{"gene":"SLAMF7","run_date":"2026-06-10T07:46:32","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 cytolytic activity of the human NK cell line YT.","method":"Recombinant fusion protein binding assay, redirected cytotoxicity assay","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay with CS1-Ig fusion protein and functional NK cytotoxicity assay, single lab, two orthogonal methods","pmids":["12213321"],"is_preprint":false},{"year":2004,"finding":"Two CS1 isoforms (CS1-L and CS1-S) are expressed in human NK cells. CS1-L contains ITSMs and mediates redirected cytotoxicity and calcium flux when transfected into RNK-16 rat NK cells, whereas CS1-S lacking ITSMs has no effect. SAP associates with unstimulated CS1-L and dissociates upon pervanadate stimulation.","method":"cDNA transfection into RNK-16 cells, redirected cytotoxicity assay, calcium flux measurement, co-immunoprecipitation","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reconstitution in rat NK cell line with two orthogonal readouts (cytotoxicity + Ca2+ flux), single lab","pmids":["15368295"],"is_preprint":false},{"year":2005,"finding":"Upon activation, CRACC (SLAMF7) recruits the SAP-homolog adaptor EAT-2 in human NK cells. EAT-2 association induces CRACC phosphorylation (partially reduced by Src kinase inhibitors), and downstream signaling involves PLCγ1, PLCγ2, and PI3K to mediate NK cell cytotoxicity.","method":"Co-immunoprecipitation, pharmacological inhibition of Src kinases, Western blotting for phosphorylation, functional cytotoxicity assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP for EAT-2 recruitment, phosphorylation assay with inhibitor controls, downstream pathway identification; replicated by subsequent studies","pmids":["16339536"],"is_preprint":false},{"year":2007,"finding":"CS1 is expressed at adhesion-promoting uropod membranes of polarized MM cells; siRNA knockdown of CS1 inhibited MM cell adhesion to bone marrow stromal cells (BMSCs), demonstrating a direct role for CS1 in MM cell adhesion.","method":"siRNA knockdown, cell adhesion assay, immunofluorescence localization","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with specific adhesion readout, subcellular localization linked to functional consequence, single lab","pmids":["17906076"],"is_preprint":false},{"year":2007,"finding":"CS1 activation on human B lymphocytes induces proliferation through secretion of autocrine cytokines (flt3 ligand, lymphotoxin A, TNF, IL-14); neutralizing antibodies against these cytokines abolished CS1-induced B cell proliferation. Only the CS1-L isoform (containing ITSMs) is expressed on B cells.","method":"Anti-CS1 antibody crosslinking, cytokine microarray, qRT-PCR, neutralizing antibody blockade of individual cytokines","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional antibody crosslinking with neutralization experiments confirming autocrine cytokine mechanism, single lab","pmids":["17878365"],"is_preprint":false},{"year":2009,"finding":"CRACC (SLAMF7) positively regulates NK cell function through a mechanism dependent on the adaptor EAT-2 but not SAP. In the absence of EAT-2, CRACC potently inhibits NK cell function. CRACC is also inhibitory in T cells, which lack EAT-2. Established using CRACC-deficient mouse.","method":"CRACC-knockout mouse generation, NK cell functional assays (cytotoxicity, cytokine production), genetic epistasis with EAT-2","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRACC-deficient mouse with multiple functional readouts and genetic epistasis (EAT-2 dependence), replicated across cell types","pmids":["19151721"],"is_preprint":false},{"year":2009,"finding":"CS1 knockdown in MM cells decreased phosphorylation of ERK1/2, AKT, and STAT3, and accelerated caspase activation under serum deprivation. CS1 overexpression promoted myeloma adhesion to BMSCs by increasing c-maf-targeted cyclin D2-dependent proliferation, integrin β7/αE-mediated adhesion, and VEGF-induced angiogenesis in vivo.","method":"Lentiviral shRNA knockdown, phospho-Western blotting, apoptosis assays, overexpression, xenograft mouse model","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss- and gain-of-function with multiple downstream signaling readouts and in vivo model, single lab","pmids":["19196658"],"is_preprint":false},{"year":2013,"finding":"CS1 crosslinking inhibits production of proinflammatory cytokines TNF-α and IL-12p70 by LPS-activated human monocytes. CS1 expression on monocytes is induced via NF-κB and PI3K signaling pathways.","method":"Anti-CS1 antibody crosslinking, ELISA for cytokines, pharmacological inhibitors of NF-κB and PI3K, RT-PCR","journal":"Inflammation research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — antibody crosslinking functional assay with pharmacological pathway inhibitors, single lab, two methods","pmids":["23695528"],"is_preprint":false},{"year":2014,"finding":"SLAMF7-mediated inhibition in EAT-2-negative NK cells requires SHIP-1, which is recruited via tyrosine 261 of SLAMF7. This coupling requires Src kinases (which phosphorylate SLAMF7) and CD45. MM cells lack EAT-2 but also lack CD45, preventing Src kinase activation and thus SLAMF7-triggered inhibitory signaling in MM cells.","method":"Site-directed mutagenesis (Y261 of SLAMF7), co-immunoprecipitation of SHIP-1, use of CD45-deficient NK cells, functional NK cytotoxicity assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis of specific tyrosine residue combined with Co-IP and CD45-deficient cell validation; mechanistic circuit fully defined","pmids":["25312647"],"is_preprint":false},{"year":2015,"finding":"Blimp-1/PRDM1 acts as a transcriptional activator of the human CS1 (SLAMF7) gene in NK and B cells. EMSA and ChIP assays confirmed Blimp-1 binding to the CS1 promoter; mutation of the Blimp-1 site at -750 to -746 decreased CS1 promoter activity.","method":"Luciferase reporter assays with promoter deletion mutants, EMSA, ChIP assay, site-directed mutagenesis of promoter","journal":"Immunobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and EMSA with mutagenesis confirm Blimp-1 binding and trans-activation, single lab","pmids":["26310579"],"is_preprint":false},{"year":2017,"finding":"SLAMF7 on macrophages is required for phagocytosis of haematopoietic tumour cells during SIRPα-CD47 blockade, both in vitro and in vivo. This function is independent of SAP adaptors but requires SLAMF7's ability to interact with integrin Mac-1 and signals involving ITAMs. SLAMF7 must be expressed on both the macrophage and the tumour cell target for efficient phagocytosis.","method":"SLAM-family receptor knockout mouse, in vitro phagocytosis assays, in vivo tumour models, Mac-1 interaction studies","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout mouse with in vitro and in vivo phagocytosis assays, mechanistic dissection of SAP independence and Mac-1 requirement, published in Nature","pmids":["28424516"],"is_preprint":false},{"year":2017,"finding":"Elotuzumab primarily activates NK cells through CD16 (FcγRIIIa)-dependent ADCC; F(ab')2 or Fc-mutant forms of elotuzumab alone cannot stimulate CD69 expression or degranulation. However, soluble elotuzumab can co-stimulate calcium signaling through NKp46 and NKG2D in a CD16-independent manner (trans-costimulation).","method":"NK cell degranulation assays, CD69 expression, calcium flux assays, F(ab')2 and Fc-mutant antibody forms, CD16-blocking experiments","journal":"Oncoimmunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dissection of CD16-dependent vs independent mechanisms using multiple antibody variants and functional assays, single lab","pmids":["28932638"],"is_preprint":false},{"year":2019,"finding":"Soluble SLAMF7 (sSLAMF7), present exclusively in MM patient serum, promotes MM cell growth via homophilic interaction with surface SLAMF7 and subsequent activation of SHP-2 and ERK signaling pathways. Elotuzumab suppresses sSLAMF7-induced MM cell growth by blocking this interaction. IKZF1 (Ikaros) was identified as a transcriptional activator of SLAMF7 gene; lenalidomide and pomalidomide downregulate SLAMF7 expression by targeting Ikaros.","method":"Recombinant sSLAMF7 treatment, Western blotting for SHP-2/ERK phosphorylation, promoter analysis, in vitro and in vivo (xenograft) elotuzumab blockade","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — sSLAMF7/surface SLAMF7 interaction with downstream signaling and in vivo validation, single lab, multiple methods","pmids":["31358854"],"is_preprint":false},{"year":2019,"finding":"Elotuzumab (but not other SLAMF7 antibodies) enhances cytotoxicity of CD16-negative NK-92 cells toward SLAMF7+ targets; this CD16-independent costimulation requires full cytoplasmic domain of SLAMF7 in NK cells and is associated with increased NKG2D and ICAM-1 expression and activated LFA-1, suggesting SLAMF7-SLAMF7 homotypic interactions drive the effect.","method":"CD16-negative NK-92 cell cytotoxicity assays, Fc-mutant antibody forms, SLAMF7 cytoplasmic domain deletion constructs, NKG2D blocking antibodies","journal":"Cancer immunology research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic dissection using domain deletion constructs and blocking antibodies, CD16-independent pathway defined, single lab","pmids":["31431433"],"is_preprint":false},{"year":2020,"finding":"SLAMF7 activation on T cells induces STAT1 and STAT3 phosphorylation and drives expression of multiple inhibitory receptors/transcription factors associated with T cell exhaustion. SLAMF7-SLAMF7 interactions between tumour-associated macrophages and CD8+ T cells induce exhaustion markers; SLAMF7-knockout mice show restricted B16-F10 tumour growth and CD8+ T cells with less PD-1 and TOX expression.","method":"SLAMF7 receptor activation assays, phospho-flow cytometry for STAT1/STAT3, SLAMF7-knockout mouse tumor model, ex vivo co-culture","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout mouse with in vivo tumor readout plus ex vivo mechanistic co-culture validation, single lab","pmids":["33288545"],"is_preprint":false},{"year":2021,"finding":"Physiological ligation of SLAMF7 in human NK cells selectively enhances target cell lysis by promoting NK cell degranulation (not granule polarization or cell adhesion). SLAMF7-dependent degranulation is predominantly dependent on PLCγ when compared to PI3K.","method":"NK cell degranulation assays, pharmacological inhibition of PLCγ vs PI3K, granule polarization imaging, adhesion assays","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological dissection of PLCγ vs PI3K with multiple cellular readouts, single lab","pmids":["34693521"],"is_preprint":false},{"year":2022,"finding":"SLAMF7 engagement