{"gene":"CD300A","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":1999,"finding":"CD300a (IRp60) is an inhibitory receptor on NK cells that, upon tyrosine phosphorylation (induced by sodium pervanadate), associates with the SH2-containing phosphatases SHP-1 and SHP-2, thereby inhibiting NK cell cytotoxicity.","method":"Monoclonal antibody generation, cross-linking assays, co-immunoprecipitation after pervanadate treatment","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP with functional inhibition readout, replicated across multiple activating receptor contexts","pmids":["10540326"],"is_preprint":false},{"year":2000,"finding":"CD300a (CMRF-35H) gene is located on human chromosome 17, encodes a single V-type Ig-like domain extracellular protein with three ITIMs in its cytoplasmic tail, and spans ~12 kb with seven exons.","method":"Genomic clone isolation, intron-exon organization mapping, chromosomal mapping","journal":"Tissue antigens","confidence":"High","confidence_rationale":"Tier 1 — direct genomic structural characterization","pmids":["10746781"],"is_preprint":false},{"year":2005,"finding":"CD300a (IRp60) cross-linking on human mast cells inhibits IgE-induced degranulation and SCF-mediated survival via tyrosine phosphorylation, phosphatase recruitment (SHP-1/SHP-2), and termination of cellular calcium influx.","method":"Cross-linking with monoclonal antibodies, flow cytometry (Ca2+ flux), tryptase/IL-4 release assays, murine allergic peritonitis model with CD300a neutralization","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (signaling, degranulation, in vivo), strong functional consequence","pmids":["16339535"],"is_preprint":false},{"year":2005,"finding":"CD300a (IRp60) cross-linking on human eosinophils inhibits IL-5-mediated JAK2 phosphorylation and eotaxin/IL-5/GM-CSF-mediated ERK1/2 and p38 phosphorylation; CD300a undergoes tyrosine phosphorylation and recruits SHP-1 but not SHP-2 in eosinophils.","method":"Cross-linking assays, Western blotting for phosphorylation, transmigration assays, cytokine/apoptosis assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — multiple signaling readouts with pathway placement, clean mechanistic follow-up","pmids":["16254138"],"is_preprint":false},{"year":2006,"finding":"CD300a co-aggregation with IgE receptor (via bispecific antibody) inhibits IgE-mediated mast cell degranulation by inhibiting FcεRI signaling events including calcium influx; linkage of CD300a to CCR3 similarly inhibits eosinophil and mast cell activation and reverses airway inflammation in a chronic asthma model.","method":"Bispecific antibody fragment generation, phosphorylation/calcium flux FACS, degranulation assays, murine passive cutaneous anaphylaxis and airway inflammation models","journal":"Journal of allergy and clinical immunology","confidence":"High","confidence_rationale":"Tier 2 — bispecific antibody strategy with multiple signaling readouts and in vivo functional validation","pmids":["16750992","17088133"],"is_preprint":false},{"year":2006,"finding":"CD300a extracellular domain adopts a monomeric immunoglobulin-like fold in solution, as determined by SAXS and homology modeling.","method":"Recombinant protein expression/refolding from E. coli, small-angle X-ray scattering (SAXS), homology modeling","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 1 — structural characterization, but no mutagenesis or functional validation in same study","pmids":["16949664"],"is_preprint":false},{"year":2007,"finding":"CD300a surface expression on human neutrophils is rapidly increased by LPS and GM-CSF via translocation of an intracellular pool to the cell surface; co-ligation of CD300a with FcγRIIa (CD32a) inhibits FcγRIIa-mediated signaling selectively without inhibiting TLR4-mediated ROS production.","method":"Flow cytometry, HL-60 differentiation model, co-ligation assays","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 — clean co-ligation functional readout with selective pathway inhibition demonstrated","pmids":["17588661"],"is_preprint":false},{"year":2008,"finding":"CD300a co-aggregation with Kit (CD117) via bispecific antibody inhibits SCF-induced signaling in mast cells, which is mediated by Kit-driven tyrosine phosphorylation of CD300a and recruitment of SHIP-1 (but not SHP-1); this impairs mast cell differentiation, survival, and activation.","method":"Bispecific antibody library, co-immunoprecipitation, Western blotting, in vitro differentiation/survival assays, murine cutaneous anaphylaxis model","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP, multiple functional readouts, phosphatase discrimination, in vivo validation","pmids":["18424727"],"is_preprint":false},{"year":2008,"finding":"CD300a/c triggering on plasmacytoid dendritic cells reduces TNF-α and increases IFN-α secretion in response to TLR7/9 ligands; IFN-α feeds back to down-regulate CD300a/c expression.","method":"Cross-linking antibody stimulation, cytokine ELISA, neutralizing antibody experiments","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 — clean functional readout with neutralizing antibody confirmation of IFN-α feedback loop","pmids":["18535206"],"is_preprint":false},{"year":2011,"finding":"CD300a extracellular domain (as Fc fusion protein) specifically binds phosphatidylserine (PS) exposed on apoptotic cells; PS binding induces SHP-1 recruitment by CD300a in mast cells in response to LPS.","method":"CD300a-Fc fusion protein, binding assay to apoptotic cells, SHP-1 co-immunoprecipitation","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 2 — direct ligand identification with functional phosphatase recruitment readout","pmids":["22185693"],"is_preprint":false},{"year":2011,"finding":"CD300a co-ligation with BCR on B cells inhibits Ca2+ mobilization and NFAT transcriptional activity; siRNA knockdown of CD300a increases BCR-mediated proliferation, confirming its inhibitory capacity.","method":"Co-ligation assays, calcium mobilization FACS, NFAT reporter assay, siRNA knockdown, proliferation assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including siRNA confirmation of inhibitory function","pmids":["21482706"],"is_preprint":false},{"year":2012,"finding":"CD300a binds phosphatidylethanolamine (PE) and phosphatidylserine (PS) on dead cells; mutational studies identified residues forming a cavity in the IgV domain where PE/PS hydrophilic heads penetrate; CD300a down-regulates macrophage phagocytosis of apoptotic cells and its ectopic expression in CD300a-negative lines decreases engulfment.","method":"Surface plasmon resonance, ultracentrifugation, ELISA, reporter cell assays, site-directed mutagenesis, structural modeling, phagocytosis assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 — multiple biophysical methods, mutagenesis identifying binding residues, functional validation","pmids":["22302738"],"is_preprint":false},{"year":2012,"finding":"CD300a is a non-phagocytic PS receptor on mast cells that delivers an inhibitory signal suppressing LPS-induced inflammatory cytokine and chemokine production; after apoptotic cell accumulation in vivo (cecal ligation and puncture), CD300a-PS interaction suppresses neutrophil chemoattractant release from mast cells.","method":"CD300a-deficient mice, peritoneal mast cell isolation, cytokine/chemokine measurement, CLP model, antibody blockade of CD300a-PS interaction","journal":"Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with specific cellular phenotype, antibody blockade confirmation, in vivo infection model","pmids":["22826299"],"is_preprint":false},{"year":2012,"finding":"CD300a ITIM tyrosine phosphorylation requires the src kinase Lck; phosphorylated ITIMs dock both SHP-1 and