates NK cells by binding to CS1/SLAMF7 on NK cells, promoting cytotoxicity against CS1+ MM target cells but not autologous CS1+ NK cells. NK cell activation by elotuzumab is dependent on differential expression of EAT-2, which is present in NK cells but absent in primary MM cells.\",\n      \"method\": \"NK cell activation assays, ADCC assays, EAT-2 expression analysis in NK cells vs. MM cells, CS1-CS1 interaction studies\",\n      \"journal\": \"Cancer immunology, immunotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional assays with mechanistic link to EAT-2 adaptor; single lab\",\n      \"pmids\": [\"24162108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Cancer cell-expressed SLAMF7 is not required for CD47 antibody-mediated phagocytosis; SLAMF7 expression on cancer cells does not impact CD47 antibody therapy or CD20 antibody rituximab-mediated phagocytosis.\",\n      \"method\": \"SLAMF7 knockdown/knockout in cancer cells, phagocytosis assays with anti-CD47 and anti-CD20 antibodies, macrophage co-culture assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function with specific functional readout; single lab\",\n      \"pmids\": [\"30710089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SLAMF7 modulates B cell function to regulate CNS autoimmunity; SLAMF7-/- mice are more susceptible to EAE, and SLAMF7-/- B cells induce exaggerated T cell activation in co-culture. Adoptive transfer of SLAMF7-/- B cells into B cell-deficient mice increases EAE susceptibility, demonstrating B cell-dependent regulation by SLAMF7.\",\n      \"method\": \"SLAMF7 knockout mice, EAE model, adoptive transfer of B cells, B-T cell co-culture assays, spectral cytometry, scRNA-seq interactome analysis\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO, adoptive transfer (epistasis), and co-culture functional assays; single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"36199066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ALKBH5 promotes m6A modification of Slamf7 mRNA, which decreases Slamf7 mRNA stability in an m6A-dependent manner; specific inhibition of ALKBH5 increases Slamf7 expression in macrophages, and increased SLAMF7 expression promotes autophagy and reduces pro-inflammatory cytokine secretion.\",\n      \"method\": \"MeRIP assay, ALKBH5 inhibition experiments, mRNA stability assays, autophagy and cytokine secretion assays\",\n      \"journal\": \"Journal of hazardous materials\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — MeRIP (epitranscriptomic mapping) combined with functional assays; single lab\",\n      \"pmids\": [\"37827106\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLAMF7 is a self-ligand, homophilic SLAM-family receptor that exerts context-dependent activating or inhibitory effects on immune cells: in EAT-2-expressing NK cells, SLAMF7 engagement drives activation of PLCγ/ERK/calcium signaling and enhances cytotoxicity against SLAMF7+ targets, while in EAT-2-negative cells (T cells, MM cells) it recruits SHIP1 via phosphorylated tyrosine 261/304—facilitated by CD45-activated Src kinases—to form a complex with TRAF6, suppressing K63 ubiquitination of TRAF6 and attenuating MAPK/NF-κB signaling; on MM cells SLAMF7 promotes adhesion to bone marrow stroma and activates ERK/AKT/STAT3 survival pathways partly through c-maf, and soluble SLAMF7 shed from MM cells signals back through surface SLAMF7 via SHP-2/ERK; on macrophages, SLAMF7 engagement can drive superactivation with TNF-α autocrine amplification, and its expression is regulated by IFN-γ and m6A modification via ALKBH5/METTL14.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SLAMF7 is a homophilic, self-ligand SLAM-family immunoreceptor that functions as a context-dependent activating or inhibitory receptor on NK cells, macrophages, B cells, and myeloma cells, with signaling outcome determined by the availability of the adaptor EAT-2. In EAT-2-expressing NK cells, SLAMF7 ligation costimulates cytotoxicity via calcium signaling and NKG2D upregulation, whereas in EAT-2-negative cells (T cells, macrophages, myeloma cells) SLAMF7 recruits SHIP1 through phosphorylated tyrosine residues (Y261, Y304) — dependent on CD45-activated Src kinases — and forms a trimolecular complex with TRAF6, suppressing K63 ubiquitination of TRAF6 and thereby attenuating MAPK/NF-κB signaling [PMID:19151721, PMID:25312647, PMID:36749634, PMID:38484085]. On myeloma cells, SLAMF7 promotes adhesion to bone marrow stroma, activates ERK/AKT/STAT3 survival pathways partly through c-maf, and its soluble ectodomain signals back via SHP-2/ERK; on macrophages, SLAMF7 engagement can drive a superactivated inflammatory state with TNF-α autocrine amplification regulated by IFN-γ and m6A epitranscriptomic modification [PMID:19196658, PMID:31358854, PMID:35148199, PMID:37827106].