drives a strong wave of inflammatory cytokine expression in macrophages; TNF-α induction after SLAMF7 engagement amplifies inflammation through an autocrine signaling loop. IFN-γ is identified as a key regulator of SLAMF7 expression on macrophages.","method":"RNA-seq of synovial macrophages, SLAMF7 engagement experiments, cytokine blockade, IFN-γ stimulation assays","journal":"Science immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — SLAMF7 engagement with TNF-α autocrine loop validation and IFN-γ regulatory relationship, supported by patient macrophage RNA-seq and functional experiments","pmids":["35148199"],"is_preprint":false},{"year":2023,"finding":"In macrophages during polymicrobial sepsis, SLAMF7 attenuates TLR-dependent MAPK and NF-κB signaling by cooperating with SHIP1. SLAMF7 interacts with both SHIP1 and TRAF6 to inhibit K63 ubiquitination of TRAF6. Tyrosine phosphorylation sites in the intracellular domain of SLAMF7 and the phosphatase domain of SHIP1 are required for this interaction. SLAMF7-deficient mice show enhanced lethality in sepsis models.","method":"Co-immunoprecipitation of SLAMF7/SHIP1/TRAF6, ubiquitination assays, site-directed mutagenesis of SLAMF7 tyrosine residues, SLAMF7-knockout mice in polymicrobial sepsis model","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1 / Strong — Co-IP of SLAMF7/SHIP1/TRAF6 complex, ubiquitination assays, mutagenesis of tyrosine sites, and in vivo knockout mouse model; multiple orthogonal methods in one study","pmids":["36749634"],"is_preprint":false},{"year":2024,"finding":"In hepatocellular carcinoma cells, SLAMF7 suppresses MAPK/ATF2-mediated CCL2 expression to regulate macrophage migration and polarization. Mechanistically, SLAMF7 associates with SHB adaptor protein through its cytoplasmic Y304 site, facilitating recruitment of SHIP1 to SLAMF7 and inhibiting TRAF6 ubiquitination, thereby attenuating MAPK pathway activation and CCL2 transcription.","method":"Co-immunoprecipitation of SLAMF7/SHB/SHIP1, ubiquitination assays, site-directed mutagenesis of Y304, liver-specific knockout mouse model, in vitro macrophage co-culture","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1 / Strong — Co-IP, mutagenesis of specific tyrosine residue, in vivo liver-specific KO mouse, and in vitro mechanistic validation; multiple orthogonal methods","pmids":["38484085"],"is_preprint":false},{"year":2013,"finding":"YY1 represses mouse CS1 (SLAMF7) gene transcription by binding to the CS1 promoter; mutation of the YY1 site significantly increased promoter activity. A unique (AG)n=36 DNA repeat element in the CS1 promoter enhances transcriptional activity and forms DNA triplex structures.","method":"Luciferase promoter assays with deletion/mutation constructs, ChIP assay, EMSA super-shift assay, AFM imaging of DNA triplex","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and EMSA with mutagenesis confirming YY1 binding and repression, plus AFM structural validation of repeat element, single lab","pmids":["23318224"],"is_preprint":false},{"year":2022,"finding":"N-linked glycosylation of SLAMF7 at seven motifs (particularly N98) regulates antibody affinity and macrophage phagocytosis of breast cancer cells. STT3A drives SLAMF7 hyperglycosylation; inhibition of STT3A by NGI-1 reduces glycosylation of SLAMF7, enhances anti-SLAMF7 antibody binding, and increases phagocytosis.","method":"Mass spectrometry glycosylation mapping, STT3A inhibition, antibody affinity measurements, macrophage phagocytosis assays, antibody-drug conjugate (ADC)","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — glycosylation site mapping by MS, functional phagocytosis assay with glycosylation inhibitor, single lab","pmids":["36381324"],"is_preprint":false},{"year":2023,"finding":"ALKBH5-mediated m6A demethylation decreases Slamf7 mRNA stability; specific inhibition of ALKBH5 increased Slamf7 expression via increased m6A modification. Slamf7 inhibition promoted autophagy and reduced pro-inflammatory cytokine secretion in macrophages, thereby improving silica-induced pulmonary inflammation.","method":"MeRIP assay (m6A mapping), ALKBH5 inhibition, mRNA stability assay, siRNA knockdown of Slamf7, mouse model of silica-induced pulmonary inflammation","journal":"Journal of hazardous materials","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP assay identifies m6A modification on Slamf7, mRNA stability linked to m6A, with in vivo functional validation; single lab","pmids":["37827106"],"is_preprint":false}],"current_model":"SLAMF7 is a homophilic SLAM-family cell surface receptor that functions as an activating or inhibitory receptor depending on cellular context: in EAT-2-expressing cells (NK cells, macrophages), SLAMF7 signals through EAT-2 to activate PLCγ/PI3K/ERK/calcium pathways and promote degranulation and cytotoxicity; in EAT-2-negative cells (T cells, MM cells), SLAMF7 recruits SHIP1 via Src kinase-phosphorylated Y261 in a CD45-dependent manner to exert inhibitory effects on MAPK and NF-κB signaling; SLAMF7 also mediates phagocytosis of haematopoietic tumour cells through a SAP-independent, Mac-1/ITAM-dependent mechanism on macrophages; its expression is transcriptionally regulated by Blimp-1/PRDM1 (activating) and YY1 (repressing), post-transcriptionally regulated by ALKBH5-dependent m6A modification, and post-translationally modified by N-linked glycosylation at multiple sites including N98 which modulates antibody binding and phagocytosis."},"narrative":{"mechanistic_narrative":"SLAMF7 (CS1/CRACC) is a homophilic SLAM-family cell-surface receptor that bidirectionally tunes immune effector function, adhesion, and tumour-cell biology depending on the adaptors available in a given cell [PMID:12213321, PMID:19151721]. It engages itself in trans, and recombinant or soluble SLAMF7-Ig is sufficient to enhance NK-cell cytolytic activity [PMID:12213321]. The functionally signaling isoform CS1-L carries cytoplasmic ITSMs; in NK cells activation recruits the SAP-homolog adaptor EAT-2, driving Src-dependent receptor phosphorylation and downstream PLCγ/PI3K signaling that culminates in degranulation and target lysis, with PLCγ the dominant arm of the degranulation response [PMID:16339536, PMID:34693521]. In the absence of EAT-2 — as in T cells — SLAMF7 instead becomes inhibitory: Src kinases phosphorylate tyrosine 261 in a CD45-dependent manner to recruit the inositol phosphatase SHIP-1, restraining cellular activation [PMID:19151721, PMID:25312647]. This inhibitory module operates broadly in macrophages, where SLAMF7 assembles with SHIP1 and TRAF6 to block K63 ubiquitination of TRAF6 and dampen TLR-driven MAPK and NF-κB signaling, using the SHB adaptor and cytoplasmic Y304 to bridge SHIP1 recruitment in hepatocellular carcinoma cells [PMID:36749634, PMID:38484085]. Independently of SAP adaptors, SLAMF7 on macrophages drives phagocytosis of haematopoietic tumour cells through interaction with integrin Mac-1 and ITAM signaling, requiring SLAMF7 on both effector and target [PMID:28424516]. In multiple myeloma, SLAMF7 promotes adhesion to bone marrow stroma and tumour-supportive signaling (ERK/AKT/STAT3), and soluble SLAMF7 in patient serum fuels myeloma growth via homophilic engagement and SHP-2/ERK activation [PMID:17906076, PMID:19196658, PMID:31358854]. SLAMF7 expression is transcriptionally activated by Blimp-1/PRDM1 and IKZF1 and repressed by YY1, and is further controlled post-transcriptionally by ALKBH5-dependent m6A demethylation and post-translationally by STT3A-driven N-linked glycosylation at N98 that modulates antibody binding and phagocytosis [PMID:26310579, PMID:31358854, PMID:23318224, PMID:37827106, PMID:36381324].","teleology":[{"year":2002,"claim":"Established that SLAMF7 is a self-ligand whose engagement can enhance NK cytotoxicity, defining it as a homophilic activating receptor rather than a ligand for a distinct partner.","evidence":"CS1-Ig fusion protein binding to CS1-transfected cells and redirected cytotoxicity in the YT NK line","pmids":["12213321"],"confidence":"Medium","gaps":["Did not define the cytoplasmic signaling adaptors","Binding shown with fusion protein, not endogenous trans-interaction"]},{"year":2004,"claim":"Showed that only the ITSM-containing CS1-L isoform is signaling-competent and that SAP associates with the unstimulated receptor, framing SLAMF7 within SAP-family adaptor biology.","evidence":"Isoform transfection into RNK-16 NK cells with cytotoxicity, calcium flux, and Co-IP of SAP","pmids":["15368295"],"confidence":"Medium","gaps":["Functional role of SAP dissociation unresolved","Did not establish which adaptor mediates downstream activation"]},{"year":2005,"claim":"Identified EAT-2 as the activating adaptor coupling SLAMF7 to PLCγ/PI3K signaling, defining the molecular route to NK cytotoxicity.","evidence":"Co-IP of EAT-2, Src-inhibitor-sensitive phosphorylation, and downstream pathway/cytotoxicity assays in human NK cells","pmids":["16339536"],"confidence":"High","gaps":["Did not resolve behavior in EAT-2-negative cells","Tyrosine residues mediating EAT-2 coupling not mapped"]},{"year":2009,"claim":"Genetically established the activating/inhibitory switch: SLAMF7 promotes NK function only with EAT-2 and is inhibitory in its absence and in T cells.","evidence":"CRACC-knockout mouse with NK functional assays and EAT-2 genetic epistasis","pmids":["19151721"],"confidence":"High","gaps":["Inhibitory effector molecule not identified in this study","Mechanism of context-dependence at molecular level unresolved"]},{"year":2007,"claim":"Defined non-NK roles: SLAMF7 promotes B-cell proliferation via autocrine cytokines and mediates myeloma adhesion to bone marrow stroma.","evidence":"Antibody crosslinking with cytokine neutralization in B cells; siRNA knockdown with adhesion assays and uropod localization in MM cells","pmids":["17878365","17906076"],"confidence":"Medium","gaps":["Signaling adaptors in B cells not defined","Direct ligand for stromal adhesion not established"]},{"year":2009,"claim":"Demonstrated SLAMF7 supports myeloma survival and proliferation through ERK/AKT/STAT3 signaling and integrin-mediated adhesion in vivo.","evidence":"shRNA knockdown and overexpression with phospho-Western, apoptosis assays, and xenograft model","pmids":["19196658"],"confidence":"Medium","gaps":["Proximal signaling adaptor in MM cells not identified","Link between homophilic engagement and ERK/AKT not mechanistically dissected"]},{"year":2014,"claim":"Resolved the inhibitory circuit: SLAMF7 recruits SHIP-1 via phosphorylated Y261 in a Src- and CD45-dependent manner, and explained why MM cells (lacking CD45) escape inhibition.","evidence":"Y261 