SHP-2, but only SHP-1 is required for CD300a inhibitory activity, as shown by siRNA knockdown and phosphatase-deficient DT40 cell lines.","method":"KIR-CD300a chimeric receptor in Jurkat T cells, siRNA knockdown of SHP-1/SHP-2/SHIP, DT40 phosphatase-deficient cell lines, calcium mobilization and proliferation assays","journal":"BMC immunology","confidence":"High","confidence_rationale":"Tier 1 — reconstituted chimeric receptor system, mutagenesis of ITIMs, genetic dissection of phosphatases","pmids":["22537350"],"is_preprint":false},{"year":2012,"finding":"CD300a selectively blocks TLR4/MyD88 and TLR9/MyD88-mediated pro-inflammatory signaling through SHP-1 activation, but does not block TLR3/TRIF-mediated signaling (unlike CD300f which requires combined SHP-1 and SHP-2); ITIM peptides of CD300a mimic this selective inhibition.","method":"THP-1/U937 stimulation with TLR ligands, luciferase NF-κB reporter assay, Western blotting, synthetic ITIM peptides, signaling inhibitors","journal":"Immunology","confidence":"High","confidence_rationale":"Tier 2 — multiple signaling pathway dissection with reporter assays and peptide validation","pmids":["22043923"],"is_preprint":false},{"year":2013,"finding":"CD300a and CD300c both bind PS and additional unknown ligand(s) on tumor cells; blocking PS-CD300a interaction increases NK cell killing of tumor cells, demonstrating a tumor immune evasion mechanism.","method":"Anti-CD300a monoclonal antibody generation, NK cell cytotoxicity assays, antibody blocking experiments","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — functional blocking with specific readout, but unknown additional ligand","pmids":["23640773"],"is_preprint":false},{"year":2013,"finding":"CD300C delivers FcRγ-dependent activating signals in mast cells and monocytes; CD300A and CD300C differ in ligand recognition at residues F56-L57 (CD300A) vs. L63-R64 (CD300C), with PE binding more strongly to CD300A; CD300A expression is dominant over CD300C in PE recognition/signaling when co-expressed.","method":"Epitope-discriminating antibodies, reporter cell lines expressing CD300A/C-CD3ζ chimeras, GFP reporter assay, cytokine production assays, co-expression experiments","journal":"Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — chimeric reporter system, residue-level mapping of ligand discrimination, functional co-expression dominance demonstrated","pmids":["23372157"],"is_preprint":false},{"year":2013,"finding":"CD300a mRNA and protein are upregulated following monocyte transendothelial migration; CD300a engagement reduces monocyte transmigration, siRNA knockdown increases transmigration rate, and activated CD300a causes F-actin cytoskeleton alterations and co-localizes with actin filaments.","method":"Transcriptional profiling, siRNA knockdown, anti-CD300a antibody treatment, migration assays, co-sedimentation with actin, immunofluorescence","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — siRNA + antibody + actin localization with functional consequence in migration","pmids":["24058511"],"is_preprint":false},{"year":2014,"finding":"PPARβ/δ directly regulates CD300a transcription in macrophages; CD300a-deficient mice on high-fat diet develop chronic intestinal inflammation with prolonged IL-6 secretion from macrophages in response to LPS/TLR4-MyD88 signaling.","method":"CD300a KO mice, high-fat diet model, bone marrow transplantation, LPS stimulation, cytokine measurement","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with defined cellular phenotype and pathway placement, bone marrow transplant confirms leukocyte origin","pmids":["24958459"],"is_preprint":false},{"year":2015,"finding":"CD300a binds DENV particles directly via PE (predominantly) and PS on the viral envelope, acting as an attachment factor that enhances DENV internalization through clathrin-mediated endocytosis; mutation of IgV domain residues critical for phospholipid binding abrogates CD300a-mediated viral enhancement.","method":"CD300a-Ig fusion binding to DENV, clathrin inhibitor experiments, site-directed mutagenesis of phospholipid-binding residues, viral infection assays, antibody inhibition in primary macrophages","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1 — direct binding assay, mutagenesis of functional residues, endocytosis pathway identification","pmids":["26468529"],"is_preprint":false},{"year":2015,"finding":"CD300a on inflammatory dendritic cells binds PS on apoptotic cells generated by alum adjuvant, promoting Th2 immune responses; CD300a-deficient mice show reduced eosinophilia, IgE, and airway hyperreactivity after alum+OVA immunization, and their DCs induce less IL-4 from CD4+ T cells.","method":"CD300a KO mice, allergic airway inflammation model, DC purification and co-culture, neutralizing antibody blockade","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic KO, neutralizing antibody, cell-type specific functional readout","pmids":["25911756"],"is_preprint":false},{"year":2015,"finding":"Pseudorabies virus US3 kinase triggers increased CD300a binding to the surface of infected cells via aminophospholipid ligands and group I p21-activated kinases (PAKs), thereby protecting virus-infected cells from NK cell-mediated lysis.","method":"Virus infection assays, NK cell cytotoxicity assays, PAK inhibitors, aminophospholipid manipulation","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 — functional NK lysis assay with inhibitor dissection of PAK pathway, mechanism linked to CD300a ligand exposure","pmids":["26581992"],"is_preprint":false},{"year":2021,"finding":"CD300a on brain myeloid cells inhibits efferocytosis of apoptotic cells by blocking CD300b-DAP12 signaling; CD300a deficiency enhances efferocytosis, reduces DAMP release, and attenuates neurological deficit after ischemic stroke; anti-CD300a neutralizing antibody ameliorates stroke outcome.","method":"CD300a KO mice, MCAO model, efferocytosis assays, DAMP measurement, neutralizing antibody treatment, neurological scoring","journal":"Science immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic KO + antibody blockade with defined pathway (CD300b-DAP12) and multiple functional readouts","pmids":["34652960"],"is_preprint":false},{"year":2021,"finding":"CD300a on dendritic cells inhibits tumor-derived extracellular vesicle (TEV)-mediated TLR3-TRIF signaling for IFN-β production; TEV co-culture with DCs induces CD300a internalization and incorporation of EVs into endosomes where CD300a suppresses TLR3-TRIF-IFN-β-Treg axis, resulting in Treg accumulation and tumor growth.","method":"CD300a KO mice, B16 melanoma transplantation, EV pharmacological inhibition, DC-TEV co-culture, endosomal fractionation, tumor-infiltrating Treg cell counting","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — genetic KO, pharmacological EV inhibition, endosomal pathway mechanism with multiple orthogonal readouts","pmids":["34751648"],"is_preprint":false},{"year":2021,"finding":"CD300a deficiency impairs neutrophil phagocytic ability during urinary tract infection despite increased accumulation at the infection site; UPEC's α-hemolysin toxin induces upregulation of CD300a ligands on infected bladder epithelial cells.","method":"CD300a KO mice, UPEC infection model, phagocytosis assays, bacterial burden measurement, α-hemolysin stimulation","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with specific phagocytic phenotype and ligand induction mechanism","pmids":["34268737"],"is_preprint":false},{"year":2021,"finding":"CD300a agonistic antibody induces apoptosis of human neutrophils via caspase-8 cleavage, contributing to resolution of MSU crystal-induced articular inflammation; CD300a KO mice show persistent neutrophil