{"gene":"SEMA4A","run_date":"2026-06-10T07:46:30","timeline":{"discoveries":[{"year":2002,"finding":"Sema4A, expressed on dendritic cells and B cells, enhances T-cell activation and differentiation in vitro and in vivo; expression cloning identified Tim-2 (a T-cell immunoglobulin and mucin domain protein expressed on activated T cells) as the Sema4A receptor.","method":"Expression cloning, in vitro T-cell activation assays, in vivo immunization, monoclonal antibody blocking experiments","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — receptor identified by expression cloning, functional validation with blocking antibodies in vivo, replicated in subsequent studies","pmids":["12374982"],"is_preprint":false},{"year":2005,"finding":"Sema4A provides a costimulatory signal required for T cell priming and Th1 differentiation; DC-derived Sema4A is important for T cell priming while T cell-derived Sema4A (upregulated on Th1-differentiating cells) is required for Th1 responses and T-bet expression. Loss of Sema4A impairs allostimulatory activity of DCs and Th differentiation.","method":"Sema4A knockout mice, bone marrow reconstitution with antigen-pulsed DCs, in vitro Th differentiation assays, in vivo antigen-specific T cell priming","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with defined cellular phenotypes, cell-type-specific reconstitution experiments, replicated across multiple assays in one rigorous study","pmids":["15780988"],"is_preprint":false},{"year":2010,"finding":"Sema4A binds Plexin-B1, -B2, and -B3 and induces growth cone collapse in hippocampal neurons through B-type plexin-mediated signaling; the intracellular signal is transmitted through Rnd1 (a Rho family GTPase), and Sema4A-induced growth cone collapse is blocked by constitutively active R-Ras, indicating that Sema4A acts by down-regulating R-Ras activity.","method":"Transfection of COS-7 cells with plexin/Rnd1 expression vectors, COS-7 cell contraction assay, hippocampal neuron growth cone collapse assay, dominant-active R-Ras rescue experiment","journal":"International journal of molecular medicine","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — receptor-ligand binding demonstrated by transfection, functional assays with mutagenesis-equivalent constructs (constitutively active R-Ras), multiple orthogonal methods in one study","pmids":["20043131"],"is_preprint":false},{"year":2012,"finding":"Sema4A mutants D345H and F350C mis-localize to the ER instead of the plasma membrane, rendering retinal pigment epithelial cells susceptible to light irradiation, oxidative stress, and ER stress, and suppressing phagocytosis; in zebrafish, human mutant SEMA4A increased ER stress marker ddit3 mRNA under ER stress conditions.","method":"Confocal microscopy for intracellular localization, overexpression of mutant vs. wild-type SEMA4A in ARPE-19 cells, GRP78 expression assay, phagocytosis assay, tunicamycin and H2O2 cell death assays, zebrafish ER stress model","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional consequence, multiple cellular assays, single lab","pmids":["22956603"],"is_preprint":false},{"year":2012,"finding":"Sema4A is shed from DCs in a metalloproteinase-dependent manner; DC-derived Sema4A promotes both Th1 and Th17 cell differentiation.","method":"Serum Sema4A measurement, DC surface expression analysis, metalloproteinase inhibitor experiments, Th1/Th17 differentiation assays in MS patients and controls","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — metalloproteinase-dependent shedding demonstrated pharmacologically, DC-derived Sema4A linked to Th differentiation, single lab, partial mechanistic follow-up","pmids":["22491253"],"is_preprint":false},{"year":2012,"finding":"Sema4A inhibits Th2-type immune responses; Sema4A-Fc directly inhibits IL-4-producing OVA-specific CD4+ T cells and ameliorates airway hyperreactivity and lung inflammation in an asthma model, with inhibitory effects observed even in Tim-2-deficient mice, indicating the inhibitory effect on Th2 is not solely through Tim-2.","method":"Sema4A knockout mice on BALB/c background, in vivo OVA-sensitization/challenge asthma model, systemic Sema4A-Fc administration, Tim-2-deficient mice, in vitro T cell cytokine assays","journal":"Journal of clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function KO and gain-of-function Fc-fusion with defined cellular phenotypes, epistasis with Tim-2 KO, single lab","pmids":["23007237"],"is_preprint":false},{"year":2014,"finding":"SEMA4A germline mutation V78M leads to significantly increased MAPK/Erk and PI3K/Akt signaling as well as enhanced cell cycle progression compared to wild-type SEMA4A when expressed in SEMA4A-deficient HCT-116 colorectal cancer cells.","method":"Re-expression of wild-type vs. V78M SEMA4A in SEMA4A-deficient HCT-116 cells, MAPK/Erk and PI3K/Akt signaling assays, cell cycle analysis","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reconstitution with mutant vs. wild-type, pathway-level readout, single lab","pmids":["25307848"],"is_preprint":false},{"year":2015,"finding":"SEMA4A regulates CD8+ T cell activation and differentiation by activating mTORC1; SEMA4A-deficient CD8+ T cells show reduced mTORC1 activity and elevated mTORC2 activity, impaired IFN-γ/TNF-α production, and reduced effector molecule expression. Plexin-B2 was identified as the functional SEMA4A receptor on CD8+ T cells. Recombinant Sema4A protein restored IFN-γ production and mTORC1 activity in SEMA4A-deficient CD8+ T cells.","method":"SEMA4A knockout mice, Listeria monocytogenes infection model, mTORC1/mTORC2 activity assays, cytokine measurement, recombinant Sema4A rescue experiment, receptor identification","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined signaling phenotype, receptor identification, rescue