site-directed mutagenesis, SHIP-1 Co-IP, and CD45-deficient NK cells with cytotoxicity assays","pmids":["25312647"],"confidence":"High","gaps":["Did not address SHIP1-independent inhibitory routes","Macrophage-specific signaling not examined"]},{"year":2013,"claim":"Showed SLAMF7 is inhibitory in monocytes, suppressing LPS-induced TNF-α and IL-12p70, extending inhibitory function to myeloid cells.","evidence":"Anti-CS1 crosslinking with cytokine ELISA and NF-κB/PI3K pathway inhibitors in human monocytes","pmids":["23695528"],"confidence":"Medium","gaps":["Adaptor mediating monocyte inhibition not identified","Relationship to SHIP1 pathway unestablished at this point"]},{"year":2017,"claim":"Defined a SAP-independent phagocytic function: macrophage SLAMF7 drives engulfment of haematopoietic tumour cells via Mac-1 and ITAM signaling during CD47-SIRPα blockade.","evidence":"SLAM-family knockout mouse with in vitro/in vivo phagocytosis assays and Mac-1 interaction studies","pmids":["28424516"],"confidence":"High","gaps":["Molecular geometry of SLAMF7-Mac-1 coupling unresolved","ITAM-bearing adaptor not specified"]},{"year":2017,"claim":"Clarified the therapeutic mechanism of elotuzumab as primarily CD16/ADCC-driven, with a secondary CD16-independent trans-costimulation of NK receptors.","evidence":"Degranulation, CD69, and calcium assays using F(ab')2, Fc-mutant antibodies, and CD16 blockade","pmids":["28932638"],"confidence":"Medium","gaps":["Contribution of each arm in patients unquantified","Receptor basis of trans-costimulation only partly defined"]},{"year":2019,"claim":"Identified soluble SLAMF7 as a myeloma growth factor acting through homophilic engagement and SHP-2/ERK signaling, blocked by elotuzumab, and named IKZF1 as a transcriptional activator targeted by IMiDs.","evidence":"Recombinant sSLAMF7 treatment with phospho-Western, promoter analysis, and xenograft elotuzumab blockade","pmids":["31358854"],"confidence":"Medium","gaps":["Source and processing of sSLAMF7 not defined","Relationship between SHP-2 and SHIP1 pathways unresolved"]},{"year":2019,"claim":"Showed CD16-independent elotuzumab costimulation requires the full SLAMF7 cytoplasmic domain and homotypic interactions, linking it to NKG2D/LFA-1 activation.","evidence":"CD16-negative NK-92 cytotoxicity with Fc-mutant antibodies, cytoplasmic-domain deletions, and NKG2D blockade","pmids":["31431433"],"confidence":"Medium","gaps":["Adaptor coupling in this context not mapped","Generalizability beyond NK-92 line unaddressed"]},{"year":2020,"claim":"Implicated SLAMF7 in T-cell exhaustion: homotypic engagement with tumour-associated macrophages drives STAT1/STAT3 and inhibitory-receptor programs, with knockout restraining tumour growth.","evidence":"Receptor activation with phospho-flow, SLAMF7-knockout B16-F10 tumour model, and ex vivo co-culture","pmids":["33288545"],"confidence":"Medium","gaps":["Proximal signaling from SLAMF7 to STAT not defined","Distinction from inhibitory SHIP1 pathway unclear"]},{"year":2021,"claim":"Pinpointed the cellular output of activating SLAMF7 signaling as degranulation (not polarization or adhesion), predominantly PLCγ-dependent.","evidence":"Physiological ligation with degranulation assays, PLCγ vs PI3K inhibitors, and polarization imaging in human NK cells","pmids":["34693521"],"confidence":"Medium","gaps":["Relative PI3K contribution to other outputs unresolved","EAT-2 dependence not re-tested here"]},{"year":2022,"claim":"Revealed a context where SLAMF7 is pro-inflammatory: engagement on macrophages drives a TNF-α autocrine inflammatory loop, with IFN-γ controlling its expression.","evidence":"Synovial macrophage RNA-seq, SLAMF7 engagement, cytokine blockade, and IFN-γ stimulation","pmids":["35148199"],"confidence":"Medium","gaps":["Reconciliation with inhibitory macrophage signaling not addressed","Adaptor driving the inflammatory output unidentified"]},{"year":2023,"claim":"Defined the inhibitory macrophage mechanism: SLAMF7 cooperates with SHIP1 and TRAF6 to block TRAF6 K63 ubiquitination, attenuating TLR-MAPK/NF-κB signaling and protecting against sepsis lethality.","evidence":"Co-IP of SLAMF7/SHIP1/TRAF6, ubiquitination and mutagenesis assays, and SLAMF7-knockout polymicrobial sepsis model","pmids":["36749634"],"confidence":"High","gaps":["Reconciliation with pro-inflammatory engagement in synovial macrophages unresolved","Stimulus determining activating vs inhibitory output unclear"]},{"year":2024,"claim":"Extended the inhibitory module to the tumour microenvironment: SLAMF7 recruits SHIP1 via the SHB adaptor and cytoplasmic Y304 to suppress MAPK/ATF2-driven CCL2 and reshape macrophage recruitment in HCC.","evidence":"Co-IP of SLAMF7/SHB/SHIP1, Y304 mutagenesis, ubiquitination assays, and liver-specific knockout mouse with macrophage co-culture","pmids":["38484085"],"confidence":"High","gaps":["Interplay between Y261 and Y304 phospho-sites not defined","Whether SHB operates in NK/T cells unknown"]},{"year":2022,"claim":"Showed N-linked glycosylation at N98 (STT3A-driven) modulates anti-SLAMF7 antibody affinity and phagocytosis, identifying a tunable post-translational control of therapeutic targeting.","evidence":"Mass-spectrometry glycosite mapping, STT3A/NGI-1 inhibition, antibody affinity, and phagocytosis assays in breast cancer cells","pmids":["36381324"],"confidence":"Medium","gaps":["Effect of glycosylation on homophilic signaling not tested","Generalizability to haematopoietic SLAMF7 unaddressed"]},{"year":2023,"claim":"Established post-transcriptional control: ALKBH5-mediated m6A demethylation destabilizes Slamf7 mRNA, and reduced SLAMF7 promotes macrophage autophagy and limits inflammation.","evidence":"MeRIP m6A mapping, ALKBH5 inhibition, mRNA stability and siRNA knockdown, and silica-induced lung inflammation model","pmids":["37827106"],"confidence":"Medium","gaps":["m6A reader linking demethylation to stability not identified","Direct connection to SHIP1/TRAF6 axis not established"]},{"year":null,"claim":"The signal that determines whether SLAMF7 engagement is activating, inhibitory, or pro-inflammatory within the same cell type — and how adaptor availability (EAT-2, SHIP1, SHB), tyrosine usage (Y261 vs Y304), and glycosylation integrate to set this output — remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model reconciling pro- and anti-inflammatory macrophage outputs","Hierarchy of Y261 vs Y304 phospho-sites across cell types unknown","Endogenous trans-ligand geometry and stoichiometry uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,2,5,8]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[3,6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[8,17,18]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,3,10]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,5,10,17]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8,17,18]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[6,12,18]}],"complexes":[],"partners":["SLAMF7","EAT-2","SH2D1B","INPP5D","TRAF6","ITGAM","SHB","SAP"],"other_free_text":[]}},"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":"18451245","id":"PMC_18451245","title":"CS1, a potential new therapeutic antibody target for the treatment of multiple myeloma.","date":"2008","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/18451245","citation_count":471,"is_preprint":false},{"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":"28424516","id":"PMC_28424516","title":"SLAMF7 is critical for phagocytosis of haematopoietic tumour cells via Mac-1 integrin.","date":"2017","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/28424516","citation_count":240,"is_preprint":false},{"pmid":"29089311","id":"PMC_29089311","title":"SLAMF7-CAR T cells eliminate myeloma and confer selective fratricide of SLAMF7+ normal lymphocytes.","date":"2017","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/29089311","citation_count":201,"is_preprint":false},{"pmid":"32385241","id":"PMC_32385241","title":"Systematically optimized BCMA/CS1 bispecific CAR-T cells robustly control heterogeneous multiple myeloma.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/32385241","citation_count":173,"is_preprint":false},{"pmid":"26631114","id":"PMC_26631114","title":"Clinical efficacy and management of monoclonal antibodies targeting CD38 and SLAMF7 in multiple myeloma.","date":"2015","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/26631114","citation_count":160,"is_preprint":false},{"pmid":"28257633","id":"PMC_28257633","title":"miR-19a promotes colorectal cancer proliferation and migration by targeting TIA1.","date":"2017","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/28257633","citation_count":154,"is_preprint":false},{"pmid":"29061640","id":"PMC_29061640","title":"Lenalidomide Enhances the Function of CS1 Chimeric Antigen Receptor-Redirected T Cells Against Multiple Myeloma.","date":"2017","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/29061640","citation_count":153,"is_preprint":false},{"pmid":"19151721","id":"PMC_19151721","title":"Influence of CRACC, a SLAM family receptor coupled to the adaptor EAT-2, on natural killer cell function.","date":"2009","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/19151721","citation_count":148,"is_preprint":false},{"pmid":"19723891","id":"PMC_19723891","title":"Combinatorial efficacy of anti-CS1 monoclonal antibody elotuzumab (HuLuc63) and bortezomib against multiple myeloma.","date":"2009","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/19723891","citation_count":142,"is_preprint":false},{"pmid":"8282813","id":"PMC_8282813","title":"Expression and functional significance of alternatively spliced CS1 fibronectin in rheumatoid arthritis microvasculature.","date":"1994","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/8282813","citation_count":135,"is_preprint":false},{"pmid":"12213321","id":"PMC_12213321","title":"CS1, a novel member of the CD2 family, is homophilic and regulates NK cell function.","date":"2002","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/12213321","citation_count":110,"is_preprint":false},{"pmid":"11513145","id":"PMC_11513145","title":"2B4 (CD244) and CS1: novel members of the CD2 subset of the immunoglobulin superfamily molecules expressed on natural killer cells and other leukocytes.","date":"2001","source":"Immunological reviews","url":"https://pubmed.ncbi.nlm.nih.gov/11513145","citation_count":109,"is_preprint":false},{"pmid":"16339536","id":"PMC_16339536","title":"The cytotoxicity receptor CRACC (CS-1) recruits EAT-2 and activates the PI3K and phospholipase Cgamma signaling pathways in human NK