influx and reduced efferocytosis after MSU injection.","method":"CD300a KO mice, MSU crystal gout model, agonistic antibody treatment, caspase-8 cleavage assay, efferocytosis quantification","journal":"Immunology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO + agonistic antibody with caspase-8 pathway identification","pmids":["34002852"],"is_preprint":false},{"year":2023,"finding":"PPARβ/δ agonist GW0742 increases CD300a expression and SHP-1 phosphorylation in mast cells, reducing Syk phosphorylation and mast cell degranulation after germinal matrix hemorrhage; CD300a siRNA abolishes the protective effects.","method":"GMH rat model, siRNA knockdown of PPARβ/δ and CD300a, Western blotting for SHP-1 and Syk phosphorylation, mast cell degranulation markers","journal":"Experimental neurology","confidence":"Medium","confidence_rationale":"Tier 2 — siRNA validation of pathway (PPARβ/δ→CD300a→SHP1→Syk inhibition) with in vivo model","pmids":["37995951"],"is_preprint":false},{"year":2025,"finding":"CD300a and CD300lf cooperate to inhibit mast cell activation; both receptors co-localize with PS externalized on the outer leaflet upon activation with polar formation; CD300lf additionally binds extracellular ceramide, providing stronger inhibition than PS binding alone; double KO mice show more severe anaphylaxis than single KOs.","method":"KO mouse bone marrow-derived mast cells (single and double KO), imaging and flow cytometry for receptor localization, passive systemic anaphylaxis model with temperature readout","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic double KO epistasis, imaging-based co-localization, in vivo anaphylaxis model with graded phenotypes","pmids":["40073110"],"is_preprint":false},{"year":2024,"finding":"CD300a specifically modulates PE-mediated phagocytic uptake by macrophages; CD300a and CD300b engage PE on apoptotic cells and extracellular vesicles through ITAM-containing adaptors and Syk kinase; CD300a expression curtails inflammatory responses of macrophages to PE particles containing LPS.","method":"Phagocytosis assays with PE-coated particles, CD300 family receptor knockdown/expression, Syk inhibitor experiments, LPS inflammatory response measurement","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — direct phagocytosis assay with pathway identification, but preprint not yet peer-reviewed","pmids":["bio_10.1101_2024.11.18.624161"],"is_preprint":true}],"current_model":"CD300a is a type I transmembrane ITIM-containing inhibitory immunoreceptor that binds phosphatidylserine (PS) and phosphatidylethanolamine (PE) exposed on apoptotic cells, activated cells, and enveloped viruses through a cavity in its IgV extracellular domain; upon ligation, CD300a ITIMs are phosphorylated (requiring Lck in T cells), recruiting primarily SHP-1 (and in some contexts SHIP-1) to suppress downstream signaling pathways including FcεRI, BCR, FcγRIIa, Kit, TLR4/9-MyD88, and CD300b-DAP12, thereby inhibiting immune cell activation, promoting apoptosis in neutrophils via caspase-8, modulating efferocytosis, and serving as an entry factor for dengue and other enveloped viruses."},"narrative":{"teleology":[{"year":1999,"claim":"Establishing CD300a as an inhibitory receptor resolved whether this orphan Ig-superfamily molecule functioned as an activating or inhibitory regulator of NK cytotoxicity, showing it recruits SHP-1 and SHP-2 upon ITIM phosphorylation to suppress killing.","evidence":"Cross-linking and co-immunoprecipitation after pervanadate treatment in human NK cells","pmids":["10540326"],"confidence":"High","gaps":["Physiological ligand unknown","Relative contribution of SHP-1 vs SHP-2 not determined","Receptor structure not yet characterized"]},{"year":2000,"claim":"Gene structure characterization defined CD300a as a single IgV-domain type I transmembrane protein with three ITIMs, establishing the molecular framework for subsequent signaling studies.","evidence":"Genomic clone isolation, exon-intron mapping, chromosomal localization to 17q25","pmids":["10746781"],"confidence":"High","gaps":["No crystal structure","ITIM functional hierarchy not tested"]},{"year":2005,"claim":"Extension beyond NK cells demonstrated CD300a inhibits FcεRI/Kit-driven mast cell degranulation and IL-5/eotaxin/GM-CSF signaling in eosinophils, establishing it as a broadly acting inhibitory receptor on innate effector cells; SHP-1 but not SHP-2 was required in eosinophils.","evidence":"Cross-linking assays, calcium flux, degranulation, and signaling Western blots in human mast cells and eosinophils; murine allergic peritonitis model","pmids":["16339535","16254138"],"confidence":"High","gaps":["Ligand still unidentified","In vivo role in allergy only partially addressed"]},{"year":2006,"claim":"Bispecific antibody co-aggregation strategy proved CD300a can be therapeutically redirected to inhibit FcεRI and CCR3 signaling, reversing airway inflammation in vivo, while SAXS revealed the extracellular domain is a monomeric Ig-fold.","evidence":"Bispecific antibody constructs with degranulation/calcium readouts; murine passive cutaneous anaphylaxis and airway inflammation models; SAXS structural analysis","pmids":["16750992","17088133","16949664"],"confidence":"High","gaps":["No atomic-resolution structure","Natural ligand unknown","Mechanism of co-ligation selectivity unclear"]},{"year":2007,"claim":"Discovery that LPS and GM-CSF rapidly upregulate CD300a surface expression from intracellular stores on neutrophils, and that CD300a selectively inhibits FcγRIIa but not TLR4-mediated ROS, revealed stimulus-dependent receptor mobilization and pathway-selective inhibition.","evidence":"Flow cytometry and co-ligation assays in neutrophils and HL-60 cells","pmids":["17588661"],"confidence":"Medium","gaps":["Intracellular pool identity not characterized","Mechanism of TLR4-ROS resistance to inhibition not explained"]},{"year":2008,"claim":"Identification that Kit-driven CD300a phosphorylation recruits SHIP-1 (not SHP-1) established that the phosphatase recruited depends on the activating receptor context, adding nuance to the inhibitory signaling model; separately, CD300a modulated TLR7/9 responses in plasmacytoid DCs with IFN-α feedback.","evidence":"Co-IP in mast cells with bispecific Kit-CD300a antibody; cytokine measurement in pDCs with cross-linking antibodies","pmids":["18424727","18535206"],"confidence":"High","gaps":["Structural basis for differential phosphatase recruitment unknown","pDC study did not distinguish CD300a from CD300c"]},{"year":2011,"claim":"Two breakthroughs identified PS as the natural ligand of CD300a and demonstrated CD300a inhibits BCR signaling in B cells, unifying the receptor's function as a sensor of aminophospholipid exposure across lymphoid and myeloid compartments.","evidence":"CD300a-Fc binding to apoptotic cells with SHP-1 co-IP; BCR co-ligation and siRNA knockdown in B cell lines","pmids":["22185693","21482706"],"confidence":"High","gaps":["PE binding not yet recognized","Binding site residues not mapped","No KO mouse data yet"]},{"year":2012,"claim":"A cluster of studies defined the molecular mechanism: PE and PS bind within a cavity in the IgV domain (mutagenesis-mapped), Lck phosphorylates the ITIMs, SHP-1 is the required effector phosphatase, and CD300a-PS interaction on apoptotic cells suppresses mast cell inflammatory cytokines in vivo during sepsis; CD300a also selectively blocks TLR4/9-MyD88 but not TLR3-TRIF signaling.","evidence":"SPR/mutagenesis for lipid binding; chimeric receptors in Jurkat/DT40 for ITIM-phosphatase dissection; CD300a KO mice in CLP sepsis model; TLR pathway dissection with NF-κB reporters and ITIM peptides","pmids":["22302738","22537350","22826299","22043923"],"confidence":"High","gaps":["No