{"gene":"SLAMF1","run_date":"2026-06-10T07:46:32","timeline":{"discoveries":[{"year":2000,"finding":"SLAMF1 (SLAM/CD150) functions as a cellular receptor for measles virus, including wild-type clinical isolates and the Edmonston strain; transfection of human SLAM cDNA into non-susceptible cell lines confers measles virus binding, replication, and cytopathic effects.","method":"Transfection of human SLAM cDNA into non-susceptible cell lines followed by virus binding assay and replication assay","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct receptor reconstitution in heterologous cells, replicated by multiple independent labs","pmids":["10972291"],"is_preprint":false},{"year":2001,"finding":"CD150 associates with SH2-containing inositol phosphatase (SHIP) or SH2-containing protein tyrosine phosphatase (SHP-2) via phosphorylated tyrosines Y281 and Y327 in its cytoplasmic tail; the adaptor SH2D1A (SAP) regulates this association by facilitating SHIP binding and blocking SHP-2 binding, acting through a TxYxxV/I immunoreceptor tyrosine-based switch motif (ITSM).","method":"Co-immunoprecipitation, GST-fusion protein pulldown with tyrosine-to-phenylalanine mutants (Y269F, Y281F, Y307F, Y327F)","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro mutagenesis with multiple mutants combined with co-IP, identifying specific binding residues","pmids":["11313386"],"is_preprint":false},{"year":2001,"finding":"CDw150/SLAM is an expression-cloned receptor for lymphotropic measles virus strains; both lymphotropic and laboratory measles virus strains bind human and marmoset CDw150 but show weak interaction with mouse CDw150; infection via CDw150 is independent of CD46.","method":"Expression cloning from B95-8 cDNA library, binding assay with soluble MV H protein, infection of CDw150-transfected CHO and HEK293T cells","journal":"Virology","confidence":"High","confidence_rationale":"Tier 1 / Strong — expression cloning with reconstitution in heterologous cells, independently replicated","pmids":["11145884"],"is_preprint":false},{"year":2001,"finding":"Measles virus hemagglutinin (H) protein, but not the fusion protein, is sufficient to downregulate SLAM (CD150) from the cell surface; downregulation can occur through intracellular interactions between H and SLAM in the ER, and also through receptor-mediated binding at the cell surface.","method":"Transfection of H protein expression plasmid, confocal microscopy, flow cytometry for surface SLAM levels","journal":"Archives of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transfection-based overexpression with two-mechanism dissection, single lab","pmids":["11855632"],"is_preprint":false},{"year":2002,"finding":"CD150 co-localizes with the TCR following CD3 triggering and is rapidly and reversibly tyrosine-phosphorylated upon TCR cross-linking; Src-like kinases Lck and Fyn phosphorylate tyrosine residues in the cytoplasmic tail of CD150. SAP binds CD150 via two distinct modes: phosphotyrosine-independent binding to Thr-Ile-Y281-Ala-Gln-Val and phosphotyrosine-dependent binding to Thr-Val-Y327-Ala-Ser-Val; a leucine residue L278 further stabilizes non-phospho binding at Y281. SAP blocks SHP-2 binding primarily at Y281.","method":"Confocal microscopy (co-localization), in vitro kinase assay, co-immunoprecipitation, site-directed mutagenesis","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay with mutagenesis plus co-localization and co-IP, multiple orthogonal methods in single rigorous study","pmids":["11806999"],"is_preprint":false},{"year":2002,"finding":"SLAM (CD150) is a cellular receptor common to all 28 measles virus strains tested; a single amino acid exchange in the hemagglutinin at position 481 (Asn/Tyr, H481NY) determines whether virus can additionally utilize CD46, demonstrating that the binding sites for SLAM and CD46 on hemagglutinin are distinct.","method":"Infection of CHO cells expressing recombinant CD46 or SLAM with a panel of MV strains; recombinant virus with site-directed mutations","journal":"The Journal of general virology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution in CHO cells with panel of strains plus mutagenesis defining binding determinants","pmids":["12029158"],"is_preprint":false},{"year":2002,"finding":"Measles virus can infect SLAM-negative cells at 2–3 log lower efficiency through an unidentified receptor distinct from both SLAM and CD46; this entry is blocked by anti-MV hemagglutinin antibody or fusion block peptide but not by anti-CD46 antibody, and occurs under conditions that inhibit endocytosis.","method":"Recombinant EGFP-expressing MV infection of SLAM-negative cell lines, antibody blocking assays, endocytosis inhibition","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reconstitution with multiple blocking conditions, single lab","pmids":["12050387"],"is_preprint":false},{"year":2004,"finding":"SLAMF1 (SLAM) knockout macrophages show defective production of IL-12, TNF, and nitric oxide in response to LPS but normal phagocytosis and normal responses to peptidoglycan or CpG; SLAM acts as a co-receptor regulating signals downstream of TLR4. SLAM-deficient CD4+ T cells show reduced TCR-induced IL-4 secretion with only slight upregulation of IFN-γ. SLAM-/- C57Bl/6 mice fail to clear Leishmania major due to defective macrophage function.","method":"Targeted gene knockout, in vitro cytokine assays, in vivo infection model (Leishmania major)","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined cellular and in vivo phenotype, multiple independent functional readouts","pmids":["15123745"],"is_preprint":false},{"year":2004,"finding":"SAP is required for phosphorylation of SLAM in thymocytes and peripheral T cells; SAP binds directly to both the SH3 domain and kinase domain of FynT, and addition of SAP to autoinhibited FynT causes a large increase in FynT catalytic activity; a SAP mutant (R78E) that cannot bind FynT SH3 domain neither activates FynT nor functions as an adaptor in T cells.","method":"In vitro kinase assay, yeast two-hybrid, GST pulldown, transfection with mutant constructs","journal":"International immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with mutagenesis and multiple binding assays demonstrating enzymatic activation","pmids":["15096483"],"is_preprint":false},{"year":2004,"finding":"Measles virus hemagglutinin (H) protein interacts with SLAM in the endoplasmic reticulum, promoting SLAM downregulation from the host cell surface; surface interactions between H and SLAM also contribute. H expression alone is sufficient for this downregulation.","method":"Plasmid transfection, co-culture experiments, flow cytometry, ER co-localization studies","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transfection-based mechanistic dissection of two pathways, single lab","pmids":["15331699"],"is_preprint":false},{"year":2005,"finding":"SLAM (CD150) V domain is necessary and sufficient for measles virus receptor function; murine SLAM differs from human SLAM in receptor function due to residues at positions 60, 61, and 63, with histidine 61 being most critical; exchange of the region at amino acids 58–67 allows mouse SLAM to function as an MV receptor.","method":"Human/mouse chimeric SLAM constructs assessed by VSV pseudotype assay with site-directed mutagenesis","journal":"The Journal of general virology","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis with functional pseudotype assay precisely mapping critical residues","pmids":["12917459"],"is_preprint":false},{"year":2007,"finding":"Homotypic interactions mediated by SLAMF1 and SLAMF6 (Ly108) on cortical thymocytes generate co-stimulatory signals during NKT cell selection; these signals involve downstream recruitment of SAP and Fyn kinase and are required for NKT lineage expansion and differentiation. These interactions only occur when selecting ligands (CD1d) are presented by thymocytes, not by epithelial cells, which do not express Slamf1/Slamf6.","method":"Genetic knockout models, epistasis analysis, in vivo NKT development assays","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with epistasis, multiple labs have replicated NKT role for SLAM/SAP","pmids":["18031695"],"is_preprint":false},{"year":2008,"finding":"Measles virus hemagglutinin residue isoleucine 194 is essential for primary SLAM binding (as measured by surface plasmon resonance); a quartet of residues on propeller blade 5 is required for SLAM-dependent membrane fusion after binding but not for initial binding, indicating receptor-specific conformational changes post-binding trigger fusion protein unfolding.","method":"Surface plasmon resonance, receptor-specific fusion assays, crystal structure localization, site-directed mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — structural localization combined with SPR binding assay and functional fusion assay with mutagenesis","pmids":["18292085"],"is_preprint":false},{"year":2010,"finding":"SLAMF1 (CD150) signaling via SAP is specifically required for IL-4 production by germinal center T follicular helper (GC TFH) cells; SAP-deficient TFH cells lack GC TFH cells and are defective in IL-4 and IL-21 production; SLAM receptor ligation is required for this IL-4 production but not for TFH or GC TFH cell differentiation.","method":"SAP-deficient and SLAM-deficient mouse models, in vivo immunization, FACS-based identification of GC TFH cells, intracellular cytokine staining","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — SLAM-specific KO with rigorous in vivo GC TFH analysis dissecting differentiation vs. cytokine function","pmids":["20525889"],"is_preprint":false},{"year":2012,"finding":"In E. coli-containing phagosomes of macrophages, SLAMF1 recruits a Beclin-1/Vps34/UVRAG protein complex; this complex regulates NOX2 (NADPH oxidase 2) activity and phagolysosomal maturation. The interaction requires the cytoplasmic tail of Slamf1 but not its ITAM motifs. Beclin-1 BD and CCD domains are required for binding to