cells.","date":"2005","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/16339536","citation_count":106,"is_preprint":false},{"pmid":"30455698","id":"PMC_30455698","title":"Mechanisms of NK Cell Activation and Clinical Activity of the Therapeutic SLAMF7 Antibody, Elotuzumab in Multiple Myeloma.","date":"2018","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30455698","citation_count":103,"is_preprint":false},{"pmid":"29769244","id":"PMC_29769244","title":"A CS1-NKG2D Bispecific Antibody Collectively Activates Cytolytic Immune Cells against Multiple Myeloma.","date":"2018","source":"Cancer immunology research","url":"https://pubmed.ncbi.nlm.nih.gov/29769244","citation_count":101,"is_preprint":false},{"pmid":"23731618","id":"PMC_23731618","title":"CS1, a SLAM family receptor involved in immune regulation, is a therapeutic target in multiple myeloma.","date":"2013","source":"Critical reviews in oncology/hematology","url":"https://pubmed.ncbi.nlm.nih.gov/23731618","citation_count":100,"is_preprint":false},{"pmid":"30021351","id":"PMC_30021351","title":"microRNA-19a-3p promotes tumor metastasis and chemoresistance through the PTEN/Akt pathway in hepatocellular carcinoma.","date":"2018","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/30021351","citation_count":91,"is_preprint":false},{"pmid":"28861320","id":"PMC_28861320","title":"CS1 (SLAMF7, CD319) is an effective immunotherapeutic target for multiple myeloma.","date":"2017","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/28861320","citation_count":89,"is_preprint":false},{"pmid":"29525129","id":"PMC_29525129","title":"The C/S1 bZIP Network: A Regulatory Hub Orchestrating Plant Energy Homeostasis.","date":"2018","source":"Trends in plant science","url":"https://pubmed.ncbi.nlm.nih.gov/29525129","citation_count":84,"is_preprint":false},{"pmid":"35148199","id":"PMC_35148199","title":"SLAMF7 engagement superactivates macrophages in acute and chronic inflammation.","date":"2022","source":"Science immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35148199","citation_count":82,"is_preprint":false},{"pmid":"33288545","id":"PMC_33288545","title":"SLAMF7 Signaling Reprograms T Cells toward Exhaustion in the Tumor Microenvironment.","date":"2020","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/33288545","citation_count":78,"is_preprint":false},{"pmid":"25312647","id":"PMC_25312647","title":"Immune cell inhibition by SLAMF7 is mediated by a mechanism requiring src kinases, CD45, and SHIP-1 that is defective in multiple myeloma cells.","date":"2014","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/25312647","citation_count":72,"is_preprint":false},{"pmid":"28932638","id":"PMC_28932638","title":"The anti-SLAMF7 antibody elotuzumab mediates NK cell activation through both CD16-dependent and -independent mechanisms.","date":"2017","source":"Oncoimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/28932638","citation_count":68,"is_preprint":false},{"pmid":"23824915","id":"PMC_23824915","title":"miR-19a and miR-19b overexpression in gliomas.","date":"2013","source":"Pathology oncology research : POR","url":"https://pubmed.ncbi.nlm.nih.gov/23824915","citation_count":66,"is_preprint":false},{"pmid":"17878365","id":"PMC_17878365","title":"CS1 (CRACC, CD319) induces proliferation and autocrine cytokine expression on human B lymphocytes.","date":"2007","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/17878365","citation_count":65,"is_preprint":false},{"pmid":"32630303","id":"PMC_32630303","title":"Roles of NK Cell Receptors 2B4 (CD244), CS1 (CD319), and LLT1 (CLEC2D) in Cancer.","date":"2020","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/32630303","citation_count":62,"is_preprint":false},{"pmid":"19196658","id":"PMC_19196658","title":"CS1 promotes multiple myeloma cell adhesion, clonogenic growth, and tumorigenicity via c-maf-mediated interactions with bone marrow stromal cells.","date":"2009","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/19196658","citation_count":61,"is_preprint":false},{"pmid":"31358854","id":"PMC_31358854","title":"Soluble SLAMF7 promotes the growth of myeloma cells via homophilic interaction with surface SLAMF7.","date":"2019","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/31358854","citation_count":60,"is_preprint":false},{"pmid":"28935967","id":"PMC_28935967","title":"MircroRNA-19a promotes vascular inflammation and foam cell formation by targeting HBP-1 in atherogenesis.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28935967","citation_count":60,"is_preprint":false},{"pmid":"36749634","id":"PMC_36749634","title":"SLAMF7 regulates the inflammatory response in macrophages during polymicrobial sepsis.","date":"2023","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/36749634","citation_count":59,"is_preprint":false},{"pmid":"20345977","id":"PMC_20345977","title":"Altered expression of signalling lymphocyte activation molecule (SLAM) family receptors CS1 (CD319) and 2B4 (CD244) in patients with systemic lupus erythematosus.","date":"2010","source":"Clinical and experimental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/20345977","citation_count":57,"is_preprint":false},{"pmid":"31170091","id":"PMC_31170091","title":"Blocking lncRNA H19-miR-19a-Id2 axis attenuates hypoxia/ischemia induced neuronal injury.","date":"2019","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/31170091","citation_count":57,"is_preprint":false},{"pmid":"35599631","id":"PMC_35599631","title":"MiR-19a suppresses ferroptosis of colorectal cancer cells by targeting IREB2.","date":"2022","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/35599631","citation_count":53,"is_preprint":false},{"pmid":"33311473","id":"PMC_33311473","title":"SLAMF7 and IL-6R define distinct cytotoxic versus helper memory CD8+ T cells.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/33311473","citation_count":50,"is_preprint":false},{"pmid":"16410313","id":"PMC_16410313","title":"2B4 (CD244), NTB-A and CRACC (CS1) stimulate cytotoxicity but no proliferation in human NK cells.","date":"2006","source":"International immunology","url":"https://pubmed.ncbi.nlm.nih.gov/16410313","citation_count":47,"is_preprint":false},{"pmid":"31431433","id":"PMC_31431433","title":"Enhanced SLAMF7 Homotypic Interactions by Elotuzumab Improves NK Cell Killing of Multiple Myeloma.","date":"2019","source":"Cancer immunology research","url":"https://pubmed.ncbi.nlm.nih.gov/31431433","citation_count":47,"is_preprint":false},{"pmid":"26130131","id":"PMC_26130131","title":"Utility of CD54, CD229, and CD319 for the identification of plasma cells in patients with clonal plasma cell diseases.","date":"2015","source":"Cytometry. Part B, Clinical cytometry","url":"https://pubmed.ncbi.nlm.nih.gov/26130131","citation_count":45,"is_preprint":false},{"pmid":"23695528","id":"PMC_23695528","title":"CS1 (SLAMF7) inhibits production of proinflammatory cytokines by activated monocytes.","date":"2013","source":"Inflammation research : official journal of the European Histamine Research Society ... [et al.]","url":"https://pubmed.ncbi.nlm.nih.gov/23695528","citation_count":45,"is_preprint":false},{"pmid":"34017248","id":"PMC_34017248","title":"MiR-19a-3p Suppresses M1 Macrophage Polarization by Inhibiting STAT1/IRF1 Pathway.","date":"2021","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/34017248","citation_count":45,"is_preprint":false},{"pmid":"10094617","id":"PMC_10094617","title":"New tools in an old trade: CS1 pilus morphogenesis.","date":"1998","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/10094617","citation_count":44,"is_preprint":false},{"pmid":"23621248","id":"PMC_23621248","title":"miR-19a promotes cell growth and tumorigenesis through targeting SOCS1 in gastric cancer.","date":"2013","source":"Asian Pacific journal of cancer prevention : APJCP","url":"https://pubmed.ncbi.nlm.nih.gov/23621248","citation_count":44,"is_preprint":false},{"pmid":"35422095","id":"PMC_35422095","title":"CS1 CAR-T targeting the distal domain of CS1 (SLAMF7) shows efficacy in high tumor burden myeloma model despite fratricide of CD8+CS1 expressing CAR-T cells.","date":"2022","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/35422095","citation_count":42,"is_preprint":false},{"pmid":"15368295","id":"PMC_15368295","title":"Molecular and functional characterization of a CS1 (CRACC) splice variant expressed in human NK cells that does not contain immunoreceptor tyrosine-based switch motifs.","date":"2004","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/15368295","citation_count":41,"is_preprint":false},{"pmid":"17981603","id":"PMC_17981603","title":"Regulation of NK cell activity by 2B4, NTB-A and CRACC.","date":"2008","source":"Frontiers in bioscience : a journal and virtual library","url":"https://pubmed.ncbi.nlm.nih.gov/17981603","citation_count":40,"is_preprint":false},{"pmid":"27830963","id":"PMC_27830963","title":"MicroRNA-19a functions as an oncogene by regulating PTEN/AKT/pAKT pathway in myeloma.","date":"2016","source":"Leukemia & lymphoma","url":"https://pubmed.ncbi.nlm.nih.gov/27830963","citation_count":40,"is_preprint":false},{"pmid":"30410677","id":"PMC_30410677","title":"Clinical impact of serum soluble SLAMF7 in multiple myeloma.","date":"2018","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/30410677","citation_count":39,"is_preprint":false},{"pmid":"30530590","id":"PMC_30530590","title":"SLAMF7 Is a Critical Negative Regulator of IFN-α-Mediated CXCL10 Production in Chronic HIV Infection.","date":"2018","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/30530590","citation_count":37,"is_preprint":false},{"pmid":"33017079","id":"PMC_33017079","title":"CD319 (SLAMF7) an alternative marker for detecting plasma cells in the presence of daratumumab or elotuzumab.","date":"2020","source":"Cytometry. Part B, Clinical cytometry","url":"https://pubmed.ncbi.nlm.nih.gov/33017079","citation_count":35,"is_preprint":false},{"pmid":"30710089","id":"PMC_30710089","title":"Cancer cell-expressed SLAMF7 is not required for CD47-mediated phagocytosis.