crystal structure of lipid-bound complex","In vivo role of individual ITIMs not tested","Relative contribution of PS vs PE in physiological settings unclear"]},{"year":2013,"claim":"Residue-level discrimination between CD300A (F56-L57) and CD300C (L63-R64) for PE binding was mapped, and CD300A was shown to dominate over the activating CD300C when co-expressed, explaining how inhibitory signaling prevails; blocking CD300a-PS enhanced NK killing of tumors, implicating PS-mediated immune evasion.","evidence":"Chimeric reporter cell lines with residue swaps; NK cytotoxicity with CD300a-blocking antibodies","pmids":["23372157","23640773"],"confidence":"High","gaps":["Unknown additional ligand(s) on tumor cells","In vivo tumor immune evasion via CD300a not yet shown"]},{"year":2015,"claim":"CD300a was identified as a viral entry factor: it binds PE/PS on dengue virus envelopes to enhance clathrin-mediated endocytic entry (mutagenesis confirmed); in allergic disease, CD300a on DCs sensing alum-induced apoptotic cells promotes Th2 skewing; and herpesvirus US3 kinase exploits CD300a ligand exposure to evade NK killing.","evidence":"CD300a-Ig DENV binding with mutagenesis and clathrin inhibitors; CD300a KO mice in airway allergy model; pseudorabies virus infection with PAK inhibitors and NK lysis assays","pmids":["26468529","25911756","26581992"],"confidence":"High","gaps":["Breadth of enveloped viruses exploiting CD300a not systematically assessed","Molecular mechanism of Th2 skewing by CD300a-PS on DCs not fully resolved"]},{"year":2021,"claim":"Multiple in vivo studies revealed CD300a as a central checkpoint: it opposes CD300b-DAP12-driven efferocytosis after stroke (KO or antibody blockade improves outcome), induces neutrophil apoptosis via caspase-8 to resolve gouty inflammation, modulates neutrophil phagocytosis during UTI, and suppresses DC TLR3-TRIF-IFN-β signaling triggered by tumor-derived EVs to promote Treg accumulation and tumor growth.","evidence":"CD300a KO mice in MCAO stroke, MSU gout, UPEC UTI, and B16 melanoma models; agonistic antibody caspase-8 cleavage assays; endosomal fractionation of DC-TEV pathway","pmids":["34652960","34002852","34268737","34751648"],"confidence":"High","gaps":["CD300a-CD300b signaling crosstalk mechanism at molecular level not defined","Caspase-8 activation pathway downstream of CD300a not fully characterized","Therapeutic window for anti-CD300a antibody in stroke or cancer not established"]},{"year":2023,"claim":"The PPARβ/δ→CD300a→SHP-1⊣Syk signaling axis was validated pharmacologically in mast cells after germinal matrix hemorrhage, confirming transcriptional regulation of CD300a feeds into its canonical inhibitory signaling cascade.","evidence":"PPARβ/δ agonist GW0742 treatment and CD300a/PPARβ/δ siRNA in a rat GMH model with Western blotting","pmids":["37995951"],"confidence":"Medium","gaps":["Direct PPARβ/δ binding to CD300a promoter not shown in this study","Rat model; human translational data lacking"]},{"year":2025,"claim":"Epistasis experiments with CD300a/CD300lf double-KO mice demonstrated cooperative inhibition of mast cell activation, with both receptors co-localizing at PS-enriched poles on activated mast cells; CD300lf additionally recognizes ceramide, providing a stronger inhibitory signal than PS alone.","evidence":"Single and double KO bone marrow-derived mast cells; imaging co-localization; passive systemic anaphylaxis with graded phenotypes","pmids":["40073110"],"confidence":"High","gaps":["Structural basis of polar co-localization not defined","Whether ceramide also engages CD300a directly is untested"]},{"year":null,"claim":"Despite extensive functional characterization, an atomic-resolution crystal or cryo-EM structure of CD300a bound to PS or PE remains unavailable, the hierarchy and individual contributions of the three ITIMs in physiological signaling are not genetically resolved in vivo, and whether CD300a serves as a viable therapeutic target in cancer immune evasion or neuroinflammation lacks clinical data.","evidence":"","pmids":[],"confidence":"High","gaps":["No atomic structure of lipid-bound CD300a","Individual ITIM contributions not resolved by knock-in mutations in vivo","No clinical trial data for CD300a-targeted therapy"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[9,11,16,19]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,2,3,10,13,14]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,6,11,17,27]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[23]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,2,3,10,12,14,15,20,22]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,7,13,14,26]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[19,21,23]}],"complexes":[],"partners":["PTPN6","PTPN11","INPP5D","LCK","CD300B","CD300C","CD300LF"],"other_free_text":[]},"mechanistic_narrative":"CD300A is an ITIM-bearing inhibitory immunoreceptor expressed broadly on myeloid and lymphoid cells that recognizes phosphatidylserine (PS) and phosphatidylethanolamine (PE) exposed on apoptotic cells, activated cells, extracellular vesicles, and enveloped virus particles through a cavity in its IgV-like extracellular domain [PMID:22185693, PMID:22302738, PMID:26468529]. Upon ligand engagement, its cytoplasmic ITIMs are phosphorylated (requiring Lck in T cells) and recruit SHP-1 as the principal effector phosphatase—or SHIP-1 in the context of Kit signaling—to suppress diverse activating pathways including FcεRI, BCR, FcγRIIa, Kit, TLR4/MyD88, TLR9/MyD88, and CD300b-DAP12, thereby dampening degranulation, cytokine production, calcium flux, proliferation, and transmigration across multiple immune cell types [PMID:10540326, PMID:22537350, PMID:18424727, PMID:22043923, PMID:34652960]. CD300A also promotes neutrophil apoptosis via caspase-8, negatively regulates efferocytosis by opposing CD300b-DAP12 activating signals on myeloid cells, and serves as an attachment factor for dengue virus through PE/PS binding that facilitates clathrin-mediated endocytic entry [PMID:34002852, PMID:34652960, PMID:26468529]. In vivo, CD300A deficiency exacerbates anaphylaxis, alters allergic airway inflammation, enhances efferocytosis after ischemic stroke, and modifies tumor immune evasion through regulation of dendritic cell–T cell crosstalk [PMID:40073110, PMID:25911756, PMID:34652960, PMID:34751648]."},"prefetch_data":{"uniprot":{"accession":"Q9UGN4","full_name":"CMRF35-like molecule 8","aliases":["CD300 antigen-like family member A","CMRF-35-H9","CMRF35-H9","CMRF35-H","IRC1/IRC2","Immunoglobulin superfamily member 12","IgSF12","Inhibitory receptor protein 60","IRp60","NK inhibitory receptor"],"length_aa":299,"mass_kda":33.2,"function":"Inhibitory receptor which may contribute to the down-regulation of cytolytic activity in natural killer (NK) cells, and to the down-regulation of mast cell degranulation (PubMed:10746781, PubMed:16339535, PubMed:9701027). Negatively regulates the Toll-like receptor (TLR) signaling mediated by MYD88 but not TRIF through activation of PTPN6 (PubMed:22043923)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9UGN4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CD300A","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CD300A","total_profiled":1310},"omim":[{"mim_id":"616560","title":"CD300H ANTIGEN; CD300H","url":"https://www.omim.org/entry/616560"},{"mim_id":"609801","title":"CD300E ANTIGEN; CD300E","url":"https://www.omim.org/entry/609801"},{"mim_id":"606790","title":"CD300A ANTIGEN; 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journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with functional inhibition readout, replicated across multiple activating receptor contexts\",\n      \"pmids\": [\"10540326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"CD300a (CMRF-35H) gene is located on human chromosome 17, encodes a single V-type Ig-like domain extracellular protein with three ITIMs in its cytoplasmic tail, and spans ~12 kb with seven exons.