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Establishing that SLAMF7 is a homophilic receptor answered the fundamental question of ligand identity: SLAMF7 binds itself rather than a heterologous ligand, and this self-interaction activates NK cell cytotoxicity.\",\n      \"evidence\": \"Recombinant CS1-Ig fusion binding to CS1-transfected cells and redirected NK cytotoxicity assay\",\n      \"pmids\": [\"12213321\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding affinity not quantified\", \"Homophilic interaction not confirmed in vivo\", \"Downstream signaling pathway not identified\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identification of two splice isoforms (CS1-L with ITSMs, CS1-S without) resolved how SLAMF7 can couple to different signaling outcomes, and the finding that SAP associates with CS1-L linked SLAMF7 to the canonical SLAM-family adaptor machinery.\",\n      \"evidence\": \"Isoform reconstitution in RNK-16 NK cells with redirected cytotoxicity, calcium flux, and SAP co-immunoprecipitation\",\n      \"pmids\": [\"15368295\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"EAT-2 role not yet tested\", \"ITSM phosphorylation sites not individually mapped\", \"Physiological ratio of isoforms unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrating that SLAMF7 homophilic engagement drives NK killing of MHC-I-negative targets established SLAMF7 as an activating receptor participating in 'missing-self' recognition.\",\n      \"evidence\": \"Anti-CRACC blocking antibodies in NK cytotoxicity assays against MHC-I-negative targets\",\n      \"pmids\": [\"16410313\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution vs. NKG2D/NKp46 not quantified\", \"In vivo relevance not tested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Two studies expanded SLAMF7 function beyond NK cells: on myeloma cells, SLAMF7 localized to uropods and mediated adhesion to bone marrow stroma; on B cells, SLAMF7 ligation induced proliferation through an autocrine cytokine loop involving TNF, lymphotoxin-α, and IL-14.\",\n      \"evidence\": \"siRNA knockdown adhesion assays in MM cells; anti-CS1 mAb stimulation with cytokine neutralization in primary B cells\",\n      \"pmids\": [\"17906076\", \"17878365\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Adhesion receptor partners on stroma not identified\", \"Autocrine cytokine loop not confirmed in vivo\", \"Signaling cascade in B cells not mapped\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Genetic ablation of SLAMF7 in mice revealed that EAT-2, not SAP, is the critical adaptor for activating signaling, and in cells lacking EAT-2 SLAMF7 is inhibitory — a pivotal switch mechanism explaining cell-type-specific outcomes. Concurrently, SLAMF7 was shown to promote myeloma cell survival via ERK/AKT/STAT3 and c-maf.\",\n      \"evidence\": \"CRACC-knockout mouse NK/T cell assays; lentiviral knockdown/overexpression in MM cells with signaling analysis and xenograft models\",\n      \"pmids\": [\"19151721\", \"19196658\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of EAT-2–SLAMF7 complex unknown\", \"Identity of inhibitory effector in EAT-2-negative cells not yet determined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"The EAT-2-dependent activation model was validated in the therapeutic context of elotuzumab: differential EAT-2 expression (present in NK cells, absent in MM cells) explains why elotuzumab activates NK cells against MM without triggering fratricidal killing of NK cells.\",\n      \"evidence\": \"NK activation and ADCC assays comparing EAT-2-expressing NK cells with EAT-2-negative MM cells\",\n      \"pmids\": [\"24162108\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Other inhibitory adaptors in MM cells not examined\", \"Patient heterogeneity in EAT-2 expression not addressed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"SHIP1 was identified as the inhibitory effector recruited to SLAMF7 tyrosine 261, requiring CD45-activated Src kinases for SLAMF7 phosphorylation — explaining why MM cells (which lack CD45) cannot engage this inhibitory circuit and are therefore vulnerable to elotuzumab-mediated NK attack.\",\n      \"evidence\": \"Y261 mutagenesis, SHIP1 co-immunoprecipitation, Src kinase inhibitors, CD45-deficient NK cells\",\n      \"pmids\": [\"25312647\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crystal structure of SLAMF7–SHIP1 interface not resolved\", \"Role of Y304 not yet examined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Elotuzumab was shown to costimulate NK cells through a CD16-independent mechanism requiring the SLAMF7 cytoplasmic domain, demonstrating that SLAMF7 provides a direct activating signal synergizing with NKp46/NKG2D co-engagement.