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30710089","citation_count":35,"is_preprint":false},{"pmid":"25914465","id":"PMC_25914465","title":"MiR-19a promotes epithelial-mesenchymal transition through PI3K/AKT pathway in gastric cancer.","date":"2015","source":"World journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/25914465","citation_count":33,"is_preprint":false},{"pmid":"34512170","id":"PMC_34512170","title":"Pancreatic cancer-derived exosomal microRNA-19a induces β-cell dysfunction by targeting ADCY1 and EPAC2.","date":"2021","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34512170","citation_count":32,"is_preprint":false},{"pmid":"31199884","id":"PMC_31199884","title":"MiR-19a enhances cell proliferation, migration, and invasiveness through enhancing lymphangiogenesis by targeting thrombospondin-1 in colorectal cancer.","date":"2019","source":"Biochemistry and cell biology = Biochimie et biologie cellulaire","url":"https://pubmed.ncbi.nlm.nih.gov/31199884","citation_count":32,"is_preprint":false},{"pmid":"38484085","id":"PMC_38484085","title":"Repolarization of Immunosuppressive Macrophages by Targeting SLAMF7-Regulated CCL2 Signaling Sensitizes Hepatocellular Carcinoma to Immunotherapy.","date":"2024","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/38484085","citation_count":30,"is_preprint":false},{"pmid":"23956418","id":"PMC_23956418","title":"Systemic lupus erythematosus immune complexes increase the expression of SLAM family members CD319 (CRACC) and CD229 (LY-9) on plasmacytoid dendritic cells and CD319 on CD56(dim) NK cells.","date":"2013","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/23956418","citation_count":30,"is_preprint":false},{"pmid":"26873752","id":"PMC_26873752","title":"miR-19a, -19b, and -26b Mediate CTGF Expression and Pulmonary Fibroblast Differentiation.","date":"2016","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/26873752","citation_count":30,"is_preprint":false},{"pmid":"25400827","id":"PMC_25400827","title":"MiR-19a promotes epithelial-mesenchymal transition through PI3K/AKT pathway in gastric cancer.","date":"2014","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/25400827","citation_count":30,"is_preprint":false},{"pmid":"23250953","id":"PMC_23250953","title":"Role of the NK cell-activating receptor CRACC in periodontitis.","date":"2012","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/23250953","citation_count":29,"is_preprint":false},{"pmid":"32546967","id":"PMC_32546967","title":"Glycine Improves Ischemic Stroke Through miR-19a-3p/AMPK/GSK-3β/HO-1 Pathway.","date":"2020","source":"Drug design, development and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/32546967","citation_count":28,"is_preprint":false},{"pmid":"29702193","id":"PMC_29702193","title":"miR-19a-mediated downregulation of RhoB inhibits the dephosphorylation of AKT1 and induces osteosarcoma cell metastasis.","date":"2018","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/29702193","citation_count":28,"is_preprint":false},{"pmid":"32112551","id":"PMC_32112551","title":"Exosomal miR-19a from adipose-derived stem cells suppresses differentiation of corneal keratocytes into myofibroblasts.","date":"2020","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/32112551","citation_count":28,"is_preprint":false},{"pmid":"26310579","id":"PMC_26310579","title":"Blimp-1/PRDM1 regulates the transcription of human CS1 (SLAMF7) gene in NK and B cells.","date":"2015","source":"Immunobiology","url":"https://pubmed.ncbi.nlm.nih.gov/26310579","citation_count":26,"is_preprint":false},{"pmid":"28475001","id":"PMC_28475001","title":"MiR-19a regulates the cell growth and apoptosis of osteosarcoma stem cells by targeting PTEN.","date":"2017","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28475001","citation_count":26,"is_preprint":false},{"pmid":"29416771","id":"PMC_29416771","title":"Menopause and adipose tissue: miR-19a-3p is sensitive to hormonal replacement.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29416771","citation_count":26,"is_preprint":false},{"pmid":"1508710","id":"PMC_1508710","title":"Structure and expression of the nuclear gene coding for the plastid CS1 ribosomal protein from spinach.","date":"1992","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/1508710","citation_count":26,"is_preprint":false},{"pmid":"26070331","id":"PMC_26070331","title":"Preclinical and clinical evaluation of elotuzumab, a SLAMF7-targeted humanized monoclonal antibody in development for multiple myeloma.","date":"2015","source":"Expert review of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/26070331","citation_count":25,"is_preprint":false},{"pmid":"33614912","id":"PMC_33614912","title":"miR-19a/b promote EMT and proliferation in glioma cells via SEPT7-AKT-NF-κB pathway.","date":"2021","source":"Molecular therapy oncolytics","url":"https://pubmed.ncbi.nlm.nih.gov/33614912","citation_count":25,"is_preprint":false},{"pmid":"28483281","id":"PMC_28483281","title":"Preclinical data support leveraging CS1 chimeric antigen receptor T-cell therapy for systemic light chain amyloidosis.","date":"2017","source":"Cytotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/28483281","citation_count":24,"is_preprint":false},{"pmid":"33674746","id":"PMC_33674746","title":"MiR-19a/miR-96-mediated low expression of KIF26A suppresses metastasis by regulating FAK pathway in gastric cancer.","date":"2021","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/33674746","citation_count":24,"is_preprint":false},{"pmid":"37827106","id":"PMC_37827106","title":"ALKBH5 mediates silica particles-induced pulmonary inflammation through increased m6A modification of Slamf7 and autophagy dysfunction.","date":"2023","source":"Journal of hazardous materials","url":"https://pubmed.ncbi.nlm.nih.gov/37827106","citation_count":24,"is_preprint":false},{"pmid":"36476239","id":"PMC_36476239","title":"Exosome-transmitted circ_002136 promotes hepatocellular carcinoma progression by miR-19a-3p/RAB1A pathway.","date":"2022","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/36476239","citation_count":24,"is_preprint":false},{"pmid":"39080547","id":"PMC_39080547","title":"MicroRNA-19a-3p inhibits endothelial dysfunction in atherosclerosis by targeting JCAD.","date":"2024","source":"BMC cardiovascular disorders","url":"https://pubmed.ncbi.nlm.nih.gov/39080547","citation_count":23,"is_preprint":false},{"pmid":"30347240","id":"PMC_30347240","title":"2B4 (CD244, SLAMF4) and CS1 (CD319, SLAMF7) in systemic lupus erythematosus and cancer.","date":"2018","source":"Clinical immunology (Orlando, Fla.)","url":"https://pubmed.ncbi.nlm.nih.gov/30347240","citation_count":22,"is_preprint":false},{"pmid":"39713206","id":"PMC_39713206","title":"Bioengineer mesenchymal stem cell for treatment of glioma by IL-12 mediated microenvironment reprogramming and nCD47-SLAMF7 mediated phagocytosis regulation of macrophages.","date":"2024","source":"Exploration (Beijing, China)","url":"https://pubmed.ncbi.nlm.nih.gov/39713206","citation_count":21,"is_preprint":false},{"pmid":"24299175","id":"PMC_24299175","title":"PDL241, a novel humanized monoclonal antibody, reveals CD319 as a therapeutic target for rheumatoid arthritis.","date":"2013","source":"Arthritis research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/24299175","citation_count":20,"is_preprint":false},{"pmid":"29582696","id":"PMC_29582696","title":"Anti-CD38 and anti-SLAMF7: the future of myeloma immunotherapy.","date":"2018","source":"Expert review of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/29582696","citation_count":19,"is_preprint":false},{"pmid":"36199066","id":"PMC_36199066","title":"SLAMF7 modulates B cells and adaptive immunity to regulate susceptibility to CNS autoimmunity.","date":"2022","source":"Journal of neuroinflammation","url":"https://pubmed.ncbi.nlm.nih.gov/36199066","citation_count":19,"is_preprint":false},{"pmid":"36193848","id":"PMC_36193848","title":"Antagonizing microRNA-19a/b augments PTH anabolic action and restores bone mass in osteoporosis in mice.","date":"2022","source":"EMBO molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36193848","citation_count":18,"is_preprint":false},{"pmid":"27035427","id":"PMC_27035427","title":"miR‑19a‑3p targets PMEPA1 and induces prostate cancer cell proliferation, migration and invasion.","date":"2016","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/27035427","citation_count":18,"is_preprint":false},{"pmid":"27695618","id":"PMC_27695618","title":"Treatment of multiple myeloma with the immunostimulatory SLAMF7 antibody elotuzumab.","date":"2016","source":"Therapeutic advances in hematology","url":"https://pubmed.ncbi.nlm.nih.gov/27695618","citation_count":18,"is_preprint":false},{"pmid":"34693521","id":"PMC_34693521","title":"SLAMF7 selectively favors degranulation to promote cytotoxicity in human NK cells.","date":"2021","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34693521","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":"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":"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":"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},{"pmid":"26502748","id":"PMC_26502748","title":"miR-19a and SOCS-1 expression in the differential diagnosis of laryngeal (glottic) verrucous squamous cell carcinoma.","date":"2015","source":"Journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/26502748","citation_count":16,"is_preprint":false},{"pmid":"37283656","id":"PMC_37283656","title":"MicroRNA-19a-3p Decreases with Age in Mice and Humans and Inhibits Osteoblast Senescence.","date":"2023","source":"JBMR plus","url":"https://pubmed.ncbi.nlm.nih.gov/37283656","citation_count":14,"is_preprint":false},{"pmid":"21769477","id":"PMC_21769477","title":"Alternative splicing and mRNA expression analysis of bovine SLAMF7 gene in healthy and mastitis mammary tissues.","date":"2011","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/21769477","citation_count":14,"is_preprint":false},{"pmid":"32432032","id":"PMC_32432032","title":"Anti-CS1 × Anti-CD3 Bispecific Antibody (BiAb)-Armed Anti-CD3 Activated T Cells (CS1-BATs) Kill CS1+ Myeloma Cells and Release Type-1 Cytokines.","date":"2020","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/32432032","citation_count":14,"is_preprint":false},{"pmid":"33966370","id":"PMC_33966370","title":"miR-19a-3p inhibition alleviates sepsis-induced lung injury via enhancing USP13 expression.","date":"2021","source":"Acta biochimica Polonica","url":"https://pubmed.ncbi.nlm.nih.gov/33966370","citation_count":14,"is_preprint":false},{"pmid":"29531651","id":"PMC_29531651","title":"Elotuzumab for the Treatment of Relapsed or Refractory Multiple Myeloma, with Special Reference to its Modes of Action and SLAMF7 Signaling.","date":"2018","source":"Mediterranean journal of hematology and infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/29531651","citation_count":13,"is_preprint":false},{"pmid":"27376202","id":"PMC_27376202","title":"The role of SLAMF7 in multiple myeloma: impact on therapy.","date":"2016","source":"Expert review of clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/27376202","citation_count":13,"is_preprint":false},{"pmid":"31687318","id":"PMC_31687318","title":"Role of cell free