with recombinant protein, in vivo infection model, multiple orthogonal methods","pmids":["26116513"],"is_preprint":false},{"year":2016,"finding":"Sema4A functions as a receptor (not only a ligand) and transduces reverse signals triggered by Plexin-B1 binding; this reverse signaling promotes interaction of Sema4A with the polarity protein Scrib, displacing Scrib from its complex with the Rac/Cdc42 exchange factor βPIX, thereby decreasing Rac1 and Cdc42 GTPase activity and regulating cell migration in cancer cells and dendritic cells.","method":"Mass spectrometry, siRNA screening, Co-IP/pulldown for Sema4A–Scrib interaction, Rac1/Cdc42 activity assays, cell migration assays in cancer cells and DCs","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — mass spectrometry identification of Scrib, confirmed by Co-IP, mechanistic pathway validated by siRNA and GTPase activity assays, multiple orthogonal methods in one study","pmids":["28007914"],"is_preprint":false},{"year":2020,"finding":"Sema4A expressed on hematopoietic cells (not CNS-resident cells) accelerates Th17 cell-mediated neuroinflammation in the effector phase; adoptive transfer of Th17-skewed encephalitogenic T cells into Sema4A-deficient recipients showed significantly reduced disease severity, while Th1-skewed transfer showed no difference.","method":"Adoptive transfer EAE model, Sema4A knockout recipient mice, bone marrow chimera experiments, clinical scoring and CNS cellular infiltration analysis","journal":"Journal of neuroinflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via KO recipients, bone marrow chimera for cell-type specificity, defined Th17-specific phenotype, single lab","pmids":["32169103"],"is_preprint":false},{"year":2021,"finding":"IL-33 induces dendritic cells to express Sema4A, and Sema4A is intrinsically required for the antitumor effects of IL-33; absence of Sema4A abolished IL-33-mediated tumor growth inhibition and IFN-γ upregulation by tumor-infiltrating CD8+ T cells.","method":"Syngeneic mouse tumor models, Sema4A knockout mice, IL-33 administration, tumor growth measurement, IFN-γ production assay by tumor-infiltrating CD8+ T cells","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined in vivo tumor phenotype, cytokine pathway placement, single lab","pmids":["34380650"],"is_preprint":false},{"year":2024,"finding":"Sema4A, produced mainly by neutrophils, signals via Plexin D1 on myeloid-biased hematopoietic stem cells (myHSC) to safeguard their epigenetic state and confer resilience to inflammatory stress; absence of Sema4A leads to myHSC inflammatory hyper-responsiveness, excessive myHSC expansion, myeloid bias, and profound loss of regenerative function with age.","method":"Sema4A knockout mice, bone marrow reconstitution, epigenetic profiling, HSC subset functional assays, cell-surface receptor identification (Plexin D1)","journal":"bioRxiv (preprint)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined HSC phenotype, receptor identification, mechanistic epigenetic readout, preprint not yet peer-reviewed","pmids":[],"is_preprint":true},{"year":2025,"finding":"In skeletal muscle, Sema4A signals through Plexin-B2 to suppress FoxO3a nuclear translocation and inhibit atrogene expression while simultaneously reactivating the PI3K-AKT-mTOR anabolic pathway; AAV-mediated Sema4A restoration attenuates dexamethasone-induced muscle atrophy and accelerates injury recovery in mice.","method":"AAV-mediated Sema4A overexpression, dexamethasone-induced atrophy model, acute injury model, C2C12 myotube gain/loss-of-function, FoxO3a nuclear translocation assay, PI3K-AKT-mTOR pathway analysis","journal":"Journal of cachexia, sarcopenia and muscle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo AAV rescue, in vitro gain/loss-of-function, defined signaling pathway readout, receptor identified, single lab","pmids":["42216457"],"is_preprint":false}],"current_model":"SEMA4A is a class IV transmembrane semaphorin that functions both as a ligand (binding Plexin-B1/B2/B3 or Tim-2 on target cells) and as a receptor undergoing reverse signaling (when bound by Plexin-B1); as a ligand it activates mTORC1, promotes Th1/Th17 differentiation and CD8+ T cell effector function, induces neuronal growth cone collapse via Rnd1 and R-Ras suppression downstream of B-type plexins, and protects skeletal muscle via PI3K-AKT-mTOR/FoxO3a signaling through Plexin-B2; as a reverse-signaling receptor it recruits the polarity protein Scrib to reduce Rac1/Cdc42 activity and regulate cell migration; disease-associated mutations (D345H, F350C) cause ER retention leading to increased susceptibility to ER/oxidative stress in retinal cells."},"narrative":{"mechanistic_narrative":"SEMA4A is a class IV transmembrane semaphorin that operates bidirectionally as both a ligand and a reverse-signaling receptor to regulate immune cell differentiation, neuronal guidance, and tissue homeostasis [PMID:12374982, PMID:20043131, PMID:28007914]. In the immune system it acts as a costimulatory ligand required for T cell priming and Th1/Th17 differentiation, with dendritic-cell-derived SEMA4A driving priming and T-cell-derived SEMA4A sustaining Th1 responses through T-bet expression [PMID:15780988]; it was first defined through the receptor Tim-2 on activated T cells [PMID:12374982], and is released from dendritic cells by metalloproteinase-dependent shedding [PMID:22491253]. On CD8+ T cells SEMA4A engages Plexin-B2 to activate mTORC1 (while restraining mTORC2), driving effector cytokine production, a role that places it downstream of IL-33 in antitumor CD8+ responses [PMID:26116513, PMID:34380650]. SEMA4A also inhibits Th2 responses through a Tim-2-independent mechanism [PMID:23007237] and, on hematopoietic cells, accelerates Th17-mediated neuroinflammation [PMID:32169103]. As a guidance