Slamf1. Slamf1 does not interact with Atg14L or Rubicon.","method":"Co-immunoprecipitation, in vitro pulldown, NOX2 activity assay in Beclin-1+/- macrophages, domain deletion mutagenesis, transfected HEK293 cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution with multiple pulldown experiments, domain mutagenesis, and functional NOX2 assay","pmids":["22493499"],"is_preprint":false},{"year":2012,"finding":"In the absence of SAP, SLAM family receptors Ly108 and 2B4 recruit increased levels of SHP-1 phosphatase, causing altered SHP-1 localization and decreased Src kinase activation at the immunological synapse. SAP-deficient CD8+ T cells show specific defects in synapse organization with B cell and low-avidity T cell targets (inefficient actin clearance), resulting in impaired cytotoxicity against these targets but not fibrosarcoma targets.","method":"SAP-deficient mouse T cells, immunological synapse imaging, phosphatase recruitment assay, cytotoxicity assays","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with detailed mechanistic synapse analysis and multiple functional readouts","pmids":["22683123"],"is_preprint":false},{"year":2015,"finding":"SLAMF1 ligation with an agonistic antibody induces ROS accumulation, phosphorylation of p38, JNK1/2, and BCL2, and promotes autophagic flux in CLL cells. Beclin-1 dissociates from BCL2 upon SLAMF1 ligation, forming an autophagy macrocomplex containing SLAMF1, beclin-1, and VPS34. SLAMF1 silencing in CLL cells increases CXCR4, CD38, and CD44 expression and enhances chemotactic responses to CXCL12; SLAMF1-low cells are resistant to autophagy-activating agents.","method":"SLAMF1 siRNA knockdown, agonistic antibody ligation, co-immunoprecipitation (SLAMF1/beclin-1/VPS34 complex), ROS assay, autophagic flux assay, transwell chemotaxis assay","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — co-IP of complex with functional autophagy and chemotaxis readouts, multiple orthogonal methods","pmids":["26619119"],"is_preprint":false},{"year":2015,"finding":"SLAMF1 and SLAMF8 oppositely regulate in vivo migration of myeloid cells during inflammation: Slamf1-/- dendritic cells and macrophages show reduced migration in vivo and in vitro, whereas Slamf8-/- cells show accelerated migration. These effects are cell-intrinsic. Inhibition of ROS production in Slamf8-/- macrophages blocks their enhanced migration, linking SLAMF1/SLAMF8-mediated ROS regulation to myeloid cell migration.","method":"Slamf1-/- and Slamf8-/- mouse models, in vivo migration assays (skin sensitization, peritonitis, intestinal repopulation), transwell migration assay, ROS inhibitor (DPI)","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with in vivo and in vitro migration assays plus pharmacological inhibitor, single lab","pmids":["25799045"],"is_preprint":false},{"year":2017,"finding":"SLAMF1 engagement by measles virus (MeV) induces macropinocytosis-like endocytic uptake of viral particles dependent on actin cytoskeletal rearrangement, membrane blebbing, and the RhoA-ROCK-myosin II signaling axis; this endocytic entry pathway is specific to SLAMF1-positive cells and occurs within 60 minutes of viral attachment.","method":"Live-cell imaging of viral particle colocalization with blebs, chemical inhibition of macropinocytosis/actin dynamics/ROCK-myosin II, infection assay in SLAMF1+ vs SLAMF1- cells","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pharmacological inhibitors and live imaging, single lab","pmids":["28100610"],"is_preprint":false},{"year":2018,"finding":"SLAMF1 is required for TLR4-mediated TRAM-TRIF-dependent signaling (IFNβ induction) and killing of Gram-negative bacteria by human macrophages. In resting macrophages, SLAMF1 localizes to the endocytic recycling compartment (ERC) and is trafficked together with TRAM to E. coli phagosomes in a Rab11-dependent manner upon bacterial stimulation. Endogenous SLAMF1 interacts with TRAM via amino acids 68–95 of TRAM and the 15 C-terminal amino acids of SLAMF1; this interaction is observed for human but not mouse proteins.","method":"SLAMF1 knockdown/knockout in human macrophages, co-immunoprecipitation (SLAMF1-TRAM), confocal microscopy of ERC-to-phagosome trafficking, domain deletion constructs, IFNβ induction assay, bacterial killing assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — co-IP with domain mutagenesis, live trafficking imaging with functional IFNβ and bacterial killing readouts, multiple orthogonal methods","pmids":["29440514"],"is_preprint":false},{"year":2019,"finding":"SLAM family receptors (SFRs), including SLAMF1, promote iNKT cell development by reducing TCR signal strength after positive selection; SFR deficiency upregulates inhibitory receptors (PD-1) to partially compensate; SLAMF6 alone can mimic SFR function and this involves the SAP-Fyn complex and phosphatase SHP-1.","method":"SFR-deficient mouse models, SLAMF6 single-receptor rescue experiments, epistasis with SAP/Fyn/SHP-1, iNKT cell development quantification, TCR signal strength assays","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with rescue experiments and multiple pathway components identified","pmids":["30833791"],"is_preprint":false},{"year":2020,"finding":"Brucella abortus outer membrane protein Omp25 specifically binds SLAMF1 in vitro; Omp25-dependent SLAMF1 engagement limits NF-κB translocation in dendritic cells, decreases pro-inflammatory cytokine secretion, impairs DC activation, and promotes bacterial persistence at the chronic stage of infection in vivo.","method":"In vitro binding assay (Omp25-SLAMF1), NF-κB translocation assay, cytokine measurement, mouse infection model","journal":"Cellular microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay plus in vivo infection model, single lab","pmids":["31953913"],"is_preprint":false},{"year":2020,"finding":"Human neutrophils upregulate SLAMF1 expression upon Mycobacterium tuberculosis (Mtb) stimulation; SLAMF1 co-localizes with LC3B+ vesicles, and SLAMF1 activation increases neutrophil autophagy induced by Mtb; tuberculosis patients' neutrophils show reduced SLAMF1 levels and lower autophagy.","method":"Flow cytometry for SLAMF1 expression, confocal microscopy (SLAMF1/LC3B co-localization), SLAMF1 agonistic antibody activation, autophagy flux assay","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-localization plus functional autophagy assay with agonistic antibody, single lab","pmids":["32954947"],"is_preprint":false},{"year":1993,"finding":"IPO-3 (later identified as CD150/SLAMF1) is a novel heavily N-glycosylated phosphoglycoprotein (~75-95 kDa, 42 kDa protein core) expressed on activated B cells and some T cells; it has an associated protein kinase activity maintained in detergent lysates; cross-linking IPO-3 on B cells triggers increases in intracellular Ca2+ and augments IL-4/anti-CD40-driven proliferation.","method":"Monoclonal antibody characterization, in vitro kinase assay, calcium flux assay, proliferation assay","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase assay and functional signaling assay, single lab at time of initial characterization","pmids":["8409422"],"is_preprint":false},{"year":2002,"finding":"CD150 (SLAMF1)-mediated T cell DNA synthesis (proliferation) induced by anti-CD150 antibody does not depend on SAP/SH2D1A, as similar levels are observed in SAP-/- T cells; however, SAP-/- T cells show higher IFN-γ production than WT upon anti-CD150 stimulation. Anti-CD150 cross-linking on CD4 T cells induces rapid serine phosphorylation of Akt/PKB.","method":"SAP-/- mouse T cells, anti-CD150 antibody stimulation, DNA synthesis assay, IFN-γ ELISA, Akt phosphorylation assay","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic KO with multiple functional readouts, single lab","pmids":["12351401"],"is_preprint":false},{"year":2004,"finding":"CD150 (SLAMF1)-induced ERK pathway activation in B cells requires SHIP but not SH2D1A (SAP); CD150-mediated Akt phosphorylation requires Syk and SH2D1A and is negatively regulated by Lyn and Btk; Lyn directly phosphorylates Y327 in CD150; the Akt pathway does not depend on CD150 tyrosine phosphorylation or CD150-SHP-2 association.","method":"DT40 B-cell sublines deficient in SHIP, SAP, Syk, Lyn, or Btk; CD150 ligation, Western blotting for ERK/Akt phosphorylation","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis using multiple DT40 deficient lines with defined signaling pathway placement","pmids":["15315965"],"is_preprint":false},{"year":2001,"finding":"SLAM (CD150) is downregulated from the surface of activated peripheral blood lymphocytes and cell lines after measles virus infection or surface contact with MV envelope proteins; blocking SLAM or CD46 prevents virus binding but does not interfere with contact-mediated proliferation inhibition, indicating these are separable functions.","method":"Flow cytometry for SLAM surface expression, antibody blocking assays, proliferation assays","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional dissection using blocking antibodies with multiple readouts, single lab","pmids":["11312320"],"is_preprint":false},{"year":2001,"finding":"SLAM (CD150) is inducible on monocytes (which are SLAM-negative at rest) after stimulation with PHA, LPS, or MV; anti-SLAM monoclonal antibodies efficiently block MV infection of activated monocytes with a wild-type strain.","method":"Flow cytometry for SLAM induction on monocytes, blocking antibody assay for MV infection","journal":"The Journal of general virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional blocking assay combined with induction kinetics, single lab","pmids":["11714966"],"is_preprint":false},{"year":2006,"finding":"CDV unable to recognize SLAM (CD150) does not spread in ferrets, formally proving that SLAM recognition is necessary for morbillivirus virulence and for lymphocyte-based dissemination into mucosal tissue and lymphatic organs.","method":"Recombinant CDV with receptor-ablating mutations in ferret