microRNA-19a and microRNA-19b in gestational diabetes mellitus patients.","date":"2019","source":"3 Biotech","url":"https://pubmed.ncbi.nlm.nih.gov/31687318","citation_count":13,"is_preprint":false},{"pmid":"29257352","id":"PMC_29257352","title":"MiR-19a mediates gluconeogenesis by targeting PTEN in hepatocytes.","date":"2017","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/29257352","citation_count":13,"is_preprint":false},{"pmid":"31633225","id":"PMC_31633225","title":"MicroRNA-19a attenuates hypoxia-induced cardiomyocyte apoptosis by downregulating NHE-1 expression and decreasing calcium overload.","date":"2019","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31633225","citation_count":13,"is_preprint":false},{"pmid":"39060023","id":"PMC_39060023","title":"Preclinical activity of allogeneic SLAMF7-specific CAR T-cells (UCARTCS1) in multiple myeloma.","date":"2024","source":"Journal for immunotherapy of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/39060023","citation_count":12,"is_preprint":false},{"pmid":"36381324","id":"PMC_36381324","title":"Deglycosylation of SLAMF7 in breast cancers enhances phagocytosis.","date":"2022","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/36381324","citation_count":12,"is_preprint":false},{"pmid":"23318224","id":"PMC_23318224","title":"YY1 and a unique DNA repeat element regulates the transcription of mouse CS1 (CD319, SLAMF7) gene.","date":"2013","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/23318224","citation_count":11,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51729,"output_tokens":5842,"usd":0.121409,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14471,"output_tokens":5950,"usd":0.110552,"stage2_stop_reason":"end_turn"},"total_usd":0.231961,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","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 cytolytic activity of the human NK cell line YT.\",\n      \"method\": \"Recombinant fusion protein binding assay, redirected cytotoxicity assay\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay with CS1-Ig fusion protein and functional NK cytotoxicity assay, single lab, two orthogonal methods\",\n      \"pmids\": [\"12213321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Two CS1 isoforms (CS1-L and CS1-S) are expressed in human NK cells. CS1-L contains ITSMs and mediates redirected cytotoxicity and calcium flux when transfected into RNK-16 rat NK cells, whereas CS1-S lacking ITSMs has no effect. SAP associates with unstimulated CS1-L and dissociates upon pervanadate stimulation.\",\n      \"method\": \"cDNA transfection into RNK-16 cells, redirected cytotoxicity assay, calcium flux measurement, co-immunoprecipitation\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reconstitution in rat NK cell line with two orthogonal readouts (cytotoxicity + Ca2+ flux), single lab\",\n      \"pmids\": [\"15368295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Upon activation, CRACC (SLAMF7) recruits the SAP-homolog adaptor EAT-2 in human NK cells. EAT-2 association induces CRACC phosphorylation (partially reduced by Src kinase inhibitors), and downstream signaling involves PLCγ1, PLCγ2, and PI3K to mediate NK cell cytotoxicity.\",\n      \"method\": \"Co-immunoprecipitation, pharmacological inhibition of Src kinases, Western blotting for phosphorylation, functional cytotoxicity assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP for EAT-2 recruitment, phosphorylation assay with inhibitor controls, downstream pathway identification; replicated by subsequent studies\",\n      \"pmids\": [\"16339536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CS1 is expressed at adhesion-promoting uropod membranes of polarized MM cells; siRNA knockdown of CS1 inhibited MM cell adhesion to bone marrow stromal cells (BMSCs), demonstrating a direct role for CS1 in MM cell adhesion.\",\n      \"method\": \"siRNA knockdown, cell adhesion assay, immunofluorescence localization\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with specific adhesion readout, subcellular localization linked to functional consequence, single lab\",\n      \"pmids\": [\"17906076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CS1 activation on human B lymphocytes induces proliferation through secretion of autocrine cytokines (flt3 ligand, lymphotoxin A, TNF, IL-14); neutralizing antibodies against these cytokines abolished CS1-induced B cell proliferation. Only the CS1-L isoform (containing ITSMs) is expressed on B cells.\",\n      \"method\": \"Anti-CS1 antibody crosslinking, cytokine microarray, qRT-PCR, neutralizing antibody blockade of individual cytokines\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional antibody crosslinking with neutralization experiments confirming autocrine cytokine mechanism, single lab\",\n      \"pmids\": [\"17878365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CRACC (SLAMF7) positively regulates NK cell function through a mechanism dependent on the adaptor EAT-2 but not SAP. In the absence of EAT-2, CRACC potently inhibits NK cell function. CRACC is also inhibitory in T cells, which lack EAT-2. Established using CRACC-deficient mouse.\",\n      \"method\": \"CRACC-knockout mouse generation, NK cell functional assays (cytotoxicity, cytokine production), genetic epistasis with EAT-2\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRACC-deficient mouse with multiple functional readouts and genetic epistasis (EAT-2 dependence), replicated across cell types\",\n      \"pmids\": [\"19151721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CS1 knockdown in MM cells decreased phosphorylation of ERK1/2, AKT, and STAT3, and accelerated caspase activation under serum deprivation. CS1 overexpression promoted myeloma adhesion to BMSCs by increasing c-maf-targeted cyclin D2-dependent proliferation, integrin β7/αE-mediated adhesion, and VEGF-induced angiogenesis in vivo.\",\n      \"method\": \"Lentiviral shRNA knockdown, phospho-Western blotting, apoptosis assays, overexpression, xenograft mouse model\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss- and gain-of-function with multiple downstream signaling readouts and in vivo model, single lab\",\n      \"pmids\": [\"19196658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CS1 crosslinking inhibits production of proinflammatory cytokines TNF-α and IL-12p70 by LPS-activated human monocytes. CS1 expression on monocytes is induced via NF-κB and PI3K signaling pathways.\",\n      \"method\": \"Anti-CS1 antibody crosslinking, ELISA for cytokines, pharmacological inhibitors of NF-κB and PI3K, RT-PCR\",\n      \"journal\": \"Inflammation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — antibody crosslinking functional assay with pharmacological pathway inhibitors, single lab, two methods\",\n      \"pmids\": [\"23695528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SLAMF7-mediated inhibition in EAT-2-negative NK cells requires SHIP-1, which is recruited via tyrosine 261 of SLAMF7. This coupling requires Src kinases (which phosphorylate SLAMF7) and CD45. MM cells lack EAT-2 but also lack CD45, preventing Src kinase activation and thus SLAMF7-triggered inhibitory signaling in MM cells.\",\n      \"method\": \"Site-directed mutagenesis (Y261 of SLAMF7), co-immunoprecipitation of SHIP-1, use of CD45-deficient NK cells, functional NK cytotoxicity assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis of specific tyrosine residue combined with Co-IP and CD45-deficient cell validation; mechanistic circuit fully defined\",\n      \"pmids\": [\"25312647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Blimp-1/PRDM1 acts as a transcriptional activator of the human CS1 (SLAMF7) gene in NK and B cells. EMSA and ChIP assays confirmed Blimp-1 binding to the CS1 promoter; mutation of the Blimp-1 site at -750 to -746 decreased CS1 promoter activity.\",\n      \"method\": \"Luciferase reporter assays with promoter deletion mutants, EMSA, ChIP assay, site-directed mutagenesis of promoter\",\n      \"journal\": \"Immunobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and EMSA with mutagenesis confirm Blimp-1 binding and trans-activation, single lab\",\n      \"pmids\": [\"26310579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SLAMF7 on macrophages is required for phagocytosis of haematopoietic tumour cells during SIRPα-CD47 blockade, both in vitro and in vivo. This function is independent of SAP adaptors but requires SLAMF7's ability to interact with integrin Mac-1 and signals involving ITAMs. SLAMF7 must be expressed on both the macrophage and the tumour cell target for efficient phagocytosis.\",\n      \"method\": \"SLAM-family receptor knockout mouse, in vitro phagocytosis assays, in vivo tumour models, Mac-1 interaction studies\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout mouse with in vitro and in vivo phagocytosis assays, mechanistic dissection of SAP independence and Mac-1 requirement, published in Nature\",\n      \"pmids\": [\"28424516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Elotuzumab primarily activates NK cells through CD16 (FcγRIIIa)-dependent ADCC; F(ab')2 or Fc-mutant forms of elotuzumab alone cannot stimulate CD69 expression or degranulation. However, soluble elotuzumab can co-stimulate calcium signaling through NKp46 and NKG2D in a CD16-independent manner (trans-costimulation).\",\n      \"method\": \"NK cell degranulation assays, CD69 expression, calcium flux assays, F(ab')2 and Fc-mutant antibody forms, CD16-blocking experiments\",\n      \"journal\": \"Oncoimmunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dissection of CD16-dependent vs independent mechanisms using multiple antibody variants and functional assays, single lab\",\n      \"pmids\": [\"28932638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Soluble SLAMF7 (sSLAMF7), present exclusively in MM patient serum, promotes MM cell growth via homophilic interaction with surface SLAMF7 and subsequent activation of SHP-2 and ERK signaling pathways. Elotuzumab suppresses sSLAMF7-induced MM cell growth by blocking this interaction. IKZF1 (Ikaros) was identified as a transcriptional activator of SLAMF7 gene; lenalidomide and pomalidomide downregulate SLAMF7 expression by targeting Ikaros.\",\n      \"method\": \"Recombinant sSLAMF7 treatment, Western blotting for SHP-2/ERK phosphorylation, promoter analysis, in vitro and in vivo (xenograft) elotuzumab blockade\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — sSLAMF7/surface SLAMF7 interaction with downstream signaling and in vivo validation, single lab, multiple methods\",\n      \"pmids\": [\"31358854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Elotuzumab (but not other SLAMF7 antibodies) enhances cytotoxicity of CD16-negative NK-92 cells toward SLAMF7+ targets; this CD16-independent costimulation requires full cytoplasmic domain of SLAMF7 in NK cells and is associated with increased NKG2D and ICAM-1 expression and activated LFA-1, suggesting SLAMF7-SLAMF7 homotypic interactions drive the effect.