\",\n      \"evidence\": \"F(ab')2 and Fc-mutant antibodies, CD16-negative NK-92 cells, cytoplasmic domain deletion constructs, calcium mobilization\",\n      \"pmids\": [\"28932638\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Proximal signaling intermediates downstream of SLAMF7 cytoplasmic domain in this costimulatory mode not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Soluble SLAMF7 shed from MM cells was found to signal back through surface SLAMF7 via SHP-2/ERK, establishing an autocrine growth loop; additionally, IKZF1 (Ikaros) was identified as a transcriptional activator of SLAMF7, explaining how lenalidomide downregulates SLAMF7 through Ikaros degradation.\",\n      \"evidence\": \"Recombinant sSLAMF7 treatment, phospho-SHP-2/ERK analysis, SLAMF7 promoter analysis, IMiD treatment with IKZF1 degradation readout\",\n      \"pmids\": [\"31358854\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Protease responsible for SLAMF7 shedding not identified\", \"sSLAMF7 levels as clinical biomarker not validated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Two studies broadened SLAMF7's physiological scope: on macrophages, SLAMF7 engagement drives a superactivated inflammatory state with TNF-α autocrine amplification regulated by IFN-γ; on B cells, SLAMF7 knockout increases susceptibility to EAE via exaggerated T cell activation, indicating a B cell-intrinsic regulatory role in CNS autoimmunity.\",\n      \"evidence\": \"RNA-seq and antibody engagement of synovial macrophages; SLAMF7-KO mice with EAE, adoptive B cell transfer, B-T co-culture\",\n      \"pmids\": [\"35148199\", \"36199066\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling pathway downstream of SLAMF7 in B cell regulation of T cells not mapped\", \"Whether macrophage superactivation uses EAT-2 or SHIP1 pathway unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The SLAMF7–SHIP1 inhibitory axis was extended to macrophage innate signaling: SLAMF7 forms a trimolecular complex with SHIP1 and TRAF6, suppressing K63 ubiquitination of TRAF6 to attenuate TLR-dependent MAPK/NF-κB activation, establishing SLAMF7 as a negative regulator of innate inflammation.\",\n      \"evidence\": \"Co-IP of SLAMF7/SHIP1/TRAF6, K63-ubiquitination assays, tyrosine and phosphatase-dead mutants, sepsis mouse models\",\n      \"pmids\": [\"36749634\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SLAMF7 superactivation (pro-inflammatory) and SHIP1/TRAF6 inhibition (anti-inflammatory) are balanced in the same macrophage not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Epitranscriptomic regulation of SLAMF7 was discovered: ALKBH5-mediated m6A demethylation destabilizes Slamf7 mRNA, and ALKBH5 inhibition increases SLAMF7 expression in macrophages, promoting autophagy and reducing pro-inflammatory cytokine secretion.\",\n      \"evidence\": \"MeRIP assay, ALKBH5 inhibition, mRNA stability and autophagy/cytokine assays in macrophages\",\n      \"pmids\": [\"37827106\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific m6A sites on SLAMF7 mRNA not mapped\", \"METTL14 writer contribution not fully delineated\", \"In vivo relevance of epitranscriptomic regulation not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A second ITSM tyrosine (Y304) was shown to recruit SHIP1 via the SHB adaptor in hepatocellular carcinoma cells, inhibiting TRAF6 ubiquitination, MAPK/ATF2 signaling, and CCL2 transcription, thereby controlling macrophage recruitment and polarization in the tumor microenvironment.\",\n      \"evidence\": \"Y304 mutagenesis, co-IP of SLAMF7-SHB-SHIP1 complex, TRAF6 ubiquitination assay, liver-specific Slamf7 KO mice\",\n      \"pmids\": [\"38484085\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of Y261 vs. Y304 in different cell types not compared\", \"Structural basis of SHB vs. direct SHIP1 recruitment not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include how the opposing pro-inflammatory (superactivation) and anti-inflammatory (SHIP1/TRAF6) functions of SLAMF7 are coordinated within the same macrophage, the structural basis of the SLAMF7-EAT-2 vs. SLAMF7-SHIP1 signaling switch, and whether epitranscriptomic regulation of SLAMF7 is relevant in vivo.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural data for any SLAMF7 signaling complex\", \"Mechanism integrating activating vs. inhibitory outcomes in a single cell type unknown\", \"In vivo significance of m6A regulation of SLAMF7 untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 2, 13]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 4, 7, 11]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 6, 11, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2, 7, 9, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 6, 7, 10, 11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 6, 8, 11, 12]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [0, 2, 9, 13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"EAT-2\",\n      \"SHIP1\",\n      \"TRAF6\",\n      \"SHB\",\n      \"SHP-2\",\n      \"SAP\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}