infection model, GFP-reporter virus tracking","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — recombinant SLAM-blind virus in relevant animal model with rigorous controls","pmids":["16731947"],"is_preprint":false},{"year":2010,"finding":"A recombinant measles virus with a single R533A substitution in hemagglutinin that is selectively unable to recognize SLAM (SLAM-blind) infects primary lymphocytes at low levels regardless of SLAM expression and causes no viremia or clinical symptoms in rhesus monkeys, formally proving that efficient SLAM recognition is necessary for MV virulence and pathogenesis.","method":"Site-directed mutagenesis of MV hemagglutinin, ex vivo lymphocyte infection assay, rhesus monkey intranasally inoculation model","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1 / Strong — single amino acid mutant virus in primate animal model formally proving receptor requirement","pmids":["20071568"],"is_preprint":false},{"year":2001,"finding":"SLAM (CD150) augments TCR-mediated cytotoxicity in both CD4+ and CD8+ T cells; SLAM engagement alone triggers cytotoxicity in herpesvirus saimiri-transformed T cells via lytic granule release, requiring extracellular Ca2+, cytoskeletal rearrangements, and MEK1/2 signaling, independent of CD95.","method":"Antibody crosslinking of SLAM on primary and transformed T cells, cytotoxicity assay, pharmacological inhibitors (MEK1/2, cytoskeletal), Ca2+ chelation","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional cytotoxicity assays with pharmacological dissection, single lab","pmids":["11536173"],"is_preprint":false},{"year":2012,"finding":"Slamf1-/- mice are completely protected from acute lethal Trypanosoma cruzi challenge; Slamf1-deficient myeloid cells are impaired in intracellular T. cruzi replication and show altered cytokine production; IFN-γ production is reduced in the heart of Slamf1-/- mice despite comparable immune cell infiltration.","method":"Slamf1-/- mouse infection model, in vitro parasite replication assay in myeloid cells, cytokine measurement, anti-Slamf1 monoclonal antibody treatment","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with in vivo infection model and in vitro myeloid cell assays, single lab","pmids":["22807679"],"is_preprint":false}],"current_model":"SLAMF1 (CD150/SLAM) is a homophilic Ig-superfamily receptor on hematopoietic cells that functions as the primary entry receptor for morbilliviruses (measles, CDV, rinderpest) via its V domain, and as a co-stimulatory and innate immune signaling receptor that recruits SAP/SH2D1A to its cytoplasmic ITSM motifs (particularly phospho-Y281 and phospho-Y327), enabling SAP-mediated activation of FynT kinase, regulation of SHP-2 and SHIP phosphatase access, downstream ERK/Akt/NF-κB signaling, and control of cytokine production (IL-4, IFN-γ, IFNβ), cytotoxicity, autophagy (via a Beclin-1/Vps34/UVRAG complex), NADPH oxidase activity in phagocytes, and myeloid cell migration; in TLR4 signaling, SLAMF1 traffics TRAM from the endocytic recycling compartment to bacterial phagosomes in a Rab11-dependent manner to enable TRIF-dependent IFNβ induction."},"narrative":{"mechanistic_narrative":"SLAMF1 (CD150/SLAM) is a hematopoietic Ig-superfamily receptor that operates both as a costimulatory/innate immune signaling receptor and as the entry receptor for morbilliviruses [PMID:10972291, PMID:15123745]. Its membrane-distal V domain is necessary and sufficient for measles virus receptor function, with residues around positions 58–67 (especially His61) determining the human-versus-mouse species barrier [PMID:12917459]; SLAM serves as a common receptor for all measles strains tested and binds hemagglutinin at a site distinct from CD46 [PMID:12029158]. SLAM recognition drives macropinocytosis-like viral uptake and triggers receptor-specific conformational changes in hemagglutinin that license membrane fusion [PMID:18292085, PMID:28100610], and SLAM-blind morbiliviruses are avirulent in ferret and primate models, establishing receptor engagement as essential for pathogenesis [PMID:16731947, PMID:20071568]. In signaling, SLAMF1 is tyrosine-phosphorylated by Src-family kinases Lck/Fyn on cytoplasmic ITSM tyrosines Y281 and Y327, which recruit the adaptor SAP/SH2D1A; SAP binds these motifs and governs the balance of SHIP versus SHP-2/SHP-1 phosphatase access, while SAP also binds and activates FynT to propagate signaling [PMID:11313386, PMID:11806999, PMID:15096483]. This SLAM–SAP–Fyn axis mediates homotypic costimulation during NKT/iNKT cell selection and is required for IL-4 production by germinal center T follicular helper cells and for cytotoxic synapse organization [PMID:18031695, PMID:20525889, PMID:22683123, PMID:30833791]. Downstream, SLAMF1 ligation activates ERK (via SHIP) and Akt (via Syk/SAP) pathways and controls cytokine output [PMID:15315965]. As a TLR4 co-receptor, SLAMF1 regulates LPS-induced IL-12/TNF/NO production and, in human macrophages, traffics from the endocytic recycling compartment with TRAM to bacterial phagosomes in a Rab11-dependent manner to enable TRIF-dependent IFNβ induction and Gram-negative bacterial killing [PMID:15123745, PMID:29440514]. In phagosomes SLAMF1 recruits a Beclin-1/Vps34/UVRAG complex through its cytoplasmic tail to regulate NOX2 activity, phagolysosomal maturation, and autophagy [PMID:22493499, PMID:26619119]. These functions place SLAMF1 at the center of host defense against intracellular pathogens including Leishmania and Trypanosoma cruzi [PMID:15123745, PMID:22807679].","teleology":[{"year":1993,"claim":"Before its identity was known, the antigen IPO-3 was characterized as an activation-induced glycoprotein with signaling capacity, establishing that SLAMF1 transduces lymphocyte activation signals.","evidence":"Monoclonal antibody characterization with in vitro kinase, calcium flux, and proliferation assays on activated B cells","pmids":["8409422"],"confidence":"Medium","gaps":["Molecular identity and cytoplasmic signaling motifs not yet defined","Associated kinase not identified"]},{"year":2000,"claim":"The question of which receptor measles virus uses was answered by showing SLAM confers susceptibility, defining SLAMF1 as a virus entry receptor.","evidence":"Transfection of human SLAM cDNA into non-susceptible cells with virus binding and replication assays","pmids":["10972291"],"confidence":"High","gaps":["Binding domain on SLAM not mapped","Post-binding entry mechanism unknown"]},{"year":2001,"claim":"How SLAMF1 couples to intracellular signaling was established by identifying ITSM tyrosines that recruit SAP, SHIP, and SHP-2, defining the adaptor switch logic.","evidence":"Co-IP and GST pulldown with Y-to-F mutants of the cytoplasmic tail","pmids":["11313386"],"confidence":"High","gaps":["Kinases responsible for tyrosine phosphorylation not identified here","Functional consequences of phosphatase switching untested"]},{"year":2002,"claim":"The kinases and dual binding modes governing SLAM signaling were resolved, showing Lck/Fyn phosphorylate the tail and SAP binds Y281/Y327 by phospho-dependent and phospho-independent modes.","evidence":"In vitro kinase assay, co-localization, co-IP, and site-directed mutagenesis","pmids":["11806999"],"confidence":"High","gaps":["Downstream effectors of SAP not yet defined","Quantitative contribution of each binding mode in vivo unknown"]},{"year":2002,"claim":"SLAM was shown to be the universal measles receptor across strains while CD46 usage maps to a separable hemagglutinin determinant, distinguishing the two receptor binding sites.","evidence":"Infection of CHO cells expressing CD46 or SLAM with a strain panel plus recombinant mutant virus","pmids":["12029158"],"confidence":"High","gaps":["Atomic-level SLAM-binding interface not resolved here"]},{"year":2003,"claim":"The receptor-determining region was mapped to the SLAM V domain, with residues 58–67 and His61 explaining the human/mouse species barrier.","evidence":"Human/mouse chimeric SLAM constructs in VSV pseudotype assays with mutagenesis","pmids":["12917459"],"confidence":"High","gaps":["Structural basis of His61 contribution not solved","Other ectodomain contacts not excluded"]},{"year":2004,"claim":"The downstream output of SAP was defined as direct FynT activation, linking SLAM engagement to a catalytic signaling event.","evidence":"Yeast two-hybrid, GST pulldown, and in vitro kinase assay with SAP R78E mutant","pmids":["15096483"],"confidence":"High","gaps":["Substrates of activated FynT downstream of SLAM not enumerated"]},{"year":2004,"claim":"Genetic deletion established SLAMF1 as a TLR4 co-receptor and an in vivo determinant of macrophage antimicrobial function and T cell cytokine polarization.","evidence":"Targeted knockout with cytokine assays and Leishmania major infection model","pmids":["15123745"],"confidence":"High","gaps":["Molecular mechanism linking SLAM to TLR4 signaling not defined here","TLR-specificity rationale unexplained"]},{"year":2004,"claim":"Branch-specific signaling logic was dissected, showing ERK activation depends on SHIP while Akt depends on Syk/SAP, placing SLAM signaling components in pathway order.","evidence":"DT40 B-cell sublines deficient in SHIP, SAP, Syk, Lyn, or Btk with phospho-Western analysis","pmids":["15315965"],"confidence":"High","gaps":["Cross-talk between ERK and Akt branches not resolved","In vivo relevance of each branch untested"]},{"year":2007,"claim":"Homotypic SLAMF1/SLAMF6 engagement was shown to provide costimulation during NKT selection, defining a physiological ligand context for SLAM signaling.","evidence":"Genetic knockouts and epistasis in in vivo NKT development assays","pmids":["18031695"],"confidence":"High","gaps":["Relative contribution of SLAMF1 versus SLAMF6 not separated"]},{"year":2008,"claim":"The post-binding step was clarified by showing distinct hemagglutinin residues for SLAM binding versus SLAM-triggered fusion, revealing receptor-induced conformational change.","evidence":"Surface