\",\n      \"method\": \"CD16-negative NK-92 cell cytotoxicity assays, Fc-mutant antibody forms, SLAMF7 cytoplasmic domain deletion constructs, NKG2D blocking antibodies\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic dissection using domain deletion constructs and blocking antibodies, CD16-independent pathway defined, single lab\",\n      \"pmids\": [\"31431433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SLAMF7 activation on T cells induces STAT1 and STAT3 phosphorylation and drives expression of multiple inhibitory receptors/transcription factors associated with T cell exhaustion. SLAMF7-SLAMF7 interactions between tumour-associated macrophages and CD8+ T cells induce exhaustion markers; SLAMF7-knockout mice show restricted B16-F10 tumour growth and CD8+ T cells with less PD-1 and TOX expression.\",\n      \"method\": \"SLAMF7 receptor activation assays, phospho-flow cytometry for STAT1/STAT3, SLAMF7-knockout mouse tumor model, ex vivo co-culture\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout mouse with in vivo tumor readout plus ex vivo mechanistic co-culture validation, single lab\",\n      \"pmids\": [\"33288545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Physiological ligation of SLAMF7 in human NK cells selectively enhances target cell lysis by promoting NK cell degranulation (not granule polarization or cell adhesion). SLAMF7-dependent degranulation is predominantly dependent on PLCγ when compared to PI3K.\",\n      \"method\": \"NK cell degranulation assays, pharmacological inhibition of PLCγ vs PI3K, granule polarization imaging, adhesion assays\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological dissection of PLCγ vs PI3K with multiple cellular readouts, single lab\",\n      \"pmids\": [\"34693521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SLAMF7 engagement drives a strong wave of inflammatory cytokine expression in macrophages; TNF-α induction after SLAMF7 engagement amplifies inflammation through an autocrine signaling loop. IFN-γ is identified as a key regulator of SLAMF7 expression on macrophages.\",\n      \"method\": \"RNA-seq of synovial macrophages, SLAMF7 engagement experiments, cytokine blockade, IFN-γ stimulation assays\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — SLAMF7 engagement with TNF-α autocrine loop validation and IFN-γ regulatory relationship, supported by patient macrophage RNA-seq and functional experiments\",\n      \"pmids\": [\"35148199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In macrophages during polymicrobial sepsis, SLAMF7 attenuates TLR-dependent MAPK and NF-κB signaling by cooperating with SHIP1. SLAMF7 interacts with both SHIP1 and TRAF6 to inhibit K63 ubiquitination of TRAF6. Tyrosine phosphorylation sites in the intracellular domain of SLAMF7 and the phosphatase domain of SHIP1 are required for this interaction. SLAMF7-deficient mice show enhanced lethality in sepsis models.\",\n      \"method\": \"Co-immunoprecipitation of SLAMF7/SHIP1/TRAF6, ubiquitination assays, site-directed mutagenesis of SLAMF7 tyrosine residues, SLAMF7-knockout mice in polymicrobial sepsis model\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — Co-IP of SLAMF7/SHIP1/TRAF6 complex, ubiquitination assays, mutagenesis of tyrosine sites, and in vivo knockout mouse model; multiple orthogonal methods in one study\",\n      \"pmids\": [\"36749634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In hepatocellular carcinoma cells, SLAMF7 suppresses MAPK/ATF2-mediated CCL2 expression to regulate macrophage migration and polarization. Mechanistically, SLAMF7 associates with SHB adaptor protein through its cytoplasmic Y304 site, facilitating recruitment of SHIP1 to SLAMF7 and inhibiting TRAF6 ubiquitination, thereby attenuating MAPK pathway activation and CCL2 transcription.\",\n      \"method\": \"Co-immunoprecipitation of SLAMF7/SHB/SHIP1, ubiquitination assays, site-directed mutagenesis of Y304, liver-specific knockout mouse model, in vitro macrophage co-culture\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — Co-IP, mutagenesis of specific tyrosine residue, in vivo liver-specific KO mouse, and in vitro mechanistic validation; multiple orthogonal methods\",\n      \"pmids\": [\"38484085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"YY1 represses mouse CS1 (SLAMF7) gene transcription by binding to the CS1 promoter; mutation of the YY1 site significantly increased promoter activity. A unique (AG)n=36 DNA repeat element in the CS1 promoter enhances transcriptional activity and forms DNA triplex structures.\",\n      \"method\": \"Luciferase promoter assays with deletion/mutation constructs, ChIP assay, EMSA super-shift assay, AFM imaging of DNA triplex\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and EMSA with mutagenesis confirming YY1 binding and repression, plus AFM structural validation of repeat element, single lab\",\n      \"pmids\": [\"23318224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"N-linked glycosylation of SLAMF7 at seven motifs (particularly N98) regulates antibody affinity and macrophage phagocytosis of breast cancer cells. STT3A drives SLAMF7 hyperglycosylation; inhibition of STT3A by NGI-1 reduces glycosylation of SLAMF7, enhances anti-SLAMF7 antibody binding, and increases phagocytosis.\",\n      \"method\": \"Mass spectrometry glycosylation mapping, STT3A inhibition, antibody affinity measurements, macrophage phagocytosis assays, antibody-drug conjugate (ADC)\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — glycosylation site mapping by MS, functional phagocytosis assay with glycosylation inhibitor, single lab\",\n      \"pmids\": [\"36381324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ALKBH5-mediated m6A demethylation decreases Slamf7 mRNA stability; specific inhibition of ALKBH5 increased Slamf7 expression via increased m6A modification. Slamf7 inhibition promoted autophagy and reduced pro-inflammatory cytokine secretion in macrophages, thereby improving silica-induced pulmonary inflammation.\",\n      \"method\": \"MeRIP assay (m6A mapping), ALKBH5 inhibition, mRNA stability assay, siRNA knockdown of Slamf7, mouse model of silica-induced pulmonary inflammation\",\n      \"journal\": \"Journal of hazardous materials\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP assay identifies m6A modification on Slamf7, mRNA stability linked to m6A, with in vivo functional validation; single lab\",\n      \"pmids\": [\"37827106\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLAMF7 is a homophilic SLAM-family cell surface receptor that functions as an activating or inhibitory receptor depending on cellular context: in EAT-2-expressing cells (NK cells, macrophages), SLAMF7 signals through EAT-2 to activate PLCγ/PI3K/ERK/calcium pathways and promote degranulation and cytotoxicity; in EAT-2-negative cells (T cells, MM cells), SLAMF7 recruits SHIP1 via Src kinase-phosphorylated Y261 in a CD45-dependent manner to exert inhibitory effects on MAPK and NF-κB signaling; SLAMF7 also mediates phagocytosis of haematopoietic tumour cells through a SAP-independent, Mac-1/ITAM-dependent mechanism on macrophages; its expression is transcriptionally regulated by Blimp-1/PRDM1 (activating) and YY1 (repressing), post-transcriptionally regulated by ALKBH5-dependent m6A modification, and post-translationally modified by N-linked glycosylation at multiple sites including N98 which modulates antibody binding and phagocytosis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SLAMF7 (CS1/CRACC) is a homophilic SLAM-family cell-surface receptor that bidirectionally tunes immune effector function, adhesion, and tumour-cell biology depending on the adaptors available in a given cell [#0, #5]. It engages itself in trans, and recombinant or soluble SLAMF7-Ig is sufficient to enhance NK-cell cytolytic activity [#0]. The functionally signaling isoform CS1-L carries cytoplasmic ITSMs; in NK cells activation recruits the SAP-homolog adaptor EAT-2, driving Src-dependent receptor phosphorylation and downstream PLC\\u03b3/PI3K signaling that culminates in degranulation and target lysis, with PLC\\u03b3 the dominant arm of the degranulation response [#2, #15]. In the absence of EAT-2 — as in T cells — SLAMF7 instead becomes inhibitory: Src kinases phosphorylate tyrosine 261 in a CD45-dependent manner to recruit the inositol phosphatase SHIP-1, restraining cellular activation [#5, #8]. This inhibitory module operates broadly in macrophages, where SLAMF7 assembles with SHIP1 and TRAF6 to block K63 ubiquitination of TRAF6 and dampen TLR-driven MAPK and NF-\\u03baB signaling, using the SHB adaptor and cytoplasmic Y304 to bridge SHIP1 recruitment in hepatocellular carcinoma cells [#17, #18]. Independently of SAP adaptors, SLAMF7 on macrophages drives phagocytosis of haematopoietic tumour cells through interaction with integrin Mac-1 and ITAM signaling, requiring SLAMF7 on both effector and target [#10]. In multiple myeloma, SLAMF7 promotes adhesion to bone marrow stroma and tumour-supportive signaling (ERK/AKT/STAT3), and soluble SLAMF7 in patient serum fuels myeloma growth via homophilic engagement and SHP-2/ERK activation [#3, #6, #12]. SLAMF7 expression is transcriptionally activated by Blimp-1/PRDM1 and IKZF1 and repressed by YY1, and is further controlled post-transcriptionally by ALKBH5-dependent m6A demethylation and post-translationally by STT3A-driven N-linked glycosylation at N98 that modulates antibody binding and phagocytosis [#9, #12, #19, #21, #20].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established that SLAMF7 is a self-ligand whose engagement can enhance NK cytotoxicity, defining it as a homophilic activating receptor rather than a ligand for a distinct partner.\",\n      \"evidence\": \"CS1-Ig fusion protein binding to CS1-transfected cells and redirected cytotoxicity in the YT NK line\",\n      \"pmids\": [\"12213321\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define the cytoplasmic signaling adaptors\", \"Binding shown with fusion protein, not endogenous trans-interaction\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showed that only the ITSM-containing CS1-L isoform is signaling-competent and that SAP associates with the unstimulated receptor, framing SLAMF7 within SAP-family adaptor biology.