\",\n      \"method\": \"Genomic clone isolation, intron-exon organization mapping, chromosomal mapping\",\n      \"journal\": \"Tissue antigens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct genomic structural characterization\",\n      \"pmids\": [\"10746781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CD300a (IRp60) cross-linking on human mast cells inhibits IgE-induced degranulation and SCF-mediated survival via tyrosine phosphorylation, phosphatase recruitment (SHP-1/SHP-2), and termination of cellular calcium influx.\",\n      \"method\": \"Cross-linking with monoclonal antibodies, flow cytometry (Ca2+ flux), tryptase/IL-4 release assays, murine allergic peritonitis model with CD300a neutralization\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (signaling, degranulation, in vivo), strong functional consequence\",\n      \"pmids\": [\"16339535\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CD300a (IRp60) cross-linking on human eosinophils inhibits IL-5-mediated JAK2 phosphorylation and eotaxin/IL-5/GM-CSF-mediated ERK1/2 and p38 phosphorylation; CD300a undergoes tyrosine phosphorylation and recruits SHP-1 but not SHP-2 in eosinophils.\",\n      \"method\": \"Cross-linking assays, Western blotting for phosphorylation, transmigration assays, cytokine/apoptosis assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple signaling readouts with pathway placement, clean mechanistic follow-up\",\n      \"pmids\": [\"16254138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CD300a co-aggregation with IgE receptor (via bispecific antibody) inhibits IgE-mediated mast cell degranulation by inhibiting FcεRI signaling events including calcium influx; linkage of CD300a to CCR3 similarly inhibits eosinophil and mast cell activation and reverses airway inflammation in a chronic asthma model.\",\n      \"method\": \"Bispecific antibody fragment generation, phosphorylation/calcium flux FACS, degranulation assays, murine passive cutaneous anaphylaxis and airway inflammation models\",\n      \"journal\": \"Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — bispecific antibody strategy with multiple signaling readouts and in vivo functional validation\",\n      \"pmids\": [\"16750992\", \"17088133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CD300a extracellular domain adopts a monomeric immunoglobulin-like fold in solution, as determined by SAXS and homology modeling.\",\n      \"method\": \"Recombinant protein expression/refolding from E. coli, small-angle X-ray scattering (SAXS), homology modeling\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — structural characterization, but no mutagenesis or functional validation in same study\",\n      \"pmids\": [\"16949664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CD300a surface expression on human neutrophils is rapidly increased by LPS and GM-CSF via translocation of an intracellular pool to the cell surface; co-ligation of CD300a with FcγRIIa (CD32a) inhibits FcγRIIa-mediated signaling selectively without inhibiting TLR4-mediated ROS production.\",\n      \"method\": \"Flow cytometry, HL-60 differentiation model, co-ligation assays\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean co-ligation functional readout with selective pathway inhibition demonstrated\",\n      \"pmids\": [\"17588661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CD300a co-aggregation with Kit (CD117) via bispecific antibody inhibits SCF-induced signaling in mast cells, which is mediated by Kit-driven tyrosine phosphorylation of CD300a and recruitment of SHIP-1 (but not SHP-1); this impairs mast cell differentiation, survival, and activation.\",\n      \"method\": \"Bispecific antibody library, co-immunoprecipitation, Western blotting, in vitro differentiation/survival assays, murine cutaneous anaphylaxis model\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP, multiple functional readouts, phosphatase discrimination, in vivo validation\",\n      \"pmids\": [\"18424727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CD300a/c triggering on plasmacytoid dendritic cells reduces TNF-α and increases IFN-α secretion in response to TLR7/9 ligands; IFN-α feeds back to down-regulate CD300a/c expression.\",\n      \"method\": \"Cross-linking antibody stimulation, cytokine ELISA, neutralizing antibody experiments\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean functional readout with neutralizing antibody confirmation of IFN-α feedback loop\",\n      \"pmids\": [\"18535206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CD300a extracellular domain (as Fc fusion protein) specifically binds phosphatidylserine (PS) exposed on apoptotic cells; PS binding induces SHP-1 recruitment by CD300a in mast cells in response to LPS.\",\n      \"method\": \"CD300a-Fc fusion protein, binding assay to apoptotic cells, SHP-1 co-immunoprecipitation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct ligand identification with functional phosphatase recruitment readout\",\n      \"pmids\": [\"22185693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CD300a co-ligation with BCR on B cells inhibits Ca2+ mobilization and NFAT transcriptional activity; siRNA knockdown of CD300a increases BCR-mediated proliferation, confirming its inhibitory capacity.\",\n      \"method\": \"Co-ligation assays, calcium mobilization FACS, NFAT reporter assay, siRNA knockdown, proliferation assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including siRNA confirmation of inhibitory function\",\n      \"pmids\": [\"21482706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CD300a binds phosphatidylethanolamine (PE) and phosphatidylserine (PS) on dead cells; mutational studies identified residues forming a cavity in the IgV domain where PE/PS hydrophilic heads penetrate; CD300a down-regulates macrophage phagocytosis of apoptotic cells and its ectopic expression in CD300a-negative lines decreases engulfment.\",\n      \"method\": \"Surface plasmon resonance, ultracentrifugation, ELISA, reporter cell assays, site-directed mutagenesis, structural modeling, phagocytosis assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple biophysical methods, mutagenesis identifying binding residues, functional validation\",\n      \"pmids\": [\"22302738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CD300a is a non-phagocytic PS receptor on mast cells that delivers an inhibitory signal suppressing LPS-induced inflammatory cytokine and chemokine production; after apoptotic cell accumulation in vivo (cecal ligation and puncture), CD300a-PS interaction suppresses neutrophil chemoattractant release from mast cells.\",\n      \"method\": \"CD300a-deficient mice, peritoneal mast cell isolation, cytokine/chemokine measurement, CLP model, antibody blockade of CD300a-PS interaction\",\n      \"journal\": \"Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with specific cellular phenotype, antibody blockade confirmation, in vivo infection model\",\n      \"pmids\": [\"22826299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CD300a ITIM tyrosine phosphorylation requires the src kinase Lck; phosphorylated ITIMs dock both SHP-1 and SHP-2, but only SHP-1 is required for CD300a inhibitory activity, as shown by siRNA knockdown and phosphatase-deficient DT40 cell lines.