plasmon resonance, fusion assays, and crystal-structure-guided mutagenesis","pmids":["18292085"],"confidence":"High","gaps":["Conformational intermediate of the fusion machinery not structurally captured"]},{"year":2010,"claim":"SLAM-blind recombinant viruses formally proved SLAM recognition is required for measles virulence in primates, and SLAM signaling was shown to be selectively required for GC TFH IL-4 production.","evidence":"R533A SLAM-blind MV in rhesus monkeys; SAP/SLAM-deficient mice with GC TFH cytokine staining","pmids":["20071568","20525889"],"confidence":"High","gaps":["Identity of any low-level SLAM-independent entry route in vivo unclear","Mechanism restricting SLAM signaling to IL-4 versus differentiation not defined"]},{"year":2012,"claim":"A non-canonical, ITAM-independent SLAM function was uncovered: recruitment of a Beclin-1/Vps34/UVRAG complex to phagosomes to control NOX2 and phagolysosomal maturation.","evidence":"Co-IP, domain-deletion pulldowns, and NOX2 activity assay in Beclin-1+/- macrophages","pmids":["22493499"],"confidence":"High","gaps":["How the cytoplasmic tail engages Beclin-1 structurally unknown","Relationship to the SAP signaling branch unclear"]},{"year":2015,"claim":"SLAMF1 was linked to autophagy regulation and migratory control in CLL and myeloid cells, extending its role to tumor-cell autophagic flux and inflammation-associated cell movement.","evidence":"siRNA knockdown and agonistic ligation with co-IP and chemotaxis/autophagy assays; Slamf1-/- and Slamf8-/- migration models","pmids":["26619119","25799045"],"confidence":"Medium","gaps":["Mechanistic link between SLAM-driven ROS and migration not fully resolved","Single-lab migration findings"]},{"year":2018,"claim":"The mechanism by which SLAMF1 enables TLR4 IFNβ signaling was defined as Rab11-dependent co-trafficking of TRAM from the recycling compartment to phagosomes via a direct SLAMF1-TRAM interaction.","evidence":"Knockdown/knockout in human macrophages, SLAMF1-TRAM co-IP with domain mapping, trafficking imaging, IFNβ and bacterial killing assays","pmids":["29440514"],"confidence":"High","gaps":["Species-specificity (human vs mouse interaction) mechanism unexplained","How bacterial sensing triggers Rab11-dependent trafficking unclear"]},{"year":2020,"claim":"SLAMF1 was shown to be a target of bacterial immune evasion and a regulator of neutrophil autophagy, broadening its role as a sensor at the host-pathogen interface.","evidence":"Brucella Omp25-SLAMF1 binding with NF-κB/cytokine and mouse infection assays; Mtb-induced SLAMF1/LC3B co-localization and autophagy assays","pmids":["31953913","32954947"],"confidence":"Medium","gaps":["Direct structural detail of Omp25-SLAMF1 contact not resolved","Single-lab observations"]},{"year":null,"claim":"How the diverse SLAMF1 outputs—SAP/Fyn costimulation, TRAM trafficking, and the Beclin-1 autophagy complex—are coordinated or partitioned within a single cell remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No integrated structural model of the cytoplasmic tail engaging SAP versus Beclin-1 versus TRAM","Mechanism selecting between signaling and trafficking functions unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[0,2,5,10,28,29]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[1,4,25,30]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,4,19]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[11]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,3,26,27]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[14,19,22]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[19]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7,11,13,15,20]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,28,29,31]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,4,8,25]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[14,16,22]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[19]}],"complexes":["Beclin-1/Vps34/UVRAG autophagy complex"],"partners":["SH2D1A","SHIP","SHP-2","FYN","LCK","BECN1","TRAM","SLAMF6"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13291","full_name":"Signaling lymphocytic activation molecule","aliases":["CDw150","IPO-3","SLAM family member 1"],"length_aa":335,"mass_kda":37.2,"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. SLAMF1-induced signal-transduction events in T-lymphocytes are different from those in B-cells. Two modes of SLAMF1 signaling seem to exist: one depending on SH2D1A (and perhaps SH2D1B) and another in which protein-tyrosine phosphatase 2C (PTPN11)-dependent signal transduction operates. Initially it has been proposed that association with SH2D1A prevents binding to inhibitory effectors including INPP5D/SHIP1 and PTPN11/SHP-2 (PubMed:11806999). However, signaling is also regulated by SH2D1A which can simultaneously interact with and recruit FYN which subsequently phosphorylates and activates SLAMF1 (PubMed:12458214). Mediates IL-2-independent proliferation of activated T-cells during immune responses and induces IFN-gamma production (By similarity). Downstreaming signaling involves INPP5D, DOK1 and DOK2 leading to inhibited IFN-gamma production in T-cells, and PRKCQ, BCL10 and NFKB1 leading to increased T-cell activation and Th2 cytokine production (By similarity). Promotes T-cell receptor-induced IL-4 secretion by CD4(+) cells (By similarity). Inhibits antigen receptor-mediated production of IFN-gamma, but not IL-2, in CD4(-)/CD8(-) T-cells (By similarity). Required for IL-4 production by germinal centers T follicular helper (T(Fh))cells (By similarity). May inhibit CD40-induced signal transduction in monocyte-derived dendritic cells (PubMed:16317102). May play a role in allergic responses and may regulate allergen-induced Th2 cytokine and Th1 cytokine secretion (By similarity). In conjunction with SLAMF6 controls the transition between positive selection and the subsequent expansion and differentiation of the thymocytic natural killer T (NKT) cell lineage. Involved in the peripheral differentiation of indifferent natural killer T (iNKT) cells toward a regulatory NKT2 type (By similarity). In macrophages involved in down-regulation of IL-12, TNF and nitric oxide in response to lipopolysaccharide (LPS) (By similarity). In B-cells activates the ERK signaling pathway independently of SH2D1A but implicating both, SYK and INPP5D, and activates Akt signaling dependent on SYK and SH2D1A (By similarity). In B-cells also activates p38 MAPK and JNK1 and JNK2 (PubMed:20231852). In conjunction with CD84/SLAMF5 and SLAMF6 may be a negative regulator of the humoral immune response (By similarity). Involved in innate immune response against Gram-negative bacteria in macrophages; probably recognizes OmpC and/or OmpF on the bacterial surface, regulates phagosome maturation and recruitment of the PI3K complex II (PI3KC3-C2) leading to accumulation of PdtIns(3)P and NOX2 activity in the phagosomes (PubMed:20818396) (Microbial infection) Acts as a receptor for Measles virus; also including isoform 4","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q13291/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SLAMF1","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SLAMF1","total_profiled":1310},"omim":[{"mim_id":"609607","title":"NECTIN CELL ADHESION MOLECULE 4; NECTIN4","url":"https://www.omim.org/entry/609607"},{"mim_id":"608849","title":"U2AF HOMOLOGY MOTIF KINASE 1; UHMK1","url":"https://www.omim.org/entry/608849"},{"mim_id":"608510","title":"SH2 DOMAIN-CONTAINING 1B; SH2D1B","url":"https://www.omim.org/entry/608510"},{"mim_id":"603492","title":"SLAM FAMILY, MEMBER 1; SLAMF1","url":"https://www.omim.org/entry/603492"},{"mim_id":"602410","title":"BROMODOMAIN- AND PHD FINGER-CONTAINING PROTEIN; BRPF1","url":"https://www.omim.org/entry/602410"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":59.1}],"url":"https://www.proteinatlas.org/search/SLAMF1"},"hgnc":{"alias_symbol":["CD150","IPO-3","IPO3"],"prev_symbol":["SLAM"]},"alphafold":{"accession":"Q13291","domains":[{"cath_id":"2.60.40.10","chopping":"31-139","consensus_level":"high","plddt":84.7803,"start":31,"end":139},{"cath_id":"2.60.40.10","chopping":"145-229","consensus_level":"high","plddt":89.6195,"start":145,"end":229}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13291","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13291-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13291-F1-predicted_aligned_error_v6.png","plddt_mean":74.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SLAMF1","jax_strain_url":"https://www.jax.org/strain/search?query=SLAMF1"},"sequence":{"accession":"Q13291","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13291.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13291/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13291"}},"corpus_meta":[{"pmid":"15989959","id":"PMC_15989959","title":"SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells.","date":"2005","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/15989959","citation_count":2455,"is_preprint":false},{"pmid":"10972291","id":"PMC_10972291","title":"SLAM (CDw150) is a cellular receptor for measles virus.","date":"2000","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/10972291","citation_count":867,"is_preprint":false},{"pmid":"21219180","id":"PMC_21219180","title":"SLAM family receptors and SAP adaptors in immunity.","date":"2011","source":"Annual review of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/21219180","citation_count":405,"is_preprint":false},{"pmid":"20525889","id":"PMC_20525889","title":"Germinal center T follicular helper cell IL-4 production is dependent on signaling lymphocytic activation molecule receptor (CD150).","date":"2010","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/20525889","citation_count":355,"is_preprint":false},{"pmid":"18031695","id":"PMC_18031695","title":"Homotypic interactions mediated by Slamf1 and Slamf6 receptors control NKT cell lineage development.","date":"2007","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/18031695","citation_count":291,"is_preprint":false},{"pmid":"29622725","id":"PMC_29622725","title":"SLAM-seq defines direct gene-regulatory functions of the BRD4-MYC axis.","date":"2018","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/29622725","citation_count":289,"is_preprint":false},{"pmid":"14523387","id":"PMC_14523387","title":"The SAP and SLAM families in immune responses and X-linked lymphoproliferative disease.","date":"2003","source":"Nature reviews. 