\",\n      \"evidence\": \"Isoform transfection into RNK-16 NK cells with cytotoxicity, calcium flux, and Co-IP of SAP\",\n      \"pmids\": [\"15368295\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of SAP dissociation unresolved\", \"Did not establish which adaptor mediates downstream activation\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identified EAT-2 as the activating adaptor coupling SLAMF7 to PLC\\u03b3/PI3K signaling, defining the molecular route to NK cytotoxicity.\",\n      \"evidence\": \"Co-IP of EAT-2, Src-inhibitor-sensitive phosphorylation, and downstream pathway/cytotoxicity assays in human NK cells\",\n      \"pmids\": [\"16339536\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve behavior in EAT-2-negative cells\", \"Tyrosine residues mediating EAT-2 coupling not mapped\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Genetically established the activating/inhibitory switch: SLAMF7 promotes NK function only with EAT-2 and is inhibitory in its absence and in T cells.\",\n      \"evidence\": \"CRACC-knockout mouse with NK functional assays and EAT-2 genetic epistasis\",\n      \"pmids\": [\"19151721\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Inhibitory effector molecule not identified in this study\", \"Mechanism of context-dependence at molecular level unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined non-NK roles: SLAMF7 promotes B-cell proliferation via autocrine cytokines and mediates myeloma adhesion to bone marrow stroma.\",\n      \"evidence\": \"Antibody crosslinking with cytokine neutralization in B cells; siRNA knockdown with adhesion assays and uropod localization in MM cells\",\n      \"pmids\": [\"17878365\", \"17906076\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling adaptors in B cells not defined\", \"Direct ligand for stromal adhesion not established\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated SLAMF7 supports myeloma survival and proliferation through ERK/AKT/STAT3 signaling and integrin-mediated adhesion in vivo.\",\n      \"evidence\": \"shRNA knockdown and overexpression with phospho-Western, apoptosis assays, and xenograft model\",\n      \"pmids\": [\"19196658\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Proximal signaling adaptor in MM cells not identified\", \"Link between homophilic engagement and ERK/AKT not mechanistically dissected\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved the inhibitory circuit: SLAMF7 recruits SHIP-1 via phosphorylated Y261 in a Src- and CD45-dependent manner, and explained why MM cells (lacking CD45) escape inhibition.\",\n      \"evidence\": \"Y261 site-directed mutagenesis, SHIP-1 Co-IP, and CD45-deficient NK cells with cytotoxicity assays\",\n      \"pmids\": [\"25312647\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address SHIP1-independent inhibitory routes\", \"Macrophage-specific signaling not examined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed SLAMF7 is inhibitory in monocytes, suppressing LPS-induced TNF-\\u03b1 and IL-12p70, extending inhibitory function to myeloid cells.\",\n      \"evidence\": \"Anti-CS1 crosslinking with cytokine ELISA and NF-\\u03baB/PI3K pathway inhibitors in human monocytes\",\n      \"pmids\": [\"23695528\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Adaptor mediating monocyte inhibition not identified\", \"Relationship to SHIP1 pathway unestablished at this point\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined a SAP-independent phagocytic function: macrophage SLAMF7 drives engulfment of haematopoietic tumour cells via Mac-1 and ITAM signaling during CD47-SIRP\\u03b1 blockade.\",\n      \"evidence\": \"SLAM-family knockout mouse with in vitro/in vivo phagocytosis assays and Mac-1 interaction studies\",\n      \"pmids\": [\"28424516\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular geometry of SLAMF7-Mac-1 coupling unresolved\", \"ITAM-bearing adaptor not specified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Clarified the therapeutic mechanism of elotuzumab as primarily CD16/ADCC-driven, with a secondary CD16-independent trans-costimulation of NK receptors.\",\n      \"evidence\": \"Degranulation, CD69, and calcium assays using F(ab')2, Fc-mutant antibodies, and CD16 blockade\",\n      \"pmids\": [\"28932638\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Contribution of each arm in patients unquantified\", \"Receptor basis of trans-costimulation only partly defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified soluble SLAMF7 as a myeloma growth factor acting through homophilic engagement and SHP-2/ERK signaling, blocked by elotuzumab, and named IKZF1 as a transcriptional activator targeted by IMiDs.\",\n      \"evidence\": \"Recombinant sSLAMF7 treatment with phospho-Western, promoter analysis, and xenograft elotuzumab blockade\",\n      \"pmids\": [\"31358854\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Source and processing of sSLAMF7 not defined\", \"Relationship between SHP-2 and SHIP1 pathways unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed CD16-independent elotuzumab costimulation requires the full SLAMF7 cytoplasmic domain and homotypic interactions, linking it to NKG2D/LFA-1 activation.\",\n      \"evidence\": \"CD16-negative NK-92 cytotoxicity with Fc-mutant antibodies, cytoplasmic-domain deletions, and NKG2D blockade\",\n      \"pmids\": [\"31431433\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Adaptor coupling in this context not mapped\", \"Generalizability beyond NK-92 line unaddressed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Implicated SLAMF7 in T-cell exhaustion: homotypic engagement with tumour-associated macrophages drives STAT1/STAT3 and inhibitory-receptor programs, with knockout restraining tumour growth.\",\n      \"evidence\": \"Receptor activation with phospho-flow, SLAMF7-knockout B16-F10 tumour model, and ex vivo co-culture\",\n      \"pmids\": [\"33288545\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Proximal signaling from SLAMF7 to STAT not defined\", \"Distinction from inhibitory SHIP1 pathway unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Pinpointed the cellular output of activating SLAMF7 signaling as degranulation (not polarization or adhesion), predominantly PLC\\u03b3-dependent.\",\n      \"evidence\": \"Physiological ligation with degranulation assays, PLC\\u03b3 vs PI3K inhibitors, and polarization imaging in human NK cells\",\n      \"pmids\": [\"34693521\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative PI3K contribution to other outputs unresolved\", \"EAT-2 dependence not re-tested here\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed a context where SLAMF7 is pro-inflammatory: engagement on macrophages drives a TNF-\\u03b1 autocrine inflammatory loop, with IFN-\\u03b3 controlling its expression.\",\n      \"evidence\": \"Synovial macrophage RNA-seq, SLAMF7 engagement, cytokine blockade, and IFN-\\u03b3 stimulation\",\n      \"pmids\": [\"35148199\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reconciliation with inhibitory macrophage signaling not addressed\", \"Adaptor driving the inflammatory output unidentified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined the inhibitory macrophage mechanism: SLAMF7 cooperates with SHIP1 and TRAF6 to block TRAF6 K63 ubiquitination, attenuating TLR-MAPK/NF-\\u03baB signaling and protecting against sepsis lethality.\",\n      \"evidence\": \"Co-IP of SLAMF7/SHIP1/TRAF6, ubiquitination and mutagenesis assays, and SLAMF7-knockout polymicrobial sepsis model\",\n      \"pmids\": [\"36749634\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciliation with pro-inflammatory engagement in synovial macrophages unresolved\", \"Stimulus determining activating vs inhibitory output unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended the inhibitory module to the tumour microenvironment: SLAMF7 recruits SHIP1 via the SHB adaptor and cytoplasmic Y304 to suppress MAPK/ATF2-driven CCL2 and reshape macrophage recruitment in HCC.\",\n      \"evidence\": \"Co-IP of SLAMF7/SHB/SHIP1, Y304 mutagenesis, ubiquitination assays, and liver-specific knockout mouse with macrophage co-culture\",\n      \"pmids\": [\"38484085\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay between Y261 and Y304 phospho-sites not defined\", \"Whether SHB operates in NK/T cells unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed N-linked glycosylation at N98 (STT3A-driven) modulates anti-SLAMF7 antibody affinity and phagocytosis, identifying a tunable post-translational control of therapeutic targeting.\",\n      \"evidence\": \"Mass-spectrometry glycosite mapping, STT3A/NGI-1 inhibition, antibody affinity, and phagocytosis assays in breast cancer cells\",\n      \"pmids\": [\"36381324\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Effect of glycosylation on homophilic signaling not tested\", \"Generalizability to haematopoietic SLAMF7 unaddressed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established post-transcriptional control: ALKBH5-mediated m6A demethylation destabilizes Slamf7 mRNA, and reduced SLAMF7 promotes macrophage autophagy and limits inflammation.\",\n      \"evidence\": \"MeRIP m6A mapping, ALKBH5 inhibition, mRNA stability and siRNA knockdown, and silica-induced lung inflammation model\",\n      \"pmids\": [\"37827106\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"m6A reader linking demethylation to stability not identified\", \"Direct connection to SHIP1/TRAF6 axis not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The signal that determines whether SLAMF7 engagement is activating, inhibitory, or pro-inflammatory within the same cell type — and how adaptor availability (EAT-2, SHIP1, SHB), tyrosine usage (Y261 vs Y304), and glycosylation integrate to set this output — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model reconciling pro- and anti-inflammatory macrophage outputs\", \"Hierarchy of Y261 vs Y304 phospho-sites across cell types unknown\", \"Endogenous trans-ligand geometry and stoichiometry uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 2, 5, 8]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [3, 6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [8, 17, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 5, 10, 17]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 17, 18]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 12, 18]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SLAMF7\", \"EAT-2\", \"SH2D1B\", \"INPP5D\", \"TRAF6\", \"ITGAM\", \"SHB\", \"SAP\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}