\",\n      \"method\": \"KIR-CD300a chimeric receptor in Jurkat T cells, siRNA knockdown of SHP-1/SHP-2/SHIP, DT40 phosphatase-deficient cell lines, calcium mobilization and proliferation assays\",\n      \"journal\": \"BMC immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted chimeric receptor system, mutagenesis of ITIMs, genetic dissection of phosphatases\",\n      \"pmids\": [\"22537350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CD300a selectively blocks TLR4/MyD88 and TLR9/MyD88-mediated pro-inflammatory signaling through SHP-1 activation, but does not block TLR3/TRIF-mediated signaling (unlike CD300f which requires combined SHP-1 and SHP-2); ITIM peptides of CD300a mimic this selective inhibition.\",\n      \"method\": \"THP-1/U937 stimulation with TLR ligands, luciferase NF-κB reporter assay, Western blotting, synthetic ITIM peptides, signaling inhibitors\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple signaling pathway dissection with reporter assays and peptide validation\",\n      \"pmids\": [\"22043923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CD300a and CD300c both bind PS and additional unknown ligand(s) on tumor cells; blocking PS-CD300a interaction increases NK cell killing of tumor cells, demonstrating a tumor immune evasion mechanism.\",\n      \"method\": \"Anti-CD300a monoclonal antibody generation, NK cell cytotoxicity assays, antibody blocking experiments\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional blocking with specific readout, but unknown additional ligand\",\n      \"pmids\": [\"23640773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CD300C delivers FcRγ-dependent activating signals in mast cells and monocytes; CD300A and CD300C differ in ligand recognition at residues F56-L57 (CD300A) vs. L63-R64 (CD300C), with PE binding more strongly to CD300A; CD300A expression is dominant over CD300C in PE recognition/signaling when co-expressed.\",\n      \"method\": \"Epitope-discriminating antibodies, reporter cell lines expressing CD300A/C-CD3ζ chimeras, GFP reporter assay, cytokine production assays, co-expression experiments\",\n      \"journal\": \"Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — chimeric reporter system, residue-level mapping of ligand discrimination, functional co-expression dominance demonstrated\",\n      \"pmids\": [\"23372157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CD300a mRNA and protein are upregulated following monocyte transendothelial migration; CD300a engagement reduces monocyte transmigration, siRNA knockdown increases transmigration rate, and activated CD300a causes F-actin cytoskeleton alterations and co-localizes with actin filaments.\",\n      \"method\": \"Transcriptional profiling, siRNA knockdown, anti-CD300a antibody treatment, migration assays, co-sedimentation with actin, immunofluorescence\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — siRNA + antibody + actin localization with functional consequence in migration\",\n      \"pmids\": [\"24058511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PPARβ/δ directly regulates CD300a transcription in macrophages; CD300a-deficient mice on high-fat diet develop chronic intestinal inflammation with prolonged IL-6 secretion from macrophages in response to LPS/TLR4-MyD88 signaling.\",\n      \"method\": \"CD300a KO mice, high-fat diet model, bone marrow transplantation, LPS stimulation, cytokine measurement\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with defined cellular phenotype and pathway placement, bone marrow transplant confirms leukocyte origin\",\n      \"pmids\": [\"24958459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CD300a binds DENV particles directly via PE (predominantly) and PS on the viral envelope, acting as an attachment factor that enhances DENV internalization through clathrin-mediated endocytosis; mutation of IgV domain residues critical for phospholipid binding abrogates CD300a-mediated viral enhancement.\",\n      \"method\": \"CD300a-Ig fusion binding to DENV, clathrin inhibitor experiments, site-directed mutagenesis of phospholipid-binding residues, viral infection assays, antibody inhibition in primary macrophages\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct binding assay, mutagenesis of functional residues, endocytosis pathway identification\",\n      \"pmids\": [\"26468529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CD300a on inflammatory dendritic cells binds PS on apoptotic cells generated by alum adjuvant, promoting Th2 immune responses; CD300a-deficient mice show reduced eosinophilia, IgE, and airway hyperreactivity after alum+OVA immunization, and their DCs induce less IL-4 from CD4+ T cells.\",\n      \"method\": \"CD300a KO mice, allergic airway inflammation model, DC purification and co-culture, neutralizing antibody blockade\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO, neutralizing antibody, cell-type specific functional readout\",\n      \"pmids\": [\"25911756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Pseudorabies virus US3 kinase triggers increased CD300a binding to the surface of infected cells via aminophospholipid ligands and group I p21-activated kinases (PAKs), thereby protecting virus-infected cells from NK cell-mediated lysis.\",\n      \"method\": \"Virus infection assays, NK cell cytotoxicity assays, PAK inhibitors, aminophospholipid manipulation\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional NK lysis assay with inhibitor dissection of PAK pathway, mechanism linked to CD300a ligand exposure\",\n      \"pmids\": [\"26581992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CD300a on brain myeloid cells inhibits efferocytosis of apoptotic cells by blocking CD300b-DAP12 signaling; CD300a deficiency enhances efferocytosis, reduces DAMP release, and attenuates neurological deficit after ischemic stroke; anti-CD300a neutralizing antibody ameliorates stroke outcome.\",\n      \"method\": \"CD300a KO mice, MCAO model, efferocytosis assays, DAMP measurement, neutralizing antibody treatment, neurological scoring\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO + antibody blockade with defined pathway (CD300b-DAP12) and multiple functional readouts\",\n      \"pmids\": [\"34652960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CD300a on dendritic cells inhibits tumor-derived extracellular vesicle (TEV)-mediated TLR3-TRIF signaling for IFN-β production; TEV co-culture with DCs induces CD300a internalization and incorporation of EVs into endosomes where CD300a suppresses TLR3-TRIF-IFN-β-Treg axis, resulting in Treg accumulation and tumor growth.\",\n      \"method\": \"CD300a KO mice, B16 melanoma transplantation, EV pharmacological inhibition, DC-TEV co-culture, endosomal fractionation, tumor-infiltrating Treg cell counting\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO, pharmacological EV inhibition, endosomal pathway mechanism with multiple orthogonal readouts\",\n      \"pmids\": [\"34751648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CD300a deficiency impairs neutrophil phagocytic ability during urinary tract infection despite increased accumulation at the infection site; UPEC's α-hemolysin toxin induces upregulation of CD300a ligands on infected bladder epithelial cells.\",\n      \"method\": \"CD300a KO mice, UPEC infection model, phagocytosis assays, bacterial burden measurement, α-hemolysin stimulation\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with specific phagocytic phenotype and ligand induction mechanism\",\n      \"pmids\": [\"34268737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CD300a agonistic antibody induces apoptosis of human neutrophils via caspase-8 cleavage, contributing to resolution of MSU crystal-induced articular inflammation; CD300a KO mice show persistent neutrophil influx and reduced efferocytosis after MSU injection.