ligand, SEMA4A binds Plexin-B1/B2/B3 to induce neuronal growth cone collapse via the Rho-family GTPase Rnd1 and downregulation of R-Ras [PMID:20043131]. Reciprocally, SEMA4A itself transduces reverse signals upon Plexin-B1 binding, recruiting the polarity protein Scrib away from the Rac/Cdc42 exchange factor βPIX to lower Rac1/Cdc42 activity and regulate cell migration [PMID:28007914]. Through Plexin-B2 it additionally protects skeletal muscle by suppressing FoxO3a nuclear translocation and reactivating PI3K-AKT-mTOR anabolic signaling [PMID:42216457]. Disease-associated mutations (D345H, F350C) cause ER retention that renders retinal pigment epithelial cells susceptible to oxidative and ER stress [PMID:22956603].","teleology":[{"year":2002,"claim":"Establishing that SEMA4A is an immune ligand rather than solely a neuronal molecule, this work showed it enhances T-cell activation and identified its first receptor.","evidence":"Expression cloning identifying Tim-2, in vitro/in vivo T-cell activation with blocking antibodies","pmids":["12374982"],"confidence":"High","gaps":["Did not establish downstream signaling from Tim-2","Did not address other receptors used by SEMA4A"]},{"year":2005,"claim":"Genetic loss-of-function defined SEMA4A as a costimulatory signal partitioned by cell source, with DC-derived protein driving priming and T-cell-derived protein driving Th1 polarization.","evidence":"Sema4A knockout mice, cell-type-specific DC reconstitution, in vitro Th differentiation","pmids":["15780988"],"confidence":"High","gaps":["Receptor on responding T cells for Th1 effect not defined","Molecular signaling linking SEMA4A to T-bet not resolved"]},{"year":2010,"claim":"This work mapped SEMA4A's neuronal guidance activity to B-type plexins and a defined intracellular GTPase cascade.","evidence":"Transfection binding assays, COS-7 contraction and hippocampal growth cone collapse, constitutively active R-Ras rescue","pmids":["20043131"],"confidence":"High","gaps":["Did not distinguish contributions of individual B-type plexins in vivo","Link between Rnd1 and R-Ras suppression not biochemically detailed"]},{"year":2012,"claim":"Disease mutations were shown to impair SEMA4A trafficking, connecting altered subcellular localization to stress susceptibility in retinal cells.","evidence":"Confocal localization of D345H/F350C mutants, ER/oxidative stress and phagocytosis assays in ARPE-19 cells, zebrafish ER stress model","pmids":["22956603"],"confidence":"Medium","gaps":["Did not establish patient-level causation in a family study","Mechanism by which ER retention triggers stress susceptibility not detailed"]},{"year":2012,"claim":"Two studies extended SEMA4A's immune role, showing metalloproteinase-dependent shedding generates a soluble form and that SEMA4A suppresses Th2 responses partly independent of Tim-2.","evidence":"Metalloproteinase inhibitor experiments and Th1/Th17 assays; Sema4A-Fc administration and Tim-2-deficient mice in an asthma model","pmids":["22491253","23007237"],"confidence":"Medium","gaps":["The non-Tim-2 receptor mediating Th2 inhibition was not identified","Protease responsible for shedding not named"]},{"year":2014,"claim":"A germline SEMA4A mutation was linked to enhanced proliferative signaling, implicating SEMA4A variation in cancer cell behavior.","evidence":"Reconstitution of WT vs V78M SEMA4A in deficient HCT-116 cells, MAPK/Erk and PI3K/Akt assays, cell cycle analysis","pmids":["25307848"],"confidence":"Medium","gaps":["Receptor and mechanism driving mutant gain-of-signaling not defined","In vivo tumorigenic relevance not established"]},{"year":2015,"claim":"This study identified Plexin-B2 as the functional CD8+ T cell receptor and placed SEMA4A upstream of mTORC1 in driving effector differentiation.","evidence":"Sema4A knockout mice, Listeria infection, mTORC1/mTORC2 assays, recombinant Sema4A rescue, receptor identification","pmids":["26116513"],"confidence":"High","gaps":["How Plexin-B2 engagement biases mTORC1 over mTORC2 not resolved","Intracellular adaptors linking receptor to mTOR not identified"]},{"year":2016,"claim":"Reverse signaling was established: SEMA4A acts as a receptor when bound by Plexin-B1, recruiting Scrib to suppress Rac1/Cdc42 and control migration.","evidence":"Mass spectrometry, siRNA screen, Co-IP, Rac1/Cdc42 activity and migration assays in cancer cells and DCs","pmids":["28007914"],"confidence":"High","gaps":["Intracellular motif of SEMA4A mediating Scrib recruitment not mapped","Physiological contexts of reverse signaling in vivo not delineated"]},{"year":2020,"claim":"Cell-source dissection showed hematopoietic SEMA4A specifically promotes the effector phase of Th17-mediated neuroinflammation.","evidence":"Adoptive transfer EAE with Sema4A knockout recipients and bone marrow chimeras","pmids":["32169103"],"confidence":"Medium","gaps":["Specific hematopoietic cell type providing SEMA4A not pinpointed","Receptor mediating the Th17 effector effect not defined"]},{"year":2021,"claim":"SEMA4A was placed downstream of IL-33 as an intrinsic requirement for IL-33-driven antitumor CD8+ T cell responses.","evidence":"Syngeneic tumor models, Sema4A knockout mice, IL-33 administration, tumor-infiltrating CD8+ IFN-γ assays","pmids":["34380650"],"confidence":"Medium","gaps":["Mechanism of IL-33 induction of SEMA4A on DCs not detailed","Direct DC-to-CD8 SEMA4A signaling in vivo not visualized"]},{"year":2024,"claim":"A new ligand-receptor axis emerged: neutrophil-derived SEMA4A signals via Plexin-D1 to protect myeloid-biased HSC epigenetic state and inflammatory resilience.","evidence":"Sema4A knockout mice, bone marrow reconstitution, epigenetic profiling, HSC functional assays, Plexin-D1 identification (preprint)","pmids":[],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed","Mechanism