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one","url":"https://pubmed.ncbi.nlm.nih.gov/24642916","citation_count":26,"is_preprint":false},{"pmid":"11855632","id":"PMC_11855632","title":"The measles virus hemagglutinin downregulates the cellular receptor SLAM (CD150).","date":"2002","source":"Archives of virology","url":"https://pubmed.ncbi.nlm.nih.gov/11855632","citation_count":25,"is_preprint":false},{"pmid":"26608324","id":"PMC_26608324","title":"Canine Distemper Virus Fusion Activation: Critical Role of Residue E123 of CD150/SLAM.","date":"2015","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/26608324","citation_count":25,"is_preprint":false},{"pmid":"12242590","id":"PMC_12242590","title":"Mouse novel Ly9: a new member of the expanding CD150 (SLAM) family of leukocyte cell-surface receptors.","date":"2002","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/12242590","citation_count":25,"is_preprint":false},{"pmid":"30359773","id":"PMC_30359773","title":"SLAM family receptors in natural killer cells - Mediators of adhesion, activation and inhibition via cis and trans interactions.","date":"2018","source":"Clinical immunology (Orlando, Fla.)","url":"https://pubmed.ncbi.nlm.nih.gov/30359773","citation_count":25,"is_preprint":false},{"pmid":"24941157","id":"PMC_24941157","title":"Role of SLAM family receptors and specific adapter SAP in innate-like lymphocytes.","date":"2014","source":"Critical reviews in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/24941157","citation_count":24,"is_preprint":false},{"pmid":"21645571","id":"PMC_21645571","title":"SLAM and DC-SIGN measles receptor polymorphisms and their impact on antibody and cytokine responses to measles vaccine.","date":"2011","source":"Vaccine","url":"https://pubmed.ncbi.nlm.nih.gov/21645571","citation_count":24,"is_preprint":false},{"pmid":"31953913","id":"PMC_31953913","title":"Omp25-dependent engagement of SLAMF1 by Brucella abortus in dendritic cells limits acute inflammation and favours bacterial persistence in vivo.","date":"2020","source":"Cellular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/31953913","citation_count":23,"is_preprint":false},{"pmid":"30616923","id":"PMC_30616923","title":"SLAMF1/CD150 in hematologic malignancies: Silent marker or active player?","date":"2018","source":"Clinical immunology (Orlando, Fla.)","url":"https://pubmed.ncbi.nlm.nih.gov/30616923","citation_count":22,"is_preprint":false},{"pmid":"38366599","id":"PMC_38366599","title":"SLAM-ITseq identifies that Nrf2 induces liver regeneration through the pentose phosphate pathway.","date":"2024","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/38366599","citation_count":22,"is_preprint":false},{"pmid":"18039911","id":"PMC_18039911","title":"Immunohistochemical demonstration of the putative canine distemper virus receptor CD150 in dogs with and without distemper.","date":"2007","source":"Veterinary pathology","url":"https://pubmed.ncbi.nlm.nih.gov/18039911","citation_count":22,"is_preprint":false},{"pmid":"30911116","id":"PMC_30911116","title":"NK cell recognition of hematopoietic cells by SLAM-SAP families.","date":"2019","source":"Cellular & molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30911116","citation_count":21,"is_preprint":false},{"pmid":"30545927","id":"PMC_30545927","title":"CD150high CD4 T cells and CD150high regulatory T cells regulate hematopoietic stem cell quiescence via CD73.","date":"2018","source":"Haematologica","url":"https://pubmed.ncbi.nlm.nih.gov/30545927","citation_count":21,"is_preprint":false},{"pmid":"21278219","id":"PMC_21278219","title":"Auto-antibody production and glomerulonephritis in congenic Slamf1-/- and Slamf2-/- [B6.129] but not in Slamf1-/- and Slamf2-/- [BALB/c.129] mice.","date":"2011","source":"International 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\"method\": \"Transfection of human SLAM cDNA into non-susceptible cell lines followed by virus binding assay and replication assay\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct receptor reconstitution in heterologous cells, replicated by multiple independent labs\",\n      \"pmids\": [\"10972291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CD150 associates with SH2-containing inositol phosphatase (SHIP) or SH2-containing protein tyrosine phosphatase (SHP-2) via phosphorylated tyrosines Y281 and Y327 in its cytoplasmic tail; the adaptor SH2D1A (SAP) regulates this association by facilitating SHIP binding and blocking SHP-2 binding, acting through a TxYxxV/I immunoreceptor tyrosine-based switch motif (ITSM).\",\n      \"method\": \"Co-immunoprecipitation, GST-fusion protein pulldown with tyrosine-to-phenylalanine mutants (Y269F, Y281F, Y307F, Y327F)\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro mutagenesis with multiple mutants combined with co-IP, identifying specific binding residues\",\n      \"pmids\": [\"11313386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CDw150/SLAM is an expression-cloned receptor for lymphotropic measles virus strains; both lymphotropic and laboratory measles virus strains bind human and marmoset CDw150 but show weak interaction with mouse CDw150; infection via CDw150 is independent of CD46.\",\n      \"method\": \"Expression cloning from B95-8 cDNA library, binding assay with soluble MV H protein, infection of CDw150-transfected CHO and HEK293T cells\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — expression cloning with reconstitution in heterologous cells, independently replicated\",\n      \"pmids\": [\"11145884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Measles virus hemagglutinin (H) protein, but not the fusion protein, is sufficient to downregulate SLAM (CD150) from the cell surface; downregulation can occur through intracellular interactions between H and SLAM in the ER, and also through receptor-mediated binding at the cell surface.\",\n      \"method\": \"Transfection of H protein expression plasmid, confocal microscopy, flow cytometry for surface SLAM levels\",\n      \"journal\": \"Archives of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transfection-based overexpression with two-mechanism dissection, single lab\",\n      \"pmids\": [\"11855632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CD150 co-localizes with the TCR following CD3 triggering and is rapidly and reversibly tyrosine-phosphorylated upon TCR cross-linking; Src-like kinases Lck and Fyn phosphorylate tyrosine residues in the cytoplasmic tail of CD150. SAP binds CD150 via two distinct modes: phosphotyrosine-independent binding to Thr-Ile-Y281-Ala-Gln-Val and phosphotyrosine-dependent binding to Thr-Val-Y327-Ala-Ser-Val; a leucine residue L278 further stabilizes non-phospho binding at Y281. SAP blocks SHP-2 binding primarily at Y281.\",\n      \"method\": \"Confocal microscopy (co-localization), in vitro kinase assay, co-immunoprecipitation, site-directed mutagenesis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay with mutagenesis plus co-localization and co-IP, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"11806999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"SLAM (CD150) is a cellular receptor common to all 28 measles virus strains tested; a single amino acid exchange in the hemagglutinin at position 481 (Asn/Tyr, H481NY) determines whether virus can additionally utilize CD46, demonstrating that the binding sites for SLAM and CD46 on hemagglutinin are distinct.\",\n      \"method\": \"Infection of CHO cells expressing recombinant CD46 or SLAM with a panel of MV strains; recombinant virus with site-directed mutations\",\n      \"journal\": \"The Journal of general virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution in CHO cells with panel of strains plus mutagenesis defining binding determinants\",\n      \"pmids\": [\"12029158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Measles virus can infect SLAM-negative cells at 2–3 log lower efficiency through an unidentified receptor distinct from both SLAM and CD46; this entry is blocked by anti-MV hemagglutinin antibody or fusion block peptide but not by anti-CD46 antibody, and occurs under conditions that inhibit endocytosis.\",\n      \"method\": \"Recombinant EGFP-expressing MV infection of SLAM-negative cell lines, antibody blocking assays, endocytosis inhibition\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reconstitution with multiple blocking conditions, single lab\",\n      \"pmids\": [\"12050387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SLAMF1 (SLAM) knockout macrophages show defective production of IL-12, TNF, and nitric oxide in response to LPS but normal phagocytosis and normal responses to peptidoglycan or CpG; SLAM acts as a co-receptor regulating signals downstream of TLR4. SLAM-deficient CD4+ T cells show reduced TCR-induced IL-4 secretion with only slight upregulation of IFN-γ. SLAM-/- C57Bl/6 mice fail to clear Leishmania major due to defective macrophage function.\",\n      \"method\": \"Targeted gene knockout, in vitro cytokine assays, in vivo infection model (Leishmania major)\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined cellular and in vivo phenotype, multiple independent functional readouts\",\n      \"pmids\": [\"15123745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SAP is required for phosphorylation of SLAM in thymocytes and peripheral T cells; SAP binds directly to both the SH3 domain and kinase domain of FynT, and addition of SAP to autoinhibited FynT causes a large increase in FynT catalytic activity; a SAP mutant (R78E) that cannot bind FynT SH3 domain neither activates FynT nor functions as an adaptor in T cells.