\",\n      \"method\": \"CD300a KO mice, MSU crystal gout model, agonistic antibody treatment, caspase-8 cleavage assay, efferocytosis quantification\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO + agonistic antibody with caspase-8 pathway identification\",\n      \"pmids\": [\"34002852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PPARβ/δ agonist GW0742 increases CD300a expression and SHP-1 phosphorylation in mast cells, reducing Syk phosphorylation and mast cell degranulation after germinal matrix hemorrhage; CD300a siRNA abolishes the protective effects.\",\n      \"method\": \"GMH rat model, siRNA knockdown of PPARβ/δ and CD300a, Western blotting for SHP-1 and Syk phosphorylation, mast cell degranulation markers\",\n      \"journal\": \"Experimental neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — siRNA validation of pathway (PPARβ/δ→CD300a→SHP1→Syk inhibition) with in vivo model\",\n      \"pmids\": [\"37995951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CD300a and CD300lf cooperate to inhibit mast cell activation; both receptors co-localize with PS externalized on the outer leaflet upon activation with polar formation; CD300lf additionally binds extracellular ceramide, providing stronger inhibition than PS binding alone; double KO mice show more severe anaphylaxis than single KOs.\",\n      \"method\": \"KO mouse bone marrow-derived mast cells (single and double KO), imaging and flow cytometry for receptor localization, passive systemic anaphylaxis model with temperature readout\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic double KO epistasis, imaging-based co-localization, in vivo anaphylaxis model with graded phenotypes\",\n      \"pmids\": [\"40073110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CD300a specifically modulates PE-mediated phagocytic uptake by macrophages; CD300a and CD300b engage PE on apoptotic cells and extracellular vesicles through ITAM-containing adaptors and Syk kinase; CD300a expression curtails inflammatory responses of macrophages to PE particles containing LPS.\",\n      \"method\": \"Phagocytosis assays with PE-coated particles, CD300 family receptor knockdown/expression, Syk inhibitor experiments, LPS inflammatory response measurement\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct phagocytosis assay with pathway identification, but preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2024.11.18.624161\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"CD300a is a type I transmembrane ITIM-containing inhibitory immunoreceptor that binds phosphatidylserine (PS) and phosphatidylethanolamine (PE) exposed on apoptotic cells, activated cells, and enveloped viruses through a cavity in its IgV extracellular domain; upon ligation, CD300a ITIMs are phosphorylated (requiring Lck in T cells), recruiting primarily SHP-1 (and in some contexts SHIP-1) to suppress downstream signaling pathways including FcεRI, BCR, FcγRIIa, Kit, TLR4/9-MyD88, and CD300b-DAP12, thereby inhibiting immune cell activation, promoting apoptosis in neutrophils via caspase-8, modulating efferocytosis, and serving as an entry factor for dengue and other enveloped viruses.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CD300A is an ITIM-bearing inhibitory immunoreceptor expressed broadly on myeloid and lymphoid cells that recognizes phosphatidylserine (PS) and phosphatidylethanolamine (PE) exposed on apoptotic cells, activated cells, extracellular vesicles, and enveloped virus particles through a cavity in its IgV-like extracellular domain [PMID:22185693, PMID:22302738, PMID:26468529]. Upon ligand engagement, its cytoplasmic ITIMs are phosphorylated (requiring Lck in T cells) and recruit SHP-1 as the principal effector phosphatase—or SHIP-1 in the context of Kit signaling—to suppress diverse activating pathways including FcεRI, BCR, FcγRIIa, Kit, TLR4/MyD88, TLR9/MyD88, and CD300b-DAP12, thereby dampening degranulation, cytokine production, calcium flux, proliferation, and transmigration across multiple immune cell types [PMID:10540326, PMID:22537350, PMID:18424727, PMID:22043923, PMID:34652960]. CD300A also promotes neutrophil apoptosis via caspase-8, negatively regulates efferocytosis by opposing CD300b-DAP12 activating signals on myeloid cells, and serves as an attachment factor for dengue virus through PE/PS binding that facilitates clathrin-mediated endocytic entry [PMID:34002852, PMID:34652960, PMID:26468529]. In vivo, CD300A deficiency exacerbates anaphylaxis, alters allergic airway inflammation, enhances efferocytosis after ischemic stroke, and modifies tumor immune evasion through regulation of dendritic cell–T cell crosstalk [PMID:40073110, PMID:25911756, PMID:34652960, PMID:34751648].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Establishing CD300a as an inhibitory receptor resolved whether this orphan Ig-superfamily molecule functioned as an activating or inhibitory regulator of NK cytotoxicity, showing it recruits SHP-1 and SHP-2 upon ITIM phosphorylation to suppress killing.\",\n      \"evidence\": \"Cross-linking and co-immunoprecipitation after pervanadate treatment in human NK cells\",\n      \"pmids\": [\"10540326\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological ligand unknown\", \"Relative contribution of SHP-1 vs SHP-2 not determined\", \"Receptor structure not yet characterized\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Gene structure characterization defined CD300a as a single IgV-domain type I transmembrane protein with three ITIMs, establishing the molecular framework for subsequent signaling studies.\",\n      \"evidence\": \"Genomic clone isolation, exon-intron mapping, chromosomal localization to 17q25\",\n      \"pmids\": [\"10746781\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal structure\", \"ITIM functional hierarchy not tested\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Extension beyond NK cells demonstrated CD300a inhibits FcεRI/Kit-driven mast cell degranulation and IL-5/eotaxin/GM-CSF signaling in eosinophils, establishing it as a broadly acting inhibitory receptor on innate effector cells; SHP-1 but not SHP-2 was required in eosinophils.\",\n      \"evidence\": \"Cross-linking assays, calcium flux, degranulation, and signaling Western blots in human mast cells and eosinophils; murine allergic peritonitis model\",\n      \"pmids\": [\"16339535\", \"16254138\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ligand still unidentified\", \"In vivo role in allergy only partially addressed\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Bispecific antibody co-aggregation strategy proved CD300a can be therapeutically redirected to inhibit FcεRI and CCR3 signaling, reversing airway inflammation in vivo, while SAXS revealed the extracellular domain is a monomeric Ig-fold.\",\n      \"evidence\": \"Bispecific antibody constructs with degranulation/calcium readouts; murine passive cutaneous anaphylaxis and airway inflammation models; SAXS structural analysis\",\n      \"pmids\": [\"16750992\", \"17088133\", \"16949664\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No atomic-resolution structure\", \"Natural ligand unknown\", \"Mechanism of co-ligation selectivity unclear\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Discovery that LPS and GM-CSF rapidly upregulate CD300a surface expression from intracellular stores on neutrophils, and that CD300a selectively inhibits FcγRIIa but not TLR4-mediated ROS, revealed stimulus-dependent receptor mobilization and pathway-selective inhibition.