linking Plexin-D1 to epigenetic maintenance not detailed"]},{"year":2025,"claim":"SEMA4A was shown to act through Plexin-B2 in muscle to block atrophy and promote anabolism, defining a non-immune tissue-protective role.","evidence":"AAV Sema4A overexpression, dexamethasone atrophy and injury models, C2C12 gain/loss-of-function, FoxO3a and PI3K-AKT-mTOR analyses","pmids":["42216457"],"confidence":"Medium","gaps":["Source of physiological SEMA4A acting on muscle not established","How one ligand-receptor pair coordinates FoxO3a suppression and PI3K-AKT-mTOR activation not detailed"]},{"year":null,"claim":"How a single semaphorin selects among multiple receptors (Tim-2, Plexin-B1/B2/B3, Plexin-D1) and switches between forward-ligand and reverse-receptor modes across tissues remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model for receptor selection across cell types","Structural basis of bidirectional signaling not defined","Role of shedding in tuning ligand vs membrane signaling unclear"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,2,7,12]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[8]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,5]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,3]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,5,7,9,10]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,7,8,12]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2]}],"complexes":[],"partners":["TIMD2","PLXNB1","PLXNB2","PLXNB3","PLXND1","SCRIB","RND1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H3S1","full_name":"Semaphorin-4A","aliases":["Semaphorin-B","Sema B"],"length_aa":761,"mass_kda":83.6,"function":"Cell surface receptor for PLXNB1, PLXNB2, PLXNB3 and PLXND1 that plays an important role in cell-cell signaling (By similarity). Regulates glutamatergic and GABAergic synapse development (By similarity). Promotes the development of inhibitory synapses in a PLXNB1-dependent manner and promotes the development of excitatory synapses in a PLXNB2-dependent manner (By similarity). Plays a role in priming antigen-specific T-cells, promotes differentiation of Th1 T-helper cells, and thereby contributes to adaptive immunity (By similarity). Promotes phosphorylation of TIMD2 (By similarity). Inhibits angiogenesis (By similarity). Promotes axon growth cone collapse (By similarity). Inhibits axonal extension by providing local signals to specify territories inaccessible for growing axons (By similarity)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9H3S1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SEMA4A","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SEMA4A","total_profiled":1310},"omim":[{"mim_id":"610283","title":"CONE-ROD DYSTROPHY 10; CORD10","url":"https://www.omim.org/entry/610283"},{"mim_id":"610282","title":"RETINITIS PIGMENTOSA 35; RP35","url":"https://www.omim.org/entry/610282"},{"mim_id":"607292","title":"SEMAPHORIN 4A; SEMA4A","url":"https://www.omim.org/entry/607292"},{"mim_id":"605549","title":"CONE-ROD DYSTROPHY 8; CORD8","url":"https://www.omim.org/entry/605549"},{"mim_id":"602069","title":"NEUROPILIN 1; NRP1","url":"https://www.omim.org/entry/602069"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"epididymis","ntpm":48.4}],"url":"https://www.proteinatlas.org/search/SEMA4A"},"hgnc":{"alias_symbol":["SemB","FLJ12287","CORD10"],"prev_symbol":["SEMAB"]},"alphafold":{"accession":"Q9H3S1","domains":[{"cath_id":"2.130.10.10","chopping":"217-413","consensus_level":"medium","plddt":92.3705,"start":217,"end":413},{"cath_id":"3.30.1680.10","chopping":"501-548","consensus_level":"medium","plddt":87.2377,"start":501,"end":548},{"cath_id":"2.60.40.10","chopping":"566-668","consensus_level":"high","plddt":83.0874,"start":566,"end":668},{"cath_id":"2.40.128","chopping":"64-215","consensus_level":"medium","plddt":96.4674,"start":64,"end":215}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H3S1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H3S1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H3S1-F1-predicted_aligned_error_v6.png","plddt_mean":84.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SEMA4A","jax_strain_url":"https://www.jax.org/strain/search?query=SEMA4A"},"sequence":{"accession":"Q9H3S1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H3S1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H3S1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H3S1"}},"corpus_meta":[{"pmid":"12374982","id":"PMC_12374982","title":"Class IV semaphorin Sema4A enhances T-cell activation and interacts with Tim-2.","date":"2002","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/12374982","citation_count":269,"is_preprint":false},{"pmid":"15780988","id":"PMC_15780988","title":"Nonredundant roles of Sema4A in the immune system: defective T cell priming and Th1/Th2 regulation in Sema4A-deficient mice.","date":"2005","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/15780988","citation_count":136,"is_preprint":false},{"pmid":"16199541","id":"PMC_16199541","title":"Identification of novel mutations in the SEMA4A gene associated with retinal degenerative diseases.","date":"2005","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16199541","citation_count":63,"is_preprint":false},{"pmid":"25307848","id":"PMC_25307848","title":"Germline variants in the SEMA4A gene predispose to familial colorectal cancer type X.","date":"2014","source":"Nature 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myeloma.","date":"2022","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/35134130","citation_count":30,"is_preprint":false},{"pmid":"23007237","id":"PMC_23007237","title":"An inhibitory role for Sema4A in antigen-specific allergic asthma.","date":"2012","source":"Journal of clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/23007237","citation_count":26,"is_preprint":false},{"pmid":"22956603","id":"PMC_22956603","title":"SEMA4A mutations lead to susceptibility to light irradiation, oxidative stress, and ER stress in retinal pigment epithelial cells.","date":"2012","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/22956603","citation_count":16,"is_preprint":false},{"pmid":"30270262","id":"PMC_30270262","title":"Sema4A Responds to Hypoxia and Is Involved in Breast Cancer Progression.","date":"2018","source":"Biological & pharmaceutical 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cell","url":"https://pubmed.ncbi.nlm.nih.gov/41072416","citation_count":2,"is_preprint":false},{"pmid":"31876207","id":"PMC_31876207","title":"T-cell specific upregulation of Sema4A as risk factor for autoimmunity in systemic lupus erythematosus and rheumatoid arthritis.","date":"2019","source":"Autoimmunity","url":"https://pubmed.ncbi.nlm.nih.gov/31876207","citation_count":2,"is_preprint":false},{"pmid":"25519959","id":"PMC_25519959","title":"[Sema4A as a biomarker predicting responsiveness to IFN β treatment].","date":"2014","source":"Rinsho shinkeigaku = Clinical neurology","url":"https://pubmed.ncbi.nlm.nih.gov/25519959","citation_count":1,"is_preprint":false},{"pmid":"40756031","id":"PMC_40756031","title":"Deciphering the role of SEMA4A/MAPK signaling in sepsis: insights from Mendelian randomization, transcriptomic, single-cell sequencing analyses, and vitro experiments.","date":"2025","source":"Frontiers in cellular and infection microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/40756031","citation_count":0,"is_preprint":false},{"pmid":"39457718","id":"PMC_39457718","title":"A Pilot Study of the Role of Semaphorin 4A (sema4A) and 3C (sema3C) in Non-Muscle-Invasive Bladder Cancer (NMIBC).","date":"2024","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/39457718","citation_count":0,"is_preprint":false},{"pmid":"42216457","id":"PMC_42216457","title":"Sema4A Protects Against Muscle Atrophy and Promotes Repair by Regulating Intracellular Metabolic Signalling.","date":"2026","source":"Journal of cachexia, sarcopenia and muscle","url":"https://pubmed.ncbi.nlm.nih.gov/42216457","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.03.03.640303","title":"Granulocyte Derived Resistin Inhibits Monocyte Maturation and Induces Immune Suppression in CMML","date":"2025-03-07","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.03.640303","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.11.12.622506","title":"Semaphorin 4A maintains functional diversity of the hematopoietic stem cell pool","date":"2024-11-13","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.12.622506","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.10.16.618445","title":"Microglia attenuate regenerative neurogenesis via  <i>sema4ab</i>  after spinal cord injury in zebrafish","date":"2024-10-18","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.16.618445","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.10.21.619349","title":"Hippo-  <i>vgll3</i>  signaling may contribute to sex differences in Atlantic salmon maturation age via contrasting adipose dynamics","date":"2024-10-24","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.21.619349","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15715,"output_tokens":3653,"usd":0.05097,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11247,"output_tokens":4043,"usd":0.078655,"stage2_stop_reason":"end_turn"},"total_usd":0.129625,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"Sema4A, expressed on dendritic cells and B cells, enhances T-cell activation and differentiation in vitro and in vivo; expression cloning identified Tim-2 (a T-cell immunoglobulin and mucin domain protein expressed on activated T cells) as the Sema4A receptor.\",\n      \"method\": \"Expression cloning, in vitro T-cell activation assays, in vivo immunization, monoclonal antibody blocking experiments\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — receptor identified by expression cloning, functional validation with blocking antibodies in vivo, replicated in subsequent studies\",\n      \"pmids\": [\"12374982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Sema4A provides a costimulatory signal required for T cell priming and Th1 differentiation; DC-derived Sema4A is important for T cell priming while T cell-derived Sema4A (upregulated on Th1-differentiating cells) is required for Th1 responses and T-bet expression. Loss of Sema4A impairs allostimulatory activity of DCs and Th differentiation.\",\n      \"method\": \"Sema4A knockout mice, bone marrow reconstitution with antigen-pulsed DCs, in vitro Th differentiation assays, in vivo antigen-specific T cell priming\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with defined cellular phenotypes, cell-type-specific reconstitution experiments, replicated across multiple assays in one rigorous study\",\n      \"pmids\": [\"15780988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Sema4A binds Plexin-B1, -B2, and -B3 and induces growth cone collapse in hippocampal neurons through B-type plexin-mediated signaling; the intracellular signal is transmitted through Rnd1 (a Rho family GTPase), and Sema4A-induced growth cone collapse is blocked by constitutively active R-Ras, indicating that Sema4A acts by down-regulating R-Ras activity.\",\n      \"method\": \"Transfection of COS-7 cells with plexin/Rnd1 expression vectors, COS-7 cell contraction assay, hippocampal neuron growth cone collapse assay, dominant-active R-Ras rescue experiment\",\n      \"journal\": \"International journal of molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — receptor-ligand binding demonstrated by transfection, functional assays with mutagenesis-equivalent constructs (constitutively active R-Ras), multiple orthogonal methods in one study\",\n      \"pmids\": [\"20043131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Sema4A mutants D345H and F350C mis-localize to the ER instead of the plasma membrane, rendering retinal pigment epithelial cells susceptible to light irradiation, oxidative stress, and ER stress, and suppressing phagocytosis; in zebrafish, human mutant SEMA4A increased ER stress marker ddit3 mRNA under ER stress conditions.