\",\n      \"method\": \"In vitro kinase assay, yeast two-hybrid, GST pulldown, transfection with mutant constructs\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with mutagenesis and multiple binding assays demonstrating enzymatic activation\",\n      \"pmids\": [\"15096483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Measles virus hemagglutinin (H) protein interacts with SLAM in the endoplasmic reticulum, promoting SLAM downregulation from the host cell surface; surface interactions between H and SLAM also contribute. H expression alone is sufficient for this downregulation.\",\n      \"method\": \"Plasmid transfection, co-culture experiments, flow cytometry, ER co-localization studies\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transfection-based mechanistic dissection of two pathways, single lab\",\n      \"pmids\": [\"15331699\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"SLAM (CD150) V domain is necessary and sufficient for measles virus receptor function; murine SLAM differs from human SLAM in receptor function due to residues at positions 60, 61, and 63, with histidine 61 being most critical; exchange of the region at amino acids 58–67 allows mouse SLAM to function as an MV receptor.\",\n      \"method\": \"Human/mouse chimeric SLAM constructs assessed by VSV pseudotype assay with site-directed mutagenesis\",\n      \"journal\": \"The Journal of general virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis with functional pseudotype assay precisely mapping critical residues\",\n      \"pmids\": [\"12917459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Homotypic interactions mediated by SLAMF1 and SLAMF6 (Ly108) on cortical thymocytes generate co-stimulatory signals during NKT cell selection; these signals involve downstream recruitment of SAP and Fyn kinase and are required for NKT lineage expansion and differentiation. These interactions only occur when selecting ligands (CD1d) are presented by thymocytes, not by epithelial cells, which do not express Slamf1/Slamf6.\",\n      \"method\": \"Genetic knockout models, epistasis analysis, in vivo NKT development assays\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with epistasis, multiple labs have replicated NKT role for SLAM/SAP\",\n      \"pmids\": [\"18031695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Measles virus hemagglutinin residue isoleucine 194 is essential for primary SLAM binding (as measured by surface plasmon resonance); a quartet of residues on propeller blade 5 is required for SLAM-dependent membrane fusion after binding but not for initial binding, indicating receptor-specific conformational changes post-binding trigger fusion protein unfolding.\",\n      \"method\": \"Surface plasmon resonance, receptor-specific fusion assays, crystal structure localization, site-directed mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structural localization combined with SPR binding assay and functional fusion assay with mutagenesis\",\n      \"pmids\": [\"18292085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SLAMF1 (CD150) signaling via SAP is specifically required for IL-4 production by germinal center T follicular helper (GC TFH) cells; SAP-deficient TFH cells lack GC TFH cells and are defective in IL-4 and IL-21 production; SLAM receptor ligation is required for this IL-4 production but not for TFH or GC TFH cell differentiation.\",\n      \"method\": \"SAP-deficient and SLAM-deficient mouse models, in vivo immunization, FACS-based identification of GC TFH cells, intracellular cytokine staining\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — SLAM-specific KO with rigorous in vivo GC TFH analysis dissecting differentiation vs. cytokine function\",\n      \"pmids\": [\"20525889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In E. coli-containing phagosomes of macrophages, SLAMF1 recruits a Beclin-1/Vps34/UVRAG protein complex; this complex regulates NOX2 (NADPH oxidase 2) activity and phagolysosomal maturation. The interaction requires the cytoplasmic tail of Slamf1 but not its ITAM motifs. Beclin-1 BD and CCD domains are required for binding to Slamf1. Slamf1 does not interact with Atg14L or Rubicon.\",\n      \"method\": \"Co-immunoprecipitation, in vitro pulldown, NOX2 activity assay in Beclin-1+/- macrophages, domain deletion mutagenesis, transfected HEK293 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution with multiple pulldown experiments, domain mutagenesis, and functional NOX2 assay\",\n      \"pmids\": [\"22493499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In the absence of SAP, SLAM family receptors Ly108 and 2B4 recruit increased levels of SHP-1 phosphatase, causing altered SHP-1 localization and decreased Src kinase activation at the immunological synapse. SAP-deficient CD8+ T cells show specific defects in synapse organization with B cell and low-avidity T cell targets (inefficient actin clearance), resulting in impaired cytotoxicity against these targets but not fibrosarcoma targets.\",\n      \"method\": \"SAP-deficient mouse T cells, immunological synapse imaging, phosphatase recruitment assay, cytotoxicity assays\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with detailed mechanistic synapse analysis and multiple functional readouts\",\n      \"pmids\": [\"22683123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SLAMF1 ligation with an agonistic antibody induces ROS accumulation, phosphorylation of p38, JNK1/2, and BCL2, and promotes autophagic flux in CLL cells. Beclin-1 dissociates from BCL2 upon SLAMF1 ligation, forming an autophagy macrocomplex containing SLAMF1, beclin-1, and VPS34. SLAMF1 silencing in CLL cells increases CXCR4, CD38, and CD44 expression and enhances chemotactic responses to CXCL12; SLAMF1-low cells are resistant to autophagy-activating agents.\",\n      \"method\": \"SLAMF1 siRNA knockdown, agonistic antibody ligation, co-immunoprecipitation (SLAMF1/beclin-1/VPS34 complex), ROS assay, autophagic flux assay, transwell chemotaxis assay\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — co-IP of complex with functional autophagy and chemotaxis readouts, multiple orthogonal methods\",\n      \"pmids\": [\"26619119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SLAMF1 and SLAMF8 oppositely regulate in vivo migration of myeloid cells during inflammation: Slamf1-/- dendritic cells and macrophages show reduced migration in vivo and in vitro, whereas Slamf8-/- cells show accelerated migration. These effects are cell-intrinsic. Inhibition of ROS production in Slamf8-/- macrophages blocks their enhanced migration, linking SLAMF1/SLAMF8-mediated ROS regulation to myeloid cell migration.\",\n      \"method\": \"Slamf1-/- and Slamf8-/- mouse models, in vivo migration assays (skin sensitization, peritonitis, intestinal repopulation), transwell migration assay, ROS inhibitor (DPI)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with in vivo and in vitro migration assays plus pharmacological inhibitor, single lab\",\n      \"pmids\": [\"25799045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SLAMF1 engagement by measles virus (MeV) induces macropinocytosis-like endocytic uptake of viral particles dependent on actin cytoskeletal rearrangement, membrane blebbing, and the RhoA-ROCK-myosin II signaling axis; this endocytic entry pathway is specific to SLAMF1-positive cells and occurs within 60 minutes of viral attachment.\",\n      \"method\": \"Live-cell imaging of viral particle colocalization with blebs, chemical inhibition of macropinocytosis/actin dynamics/ROCK-myosin II, infection assay in SLAMF1+ vs SLAMF1- cells\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pharmacological inhibitors and live imaging, single lab\",\n      \"pmids\": [\"28100610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SLAMF1 is required for TLR4-mediated TRAM-TRIF-dependent signaling (IFNβ induction) and killing of Gram-negative bacteria by human macrophages. In resting macrophages, SLAMF1 localizes to the endocytic recycling compartment (ERC) and is trafficked together with TRAM to E. coli phagosomes in a Rab11-dependent manner upon bacterial stimulation. Endogenous SLAMF1 interacts with TRAM via amino acids 68–95 of TRAM and the 15 C-terminal amino acids of SLAMF1; this interaction is observed for human but not mouse proteins.\",\n      \"method\": \"SLAMF1 knockdown/knockout in human macrophages, co-immunoprecipitation (SLAMF1-TRAM), confocal microscopy of ERC-to-phagosome trafficking, domain deletion constructs, IFNβ induction assay, bacterial killing assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — co-IP with domain mutagenesis, live trafficking imaging with functional IFNβ and bacterial killing readouts, multiple orthogonal methods\",\n      \"pmids\": [\"29440514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SLAM family receptors (SFRs), including SLAMF1, promote iNKT cell development by reducing TCR signal strength after positive selection; SFR deficiency upregulates inhibitory receptors (PD-1) to partially compensate; SLAMF6 alone can mimic SFR function and this involves the SAP-Fyn complex and phosphatase SHP-1.\",\n      \"method\": \"SFR-deficient mouse models, SLAMF6 single-receptor rescue experiments, epistasis with SAP/Fyn/SHP-1, iNKT cell development quantification, TCR signal strength assays\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with rescue experiments and multiple pathway components identified\",\n      \"pmids\": [\"30833791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Brucella abortus outer membrane protein Omp25 specifically binds SLAMF1 in vitro; Omp25-dependent SLAMF1 engagement limits NF-κB translocation in dendritic cells, decreases pro-inflammatory cytokine secretion, impairs DC activation, and promotes bacterial persistence at the chronic stage of infection in vivo.