\",\n      \"evidence\": \"Flow cytometry and co-ligation assays in neutrophils and HL-60 cells\",\n      \"pmids\": [\"17588661\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Intracellular pool identity not characterized\", \"Mechanism of TLR4-ROS resistance to inhibition not explained\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identification that Kit-driven CD300a phosphorylation recruits SHIP-1 (not SHP-1) established that the phosphatase recruited depends on the activating receptor context, adding nuance to the inhibitory signaling model; separately, CD300a modulated TLR7/9 responses in plasmacytoid DCs with IFN-α feedback.\",\n      \"evidence\": \"Co-IP in mast cells with bispecific Kit-CD300a antibody; cytokine measurement in pDCs with cross-linking antibodies\",\n      \"pmids\": [\"18424727\", \"18535206\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for differential phosphatase recruitment unknown\", \"pDC study did not distinguish CD300a from CD300c\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Two breakthroughs identified PS as the natural ligand of CD300a and demonstrated CD300a inhibits BCR signaling in B cells, unifying the receptor's function as a sensor of aminophospholipid exposure across lymphoid and myeloid compartments.\",\n      \"evidence\": \"CD300a-Fc binding to apoptotic cells with SHP-1 co-IP; BCR co-ligation and siRNA knockdown in B cell lines\",\n      \"pmids\": [\"22185693\", \"21482706\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"PE binding not yet recognized\", \"Binding site residues not mapped\", \"No KO mouse data yet\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"A cluster of studies defined the molecular mechanism: PE and PS bind within a cavity in the IgV domain (mutagenesis-mapped), Lck phosphorylates the ITIMs, SHP-1 is the required effector phosphatase, and CD300a-PS interaction on apoptotic cells suppresses mast cell inflammatory cytokines in vivo during sepsis; CD300a also selectively blocks TLR4/9-MyD88 but not TLR3-TRIF signaling.\",\n      \"evidence\": \"SPR/mutagenesis for lipid binding; chimeric receptors in Jurkat/DT40 for ITIM-phosphatase dissection; CD300a KO mice in CLP sepsis model; TLR pathway dissection with NF-κB reporters and ITIM peptides\",\n      \"pmids\": [\"22302738\", \"22537350\", \"22826299\", \"22043923\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal structure of lipid-bound complex\", \"In vivo role of individual ITIMs not tested\", \"Relative contribution of PS vs PE in physiological settings unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Residue-level discrimination between CD300A (F56-L57) and CD300C (L63-R64) for PE binding was mapped, and CD300A was shown to dominate over the activating CD300C when co-expressed, explaining how inhibitory signaling prevails; blocking CD300a-PS enhanced NK killing of tumors, implicating PS-mediated immune evasion.\",\n      \"evidence\": \"Chimeric reporter cell lines with residue swaps; NK cytotoxicity with CD300a-blocking antibodies\",\n      \"pmids\": [\"23372157\", \"23640773\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Unknown additional ligand(s) on tumor cells\", \"In vivo tumor immune evasion via CD300a not yet shown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"CD300a was identified as a viral entry factor: it binds PE/PS on dengue virus envelopes to enhance clathrin-mediated endocytic entry (mutagenesis confirmed); in allergic disease, CD300a on DCs sensing alum-induced apoptotic cells promotes Th2 skewing; and herpesvirus US3 kinase exploits CD300a ligand exposure to evade NK killing.\",\n      \"evidence\": \"CD300a-Ig DENV binding with mutagenesis and clathrin inhibitors; CD300a KO mice in airway allergy model; pseudorabies virus infection with PAK inhibitors and NK lysis assays\",\n      \"pmids\": [\"26468529\", \"25911756\", \"26581992\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Breadth of enveloped viruses exploiting CD300a not systematically assessed\", \"Molecular mechanism of Th2 skewing by CD300a-PS on DCs not fully resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Multiple in vivo studies revealed CD300a as a central checkpoint: it opposes CD300b-DAP12-driven efferocytosis after stroke (KO or antibody blockade improves outcome), induces neutrophil apoptosis via caspase-8 to resolve gouty inflammation, modulates neutrophil phagocytosis during UTI, and suppresses DC TLR3-TRIF-IFN-β signaling triggered by tumor-derived EVs to promote Treg accumulation and tumor growth.\",\n      \"evidence\": \"CD300a KO mice in MCAO stroke, MSU gout, UPEC UTI, and B16 melanoma models; agonistic antibody caspase-8 cleavage assays; endosomal fractionation of DC-TEV pathway\",\n      \"pmids\": [\"34652960\", \"34002852\", \"34268737\", \"34751648\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"CD300a-CD300b signaling crosstalk mechanism at molecular level not defined\", \"Caspase-8 activation pathway downstream of CD300a not fully characterized\", \"Therapeutic window for anti-CD300a antibody in stroke or cancer not established\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The PPARβ/δ→CD300a→SHP-1⊣Syk signaling axis was validated pharmacologically in mast cells after germinal matrix hemorrhage, confirming transcriptional regulation of CD300a feeds into its canonical inhibitory signaling cascade.\",\n      \"evidence\": \"PPARβ/δ agonist GW0742 treatment and CD300a/PPARβ/δ siRNA in a rat GMH model with Western blotting\",\n      \"pmids\": [\"37995951\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct PPARβ/δ binding to CD300a promoter not shown in this study\", \"Rat model; human translational data lacking\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Epistasis experiments with CD300a/CD300lf double-KO mice demonstrated cooperative inhibition of mast cell activation, with both receptors co-localizing at PS-enriched poles on activated mast cells; CD300lf additionally recognizes ceramide, providing a stronger inhibitory signal than PS alone.\",\n      \"evidence\": \"Single and double KO bone marrow-derived mast cells; imaging co-localization; passive systemic anaphylaxis with graded phenotypes\",\n      \"pmids\": [\"40073110\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of polar co-localization not defined\", \"Whether ceramide also engages CD300a directly is untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Despite extensive functional characterization, an atomic-resolution crystal or cryo-EM structure of CD300a bound to PS or PE remains unavailable, the hierarchy and individual contributions of the three ITIMs in physiological signaling are not genetically resolved in vivo, and whether CD300a serves as a viable therapeutic target in cancer immune evasion or neuroinflammation lacks clinical data.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No atomic structure of lipid-bound CD300a\", \"Individual ITIM contributions not resolved by knock-in mutations in vivo\", \"No clinical trial data for CD300a-targeted therapy\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [9, 11, 16, 19]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 2, 3, 10, 13, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 6, 11, 17, 27]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [23]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 2, 3, 10, 12, 14, 15, 20, 22]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 7, 13, 14, 26]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [19, 21, 23]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PTPN6\",\n      \"PTPN11\",\n      \"INPP5D\",\n      \"LCK\",\n      \"CD300B\",\n      \"CD300C\",\n      \"CD300LF\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}