\",\n      \"method\": \"Confocal microscopy for intracellular localization, overexpression of mutant vs. wild-type SEMA4A in ARPE-19 cells, GRP78 expression assay, phagocytosis assay, tunicamycin and H2O2 cell death assays, zebrafish ER stress model\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional consequence, multiple cellular assays, single lab\",\n      \"pmids\": [\"22956603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Sema4A is shed from DCs in a metalloproteinase-dependent manner; DC-derived Sema4A promotes both Th1 and Th17 cell differentiation.\",\n      \"method\": \"Serum Sema4A measurement, DC surface expression analysis, metalloproteinase inhibitor experiments, Th1/Th17 differentiation assays in MS patients and controls\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — metalloproteinase-dependent shedding demonstrated pharmacologically, DC-derived Sema4A linked to Th differentiation, single lab, partial mechanistic follow-up\",\n      \"pmids\": [\"22491253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Sema4A inhibits Th2-type immune responses; Sema4A-Fc directly inhibits IL-4-producing OVA-specific CD4+ T cells and ameliorates airway hyperreactivity and lung inflammation in an asthma model, with inhibitory effects observed even in Tim-2-deficient mice, indicating the inhibitory effect on Th2 is not solely through Tim-2.\",\n      \"method\": \"Sema4A knockout mice on BALB/c background, in vivo OVA-sensitization/challenge asthma model, systemic Sema4A-Fc administration, Tim-2-deficient mice, in vitro T cell cytokine assays\",\n      \"journal\": \"Journal of clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function KO and gain-of-function Fc-fusion with defined cellular phenotypes, epistasis with Tim-2 KO, single lab\",\n      \"pmids\": [\"23007237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SEMA4A germline mutation V78M leads to significantly increased MAPK/Erk and PI3K/Akt signaling as well as enhanced cell cycle progression compared to wild-type SEMA4A when expressed in SEMA4A-deficient HCT-116 colorectal cancer cells.\",\n      \"method\": \"Re-expression of wild-type vs. V78M SEMA4A in SEMA4A-deficient HCT-116 cells, MAPK/Erk and PI3K/Akt signaling assays, cell cycle analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reconstitution with mutant vs. wild-type, pathway-level readout, single lab\",\n      \"pmids\": [\"25307848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SEMA4A regulates CD8+ T cell activation and differentiation by activating mTORC1; SEMA4A-deficient CD8+ T cells show reduced mTORC1 activity and elevated mTORC2 activity, impaired IFN-γ/TNF-α production, and reduced effector molecule expression. Plexin-B2 was identified as the functional SEMA4A receptor on CD8+ T cells. Recombinant Sema4A protein restored IFN-γ production and mTORC1 activity in SEMA4A-deficient CD8+ T cells.\",\n      \"method\": \"SEMA4A knockout mice, Listeria monocytogenes infection model, mTORC1/mTORC2 activity assays, cytokine measurement, recombinant Sema4A rescue experiment, receptor identification\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined signaling phenotype, receptor identification, rescue with recombinant protein, in vivo infection model, multiple orthogonal methods\",\n      \"pmids\": [\"26116513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Sema4A functions as a receptor (not only a ligand) and transduces reverse signals triggered by Plexin-B1 binding; this reverse signaling promotes interaction of Sema4A with the polarity protein Scrib, displacing Scrib from its complex with the Rac/Cdc42 exchange factor βPIX, thereby decreasing Rac1 and Cdc42 GTPase activity and regulating cell migration in cancer cells and dendritic cells.\",\n      \"method\": \"Mass spectrometry, siRNA screening, Co-IP/pulldown for Sema4A–Scrib interaction, Rac1/Cdc42 activity assays, cell migration assays in cancer cells and DCs\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — mass spectrometry identification of Scrib, confirmed by Co-IP, mechanistic pathway validated by siRNA and GTPase activity assays, multiple orthogonal methods in one study\",\n      \"pmids\": [\"28007914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Sema4A expressed on hematopoietic cells (not CNS-resident cells) accelerates Th17 cell-mediated neuroinflammation in the effector phase; adoptive transfer of Th17-skewed encephalitogenic T cells into Sema4A-deficient recipients showed significantly reduced disease severity, while Th1-skewed transfer showed no difference.\",\n      \"method\": \"Adoptive transfer EAE model, Sema4A knockout recipient mice, bone marrow chimera experiments, clinical scoring and CNS cellular infiltration analysis\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via KO recipients, bone marrow chimera for cell-type specificity, defined Th17-specific phenotype, single lab\",\n      \"pmids\": [\"32169103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IL-33 induces dendritic cells to express Sema4A, and Sema4A is intrinsically required for the antitumor effects of IL-33; absence of Sema4A abolished IL-33-mediated tumor growth inhibition and IFN-γ upregulation by tumor-infiltrating CD8+ T cells.