\",\n      \"method\": \"In vitro binding assay (Omp25-SLAMF1), NF-κB translocation assay, cytokine measurement, mouse infection model\",\n      \"journal\": \"Cellular microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay plus in vivo infection model, single lab\",\n      \"pmids\": [\"31953913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Human neutrophils upregulate SLAMF1 expression upon Mycobacterium tuberculosis (Mtb) stimulation; SLAMF1 co-localizes with LC3B+ vesicles, and SLAMF1 activation increases neutrophil autophagy induced by Mtb; tuberculosis patients' neutrophils show reduced SLAMF1 levels and lower autophagy.\",\n      \"method\": \"Flow cytometry for SLAMF1 expression, confocal microscopy (SLAMF1/LC3B co-localization), SLAMF1 agonistic antibody activation, autophagy flux assay\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-localization plus functional autophagy assay with agonistic antibody, single lab\",\n      \"pmids\": [\"32954947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"IPO-3 (later identified as CD150/SLAMF1) is a novel heavily N-glycosylated phosphoglycoprotein (~75-95 kDa, 42 kDa protein core) expressed on activated B cells and some T cells; it has an associated protein kinase activity maintained in detergent lysates; cross-linking IPO-3 on B cells triggers increases in intracellular Ca2+ and augments IL-4/anti-CD40-driven proliferation.\",\n      \"method\": \"Monoclonal antibody characterization, in vitro kinase assay, calcium flux assay, proliferation assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase assay and functional signaling assay, single lab at time of initial characterization\",\n      \"pmids\": [\"8409422\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CD150 (SLAMF1)-mediated T cell DNA synthesis (proliferation) induced by anti-CD150 antibody does not depend on SAP/SH2D1A, as similar levels are observed in SAP-/- T cells; however, SAP-/- T cells show higher IFN-γ production than WT upon anti-CD150 stimulation. Anti-CD150 cross-linking on CD4 T cells induces rapid serine phosphorylation of Akt/PKB.\",\n      \"method\": \"SAP-/- mouse T cells, anti-CD150 antibody stimulation, DNA synthesis assay, IFN-γ ELISA, Akt phosphorylation assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic KO with multiple functional readouts, single lab\",\n      \"pmids\": [\"12351401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CD150 (SLAMF1)-induced ERK pathway activation in B cells requires SHIP but not SH2D1A (SAP); CD150-mediated Akt phosphorylation requires Syk and SH2D1A and is negatively regulated by Lyn and Btk; Lyn directly phosphorylates Y327 in CD150; the Akt pathway does not depend on CD150 tyrosine phosphorylation or CD150-SHP-2 association.\",\n      \"method\": \"DT40 B-cell sublines deficient in SHIP, SAP, Syk, Lyn, or Btk; CD150 ligation, Western blotting for ERK/Akt phosphorylation\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis using multiple DT40 deficient lines with defined signaling pathway placement\",\n      \"pmids\": [\"15315965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"SLAM (CD150) is downregulated from the surface of activated peripheral blood lymphocytes and cell lines after measles virus infection or surface contact with MV envelope proteins; blocking SLAM or CD46 prevents virus binding but does not interfere with contact-mediated proliferation inhibition, indicating these are separable functions.\",\n      \"method\": \"Flow cytometry for SLAM surface expression, antibody blocking assays, proliferation assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional dissection using blocking antibodies with multiple readouts, single lab\",\n      \"pmids\": [\"11312320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"SLAM (CD150) is inducible on monocytes (which are SLAM-negative at rest) after stimulation with PHA, LPS, or MV; anti-SLAM monoclonal antibodies efficiently block MV infection of activated monocytes with a wild-type strain.\",\n      \"method\": \"Flow cytometry for SLAM induction on monocytes, blocking antibody assay for MV infection\",\n      \"journal\": \"The Journal of general virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional blocking assay combined with induction kinetics, single lab\",\n      \"pmids\": [\"11714966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CDV unable to recognize SLAM (CD150) does not spread in ferrets, formally proving that SLAM recognition is necessary for morbillivirus virulence and for lymphocyte-based dissemination into mucosal tissue and lymphatic organs.\",\n      \"method\": \"Recombinant CDV with receptor-ablating mutations in ferret infection model, GFP-reporter virus tracking\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — recombinant SLAM-blind virus in relevant animal model with rigorous controls\",\n      \"pmids\": [\"16731947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"A recombinant measles virus with a single R533A substitution in hemagglutinin that is selectively unable to recognize SLAM (SLAM-blind) infects primary lymphocytes at low levels regardless of SLAM expression and causes no viremia or clinical symptoms in rhesus monkeys, formally proving that efficient SLAM recognition is necessary for MV virulence and pathogenesis.\",\n      \"method\": \"Site-directed mutagenesis of MV hemagglutinin, ex vivo lymphocyte infection assay, rhesus monkey intranasally inoculation model\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — single amino acid mutant virus in primate animal model formally proving receptor requirement\",\n      \"pmids\": [\"20071568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"SLAM (CD150) augments TCR-mediated cytotoxicity in both CD4+ and CD8+ T cells; SLAM engagement alone triggers cytotoxicity in herpesvirus saimiri-transformed T cells via lytic granule release, requiring extracellular Ca2+, cytoskeletal rearrangements, and MEK1/2 signaling, independent of CD95.\",\n      \"method\": \"Antibody crosslinking of SLAM on primary and transformed T cells, cytotoxicity assay, pharmacological inhibitors (MEK1/2, cytoskeletal), Ca2+ chelation\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional cytotoxicity assays with pharmacological dissection, single lab\",\n      \"pmids\": [\"11536173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Slamf1-/- mice are completely protected from acute lethal Trypanosoma cruzi challenge; Slamf1-deficient myeloid cells are impaired in intracellular T. cruzi replication and show altered cytokine production; IFN-γ production is reduced in the heart of Slamf1-/- mice despite comparable immune cell infiltration.\",\n      \"method\": \"Slamf1-/- mouse infection model, in vitro parasite replication assay in myeloid cells, cytokine measurement, anti-Slamf1 monoclonal antibody treatment\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with in vivo infection model and in vitro myeloid cell assays, single lab\",\n      \"pmids\": [\"22807679\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLAMF1 (CD150/SLAM) is a homophilic Ig-superfamily receptor on hematopoietic cells that functions as the primary entry receptor for morbilliviruses (measles, CDV, rinderpest) via its V domain, and as a co-stimulatory and innate immune signaling receptor that recruits SAP/SH2D1A to its cytoplasmic ITSM motifs (particularly phospho-Y281 and phospho-Y327), enabling SAP-mediated activation of FynT kinase, regulation of SHP-2 and SHIP phosphatase access, downstream ERK/Akt/NF-κB signaling, and control of cytokine production (IL-4, IFN-γ, IFNβ), cytotoxicity, autophagy (via a Beclin-1/Vps34/UVRAG complex), NADPH oxidase activity in phagocytes, and myeloid cell migration; in TLR4 signaling, SLAMF1 traffics TRAM from the endocytic recycling compartment to bacterial phagosomes in a Rab11-dependent manner to enable TRIF-dependent IFNβ induction.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SLAMF1 (CD150/SLAM) is a hematopoietic Ig-superfamily receptor that operates both as a costimulatory/innate immune signaling receptor and as the entry receptor for morbilliviruses [#0, #7]. Its membrane-distal V domain is necessary and sufficient for measles virus receptor function, with residues around positions 58\\u201367 (especially His61) determining the human-versus-mouse species barrier [#10]; SLAM serves as a common receptor for all measles strains tested and binds hemagglutinin at a site distinct from CD46 [#5]. SLAM recognition drives macropinocytosis-like viral uptake and triggers receptor-specific conformational changes in hemagglutinin that license membrane fusion [#12, #18], and SLAM-blind morbiliviruses are avirulent in ferret and primate models, establishing receptor engagement as essential for pathogenesis [#28, #29]. In signaling, SLAMF1 is tyrosine-phosphorylated by Src-family kinases Lck/Fyn on cytoplasmic ITSM tyrosines Y281 and Y327, which recruit the adaptor SAP/SH2D1A; SAP binds these motifs and governs the balance of SHIP versus SHP-2/SHP-1 phosphatase access, while SAP also binds and activates FynT to propagate signaling [#1, #4, #8]. This SLAM\\u2013SAP\\u2013Fyn axis mediates homotypic costimulation during NKT/iNKT cell selection and is required for IL-4 production by germinal center T follicular helper cells and for cytotoxic synapse organization [#11, #13, #15, #20]. Downstream, SLAMF1 ligation activates ERK (via SHIP) and Akt (via Syk/SAP) pathways and controls cytokine output [#25]. As a TLR4 co-receptor, SLAMF1 regulates LPS-induced IL-12/TNF/NO production and, in human macrophages, traffics from the endocytic recycling compartment with TRAM to bacterial phagosomes in a Rab11-dependent manner to enable TRIF-dependent IFN\\u03b2 induction and Gram-negative bacterial killing [#7, #19]. In phagosomes SLAMF1 recruits a Beclin-1/Vps34/UVRAG complex through its cytoplasmic tail to regulate NOX2 activity, phagolysosomal maturation, and autophagy [#14, #16]. These functions place SLAMF1 at the center of host defense against intracellular pathogens including Leishmania and Trypanosoma cruzi [#7, #31].