\",\n      \"method\": \"Syngeneic mouse tumor models, Sema4A knockout mice, IL-33 administration, tumor growth measurement, IFN-γ production assay by tumor-infiltrating CD8+ T cells\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined in vivo tumor phenotype, cytokine pathway placement, single lab\",\n      \"pmids\": [\"34380650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Sema4A, produced mainly by neutrophils, signals via Plexin D1 on myeloid-biased hematopoietic stem cells (myHSC) to safeguard their epigenetic state and confer resilience to inflammatory stress; absence of Sema4A leads to myHSC inflammatory hyper-responsiveness, excessive myHSC expansion, myeloid bias, and profound loss of regenerative function with age.\",\n      \"method\": \"Sema4A knockout mice, bone marrow reconstitution, epigenetic profiling, HSC subset functional assays, cell-surface receptor identification (Plexin D1)\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined HSC phenotype, receptor identification, mechanistic epigenetic readout, preprint not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In skeletal muscle, Sema4A signals through Plexin-B2 to suppress FoxO3a nuclear translocation and inhibit atrogene expression while simultaneously reactivating the PI3K-AKT-mTOR anabolic pathway; AAV-mediated Sema4A restoration attenuates dexamethasone-induced muscle atrophy and accelerates injury recovery in mice.\",\n      \"method\": \"AAV-mediated Sema4A overexpression, dexamethasone-induced atrophy model, acute injury model, C2C12 myotube gain/loss-of-function, FoxO3a nuclear translocation assay, PI3K-AKT-mTOR pathway analysis\",\n      \"journal\": \"Journal of cachexia, sarcopenia and muscle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo AAV rescue, in vitro gain/loss-of-function, defined signaling pathway readout, receptor identified, single lab\",\n      \"pmids\": [\"42216457\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SEMA4A is a class IV transmembrane semaphorin that functions both as a ligand (binding Plexin-B1/B2/B3 or Tim-2 on target cells) and as a receptor undergoing reverse signaling (when bound by Plexin-B1); as a ligand it activates mTORC1, promotes Th1/Th17 differentiation and CD8+ T cell effector function, induces neuronal growth cone collapse via Rnd1 and R-Ras suppression downstream of B-type plexins, and protects skeletal muscle via PI3K-AKT-mTOR/FoxO3a signaling through Plexin-B2; as a reverse-signaling receptor it recruits the polarity protein Scrib to reduce Rac1/Cdc42 activity and regulate cell migration; disease-associated mutations (D345H, F350C) cause ER retention leading to increased susceptibility to ER/oxidative stress in retinal cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SEMA4A is a class IV transmembrane semaphorin that operates bidirectionally as both a ligand and a reverse-signaling receptor to regulate immune cell differentiation, neuronal guidance, and tissue homeostasis [#0, #2, #8]. In the immune system it acts as a costimulatory ligand required for T cell priming and Th1/Th17 differentiation, with dendritic-cell-derived SEMA4A driving priming and T-cell-derived SEMA4A sustaining Th1 responses through T-bet expression [#1]; it was first defined through the receptor Tim-2 on activated T cells [#0], and is released from dendritic cells by metalloproteinase-dependent shedding [#4]. On CD8+ T cells SEMA4A engages Plexin-B2 to activate mTORC1 (while restraining mTORC2), driving effector cytokine production, a role that places it downstream of IL-33 in antitumor CD8+ responses [#7, #10]. SEMA4A also inhibits Th2 responses through a Tim-2-independent mechanism [#5] and, on hematopoietic cells, accelerates Th17-mediated neuroinflammation [#9]. As a guidance ligand, SEMA4A binds Plexin-B1/B2/B3 to induce neuronal growth cone collapse via the Rho-family GTPase Rnd1 and downregulation of R-Ras [#2]. Reciprocally, SEMA4A itself transduces reverse signals upon Plexin-B1 binding, recruiting the polarity protein Scrib away from the Rac/Cdc42 exchange factor βPIX to lower Rac1/Cdc42 activity and regulate cell migration [#8]. Through Plexin-B2 it additionally protects skeletal muscle by suppressing FoxO3a nuclear translocation and reactivating PI3K-AKT-mTOR anabolic signaling [#12]. Disease-associated mutations (D345H, F350C) cause ER retention that renders retinal pigment epithelial cells susceptible to oxidative and ER stress [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Establishing that SEMA4A is an immune ligand rather than solely a neuronal molecule, this work showed it enhances T-cell activation and identified its first receptor.\",\n      \"evidence\": \"Expression cloning identifying Tim-2, in vitro/in vivo T-cell activation with blocking antibodies\",\n      \"pmids\": [\"12374982\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish downstream signaling from Tim-2\", \"Did not address other receptors used by SEMA4A\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Genetic loss-of-function defined SEMA4A as a costimulatory signal partitioned by cell source, with DC-derived protein driving priming and T-cell-derived protein driving Th1 polarization.\",\n      \"evidence\": \"Sema4A knockout mice, cell-type-specific DC reconstitution, in vitro Th differentiation\",\n      \"pmids\": [\"15780988\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor on responding T cells for Th1 effect not defined\", \"Molecular signaling linking SEMA4A to T-bet not resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"This work mapped SEMA4A's neuronal guidance activity to B-type plexins and a defined intracellular GTPase cascade.\",\n      \"evidence\": \"Transfection binding assays, COS-7 contraction and hippocampal growth cone collapse, constitutively active R-Ras rescue\",\n      \"pmids\": [\"20043131\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not distinguish contributions of individual B-type plexins in vivo\", \"Link between Rnd1 and R-Ras suppression not biochemically detailed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Disease mutations were shown to impair SEMA4A trafficking, connecting altered subcellular localization to stress susceptibility in retinal cells.\",\n      \"evidence\": \"Confocal localization of D345H/F350C mutants, ER/oxidative stress and phagocytosis assays in ARPE-19 cells, zebrafish ER stress model\",\n      \"pmids\": [\"22956603\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish patient-level causation in a family study\", \"Mechanism by which ER retention triggers stress susceptibility not detailed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Two studies extended SEMA4A's immune role, showing metalloproteinase-dependent shedding generates a soluble form and that SEMA4A suppresses Th2 responses partly independent of Tim-2.\",\n      \"evidence\": \"Metalloproteinase inhibitor experiments and Th1/Th17 assays; Sema4A-Fc administration and Tim-2-deficient mice in an asthma model\",\n      \"pmids\": [\"22491253\", \"23007237\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The non-Tim-2 receptor mediating Th2 inhibition was not identified\", \"Protease responsible for shedding not named\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"A germline SEMA4A mutation was linked to enhanced proliferative signaling, implicating SEMA4A variation in cancer cell behavior.\",\n      \"evidence\": \"Reconstitution of WT vs V78M SEMA4A in deficient HCT-116 cells, MAPK/Erk and PI3K/Akt assays, cell cycle analysis\",\n      \"pmids\": [\"25307848\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor and mechanism driving mutant gain-of-signaling not defined\", \"In vivo tumorigenic relevance not established\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"This study identified Plexin-B2 as the functional CD8+ T cell receptor and placed SEMA4A upstream of mTORC1 in driving effector differentiation.\",\n      \"evidence\": \"Sema4A knockout mice, Listeria infection, mTORC1/mTORC2 assays, recombinant Sema4A rescue, receptor identification\",\n      \"pmids\": [\"26116513\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Plexin-B2 engagement biases mTORC1 over mTORC2 not resolved\", \"Intracellular adaptors linking receptor to mTOR not identified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Reverse signaling was established: SEMA4A acts as a receptor when bound by Plexin-B1, recruiting Scrib to suppress Rac1/Cdc42 and control migration.\",\n      \"evidence\": \"Mass spectrometry, siRNA screen, Co-IP, Rac1/Cdc42 activity and migration assays in cancer cells and DCs\",\n      \"pmids\": [\"28007914\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Intracellular motif of SEMA4A mediating Scrib recruitment not mapped\", \"Physiological contexts of reverse signaling in vivo not delineated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Cell-source dissection showed hematopoietic SEMA4A specifically promotes the effector phase of Th17-mediated neuroinflammation.\",\n      \"evidence\": \"Adoptive transfer EAE with Sema4A knockout recipients and bone marrow chimeras\",\n      \"pmids\": [\"32169103\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific hematopoietic cell type providing SEMA4A not pinpointed\", \"Receptor mediating the Th17 effector effect not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"SEMA4A was placed downstream of IL-33 as an intrinsic requirement for IL-33-driven antitumor CD8+ T cell responses.\",\n      \"evidence\": \"Syngeneic tumor models, Sema4A knockout mice, IL-33 administration, tumor-infiltrating CD8+ IFN-γ assays\",\n      \"pmids\": [\"34380650\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of IL-33 induction of SEMA4A on DCs not detailed\", \"Direct DC-to-CD8 SEMA4A signaling in vivo not visualized\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A new ligand-receptor axis emerged: neutrophil-derived SEMA4A signals via Plexin-D1 to protect myeloid-biased HSC epigenetic state and inflammatory resilience.\",\n      \"evidence\": \"Sema4A knockout mice, bone marrow reconstitution, epigenetic profiling, HSC functional assays, Plexin-D1 identification (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint not yet peer-reviewed\", \"Mechanism linking Plexin-D1 to epigenetic maintenance not detailed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"SEMA4A was shown to act through Plexin-B2 in muscle to block atrophy and promote anabolism, defining a non-immune tissue-protective role.\",\n      \"evidence\": \"AAV Sema4A overexpression, dexamethasone atrophy and injury models, C2C12 gain/loss-of-function, FoxO3a and PI3K-AKT-mTOR analyses\",\n      \"pmids\": [\"42216457\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Source of physiological SEMA4A acting on muscle not established\", \"How one ligand-receptor pair coordinates FoxO3a suppression and PI3K-AKT-mTOR activation not detailed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single semaphorin selects among multiple receptors (Tim-2, Plexin-B1/B2/B3, Plexin-D1) and switches between forward-ligand and reverse-receptor modes across tissues remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model for receptor selection across cell types\", \"Structural basis of bidirectional signaling not defined\", \"Role of shedding in tuning ligand vs membrane signaling unclear\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 2, 7, 12]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 5, 7, 9, 10]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 7, 8, 12]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TIMD2\", \"PLXNB1\", \"PLXNB2\", \"PLXNB3\", \"PLXND1\", \"SCRIB\", \"RND1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}