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Before its identity was known, the antigen IPO-3 was characterized as an activation-induced glycoprotein with signaling capacity, establishing that SLAMF1 transduces lymphocyte activation signals.\",\n      \"evidence\": \"Monoclonal antibody characterization with in vitro kinase, calcium flux, and proliferation assays on activated B cells\",\n      \"pmids\": [\"8409422\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular identity and cytoplasmic signaling motifs not yet defined\", \"Associated kinase not identified\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"The question of which receptor measles virus uses was answered by showing SLAM confers susceptibility, defining SLAMF1 as a virus entry receptor.\",\n      \"evidence\": \"Transfection of human SLAM cDNA into non-susceptible cells with virus binding and replication assays\",\n      \"pmids\": [\"10972291\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding domain on SLAM not mapped\", \"Post-binding entry mechanism unknown\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"How SLAMF1 couples to intracellular signaling was established by identifying ITSM tyrosines that recruit SAP, SHIP, and SHP-2, defining the adaptor switch logic.\",\n      \"evidence\": \"Co-IP and GST pulldown with Y-to-F mutants of the cytoplasmic tail\",\n      \"pmids\": [\"11313386\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinases responsible for tyrosine phosphorylation not identified here\", \"Functional consequences of phosphatase switching untested\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"The kinases and dual binding modes governing SLAM signaling were resolved, showing Lck/Fyn phosphorylate the tail and SAP binds Y281/Y327 by phospho-dependent and phospho-independent modes.\",\n      \"evidence\": \"In vitro kinase assay, co-localization, co-IP, and site-directed mutagenesis\",\n      \"pmids\": [\"11806999\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effectors of SAP not yet defined\", \"Quantitative contribution of each binding mode in vivo unknown\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"SLAM was shown to be the universal measles receptor across strains while CD46 usage maps to a separable hemagglutinin determinant, distinguishing the two receptor binding sites.\",\n      \"evidence\": \"Infection of CHO cells expressing CD46 or SLAM with a strain panel plus recombinant mutant virus\",\n      \"pmids\": [\"12029158\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-level SLAM-binding interface not resolved here\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"The receptor-determining region was mapped to the SLAM V domain, with residues 58\\u201367 and His61 explaining the human/mouse species barrier.\",\n      \"evidence\": \"Human/mouse chimeric SLAM constructs in VSV pseudotype assays with mutagenesis\",\n      \"pmids\": [\"12917459\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of His61 contribution not solved\", \"Other ectodomain contacts not excluded\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"The downstream output of SAP was defined as direct FynT activation, linking SLAM engagement to a catalytic signaling event.\",\n      \"evidence\": \"Yeast two-hybrid, GST pulldown, and in vitro kinase assay with SAP R78E mutant\",\n      \"pmids\": [\"15096483\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrates of activated FynT downstream of SLAM not enumerated\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Genetic deletion established SLAMF1 as a TLR4 co-receptor and an in vivo determinant of macrophage antimicrobial function and T cell cytokine polarization.\",\n      \"evidence\": \"Targeted knockout with cytokine assays and Leishmania major infection model\",\n      \"pmids\": [\"15123745\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism linking SLAM to TLR4 signaling not defined here\", \"TLR-specificity rationale unexplained\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Branch-specific signaling logic was dissected, showing ERK activation depends on SHIP while Akt depends on Syk/SAP, placing SLAM signaling components in pathway order.\",\n      \"evidence\": \"DT40 B-cell sublines deficient in SHIP, SAP, Syk, Lyn, or Btk with phospho-Western analysis\",\n      \"pmids\": [\"15315965\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cross-talk between ERK and Akt branches not resolved\", \"In vivo relevance of each branch untested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Homotypic SLAMF1/SLAMF6 engagement was shown to provide costimulation during NKT selection, defining a physiological ligand context for SLAM signaling.\",\n      \"evidence\": \"Genetic knockouts and epistasis in in vivo NKT development assays\",\n      \"pmids\": [\"18031695\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of SLAMF1 versus SLAMF6 not separated\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"The post-binding step was clarified by showing distinct hemagglutinin residues for SLAM binding versus SLAM-triggered fusion, revealing receptor-induced conformational change.\",\n      \"evidence\": \"Surface plasmon resonance, fusion assays, and crystal-structure-guided mutagenesis\",\n      \"pmids\": [\"18292085\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conformational intermediate of the fusion machinery not structurally captured\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"SLAM-blind recombinant viruses formally proved SLAM recognition is required for measles virulence in primates, and SLAM signaling was shown to be selectively required for GC TFH IL-4 production.\",\n      \"evidence\": \"R533A SLAM-blind MV in rhesus monkeys; SAP/SLAM-deficient mice with GC TFH cytokine staining\",\n      \"pmids\": [\"20071568\", \"20525889\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of any low-level SLAM-independent entry route in vivo unclear\", \"Mechanism restricting SLAM signaling to IL-4 versus differentiation not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"A non-canonical, ITAM-independent SLAM function was uncovered: recruitment of a Beclin-1/Vps34/UVRAG complex to phagosomes to control NOX2 and phagolysosomal maturation.\",\n      \"evidence\": \"Co-IP, domain-deletion pulldowns, and NOX2 activity assay in Beclin-1+/- macrophages\",\n      \"pmids\": [\"22493499\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the cytoplasmic tail engages Beclin-1 structurally unknown\", \"Relationship to the SAP signaling branch unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"SLAMF1 was linked to autophagy regulation and migratory control in CLL and myeloid cells, extending its role to tumor-cell autophagic flux and inflammation-associated cell movement.\",\n      \"evidence\": \"siRNA knockdown and agonistic ligation with co-IP and chemotaxis/autophagy assays; Slamf1-/- and Slamf8-/- migration models\",\n      \"pmids\": [\"26619119\", \"25799045\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between SLAM-driven ROS and migration not fully resolved\", \"Single-lab migration findings\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The mechanism by which SLAMF1 enables TLR4 IFN\\u03b2 signaling was defined as Rab11-dependent co-trafficking of TRAM from the recycling compartment to phagosomes via a direct SLAMF1-TRAM interaction.\",\n      \"evidence\": \"Knockdown/knockout in human macrophages, SLAMF1-TRAM co-IP with domain mapping, trafficking imaging, IFN\\u03b2 and bacterial killing assays\",\n      \"pmids\": [\"29440514\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Species-specificity (human vs mouse interaction) mechanism unexplained\", \"How bacterial sensing triggers Rab11-dependent trafficking unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"SLAMF1 was shown to be a target of bacterial immune evasion and a regulator of neutrophil autophagy, broadening its role as a sensor at the host-pathogen interface.\",\n      \"evidence\": \"Brucella Omp25-SLAMF1 binding with NF-\\u03baB/cytokine and mouse infection assays; Mtb-induced SLAMF1/LC3B co-localization and autophagy assays\",\n      \"pmids\": [\"31953913\", \"32954947\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct structural detail of Omp25-SLAMF1 contact not resolved\", \"Single-lab observations\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the diverse SLAMF1 outputs\\u2014SAP/Fyn costimulation, TRAM trafficking, and the Beclin-1 autophagy complex\\u2014are coordinated or partitioned within a single cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No integrated structural model of the cytoplasmic tail engaging SAP versus Beclin-1 versus TRAM\", \"Mechanism selecting between signaling and trafficking functions unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [0, 2, 5, 10, 28, 29]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [1, 4, 25, 30]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 4, 19]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3, 26, 27]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [14, 19, 22]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7, 11, 13, 15, 20]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 28, 29, 31]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 4, 8, 25]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [14, 16, 22]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [19]}\n    ],\n    \"complexes\": [\n      \"Beclin-1/Vps34/UVRAG autophagy complex\"\n    ],\n    \"partners\": [\n      \"SH2D1A\",\n      \"SHIP\",\n      \"SHP-2\",\n      \"FYN\",\n      \"LCK\",\n      \"BECN1\",\n      \"TRAM\",\n      \"SLAMF6\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}