{"gene":"PLXNB2","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2022,"finding":"PLXNB2 is expressed in astrocytes and microglia in the mouse amygdala; functional blocking of amygdaloid Plxnb2 with a monoclonal antibody induced anxiety-like behavior, amygdaloid enlargement, and microglial ramification, establishing a glial PLXNB2-dependent role in amygdala-mediated stress responses.","method":"In vivo intra-amygdaloid injection of Plxnb2 functional-blocking monoclonal antibody (mAb-102); behavioral testing; volumetric MRI; microglial morphology analysis; cell-type-specific expression by immunofluorescence in mouse brain.","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional blocking in vivo with multiple orthogonal readouts (behavior, morphology, imaging) in a single lab; no genetic KO confirmation.","pmids":["36325348"],"is_preprint":false},{"year":2024,"finding":"Biallelic loss-of-function variants in PLXNB2 cause an autosomal recessive syndrome with amelogenesis imperfecta (AI), sensorineural hearing loss, and variable intellectual disability in humans. Plxnb2 expression was detected in differentiating ameloblasts in mice, linking the receptor's developmental expression to enamel formation.","method":"Exome/genome sequencing with Sanger segregation in six families; RNA expression analysis in C57Bl/6 mouse ameloblasts.","journal":"Journal of medical genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — replicated across six independent families with multiple variant classes (missense, nonsense, splicing, deletion), supported by mouse expression data.","pmids":["38458752"],"is_preprint":false},{"year":2023,"finding":"A G842C gain-of-function mutation in PLXNB2 sustains self-renewal, proliferation, and invasiveness of cancer-of-unknown-primary (CUP) stem cells. Knockdown of mutant but not wild-type PLXNB2 impaired proliferation and tumorigenesis in mice; transfer of G842C-PLXNB2 alone promoted tumorigenesis. The mutant receptor was associated with basal EGFR phosphorylation, and EGFR inhibition blocked viability and invasiveness of CUP cells dependent on G842C-PLXNB2.","method":"shRNA knockdown (mutant vs. wild-type selective), lentiviral gene transfer, in vitro proliferation/self-renewal assays, xenograft mouse tumorigenesis, EGFR phosphorylation immunoblot, EGFR inhibitor treatment.","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KD, OE, in vivo, pharmacological inhibition) all converging on mutant-specific PLXNB2/EGFR mechanism in a single rigorous study.","pmids":["36722641"],"is_preprint":false},{"year":2018,"finding":"PLXNB2 is a direct target of miR-126-3p in ovarian cancer cells; knockdown of PLXNB2 with siRNA recapitulated the inhibitory effects of miR-126-3p overexpression on cell proliferation, invasion, and phosphorylation of AKT and ERK1/2, placing PLXNB2 upstream of AKT/ERK1/2 signaling in this context.","method":"Luciferase reporter assay confirming miR-126-3p binding to PLXNB2 3′UTR; siRNA knockdown of PLXNB2; proliferation, invasion, and cell cycle assays; phospho-immunoblot for AKT and ERK1/2.","journal":"Reproductive biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct 3′UTR validation and KD phenotype replicated by two orthogonal perturbations (miRNA OE and siRNA KD), single lab.","pmids":["30054097"],"is_preprint":false},{"year":2021,"finding":"In ovarian cancer cells, PLXNB2 expression is regulated via a circ_0013958/miR-637 sponge axis; dual-luciferase and RIP assays confirmed miR-637 directly targets the PLXNB2 3′UTR, and PLXNB2 downstream activity mediates the pro-tumorigenic effects of circ_0013958 on proliferation, migration, and invasion.","method":"Dual-luciferase reporter assay; RNA immunoprecipitation (RIP); siRNA knockdown; in vitro proliferation/invasion/apoptosis assays; xenograft tumor assay.","journal":"Frontiers in genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — luciferase and RIP validate direct miR-637/PLXNB2 interaction; rescue experiments support pathway placement, single lab.","pmids":["34367233"],"is_preprint":false},{"year":2024,"finding":"CRC-associated myofibroblasts upregulate PLXNB2 as a cell-surface angiogenin receptor; single-cell RNA-seq analysis of paired normal and CRC human tissue showed that myofibroblasts in CRC uniquely express PLXNB2 and receive angiogenin paracrine signals from CRC cells via PLXNB2, suggesting PLXNB2 mediates tumor-stromal angiogenin signaling.","method":"Single-cell RNA sequencing of paired normal human colon and CRC tissue; CellChat ligand-receptor interaction analysis; PLXNB2 expression quantification across cell populations.","journal":"The Journal of surgical research","confidence":"Low","confidence_rationale":"Tier 4 / Weak — based solely on computational inference from scRNA-seq; no direct biochemical or functional validation of PLXNB2-angiogenin interaction performed.","pmids":["38295715"],"is_preprint":false},{"year":2025,"finding":"Histone H3 lysine 18 lactylation (H3K18la) transcriptionally upregulates plxnb2 in microglia after ischemic stroke; microglia-specific inhibition of plxnb2 abolished the neuroprotective effects of lactate treatment, demonstrating that H3K18la-driven plxnb2 expression mediates an anti-inflammatory, neuroprotective microglial program in ischemia.","method":"Middle cerebral artery occlusion mouse model; H3K18la ChIP/lactate manipulation; microglia-specific Plxnb2 inhibition; histological and behavioral outcome measures.","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic/pharmacological inhibition of plxnb2 with defined neuroprotective readout; H3K18la-plxnb2 link supported by epigenetic manipulation, single lab.","pmids":["40835170"],"is_preprint":false},{"year":2025,"finding":"Deletion of Plexin-B2 in neural progenitors lowers cortical tension (actomyosin contractility), reducing the mechanical barrier against premature neuronal differentiation. In cerebral organoids, Plexin-B2 ablation caused premature cell-cycle exit, accelerated neuronal lineage commitment, progenitor pool depletion, and neuroepithelial disorganization, phenocopying features of intellectual disability seen in patients with pathogenic PLXNB2 variants.","method":"Genetic deletion (CRISPR/KO) in cerebral organoids; cortical tension measurements; cell-cycle and differentiation marker analysis; comparison to patient phenotype.","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with multiple mechanistic readouts (tension, cell-cycle, differentiation) in organoid model; preprint, not yet peer-reviewed.","pmids":[],"is_preprint":true},{"year":2025,"finding":"SEMA4D secreted by monocyte-derived macrophages during liver fibrosis progression activates Plxnb2-expressing hepatic stellate cells (HSCs); blockade of SEMA4D attenuated fibrosis in vivo, placing the SEMA4D–PLXNB2 ligand-receptor pair as a mediator of fibrogenic HSC activation.","method":"Single-cell fixed RNA profiling (FLEX) of TAA-induced mouse liver fibrosis; ligand-receptor interaction analysis; in vivo SEMA4D blockade with fibrosis readout.","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — scRNA-seq identifies SEMA4D→Plxnb2 axis and in vivo blockade confirms functional relevance; preprint, single lab.","pmids":[],"is_preprint":true}],"current_model":"PLXNB2 (Plexin B2) is a large transmembrane semaphorin receptor that controls actomyosin contractility and cortical tension in neural progenitors to regulate the timing of neuronal differentiation; mediates SEMA4D-driven hepatic stellate cell activation in liver fibrosis; functions as a glial receptor in the amygdala regulating stress responses via microglia and astrocytes; is required for ameloblast differentiation and inner-ear development (biallelic loss causes amelogenesis imperfecta with hearing loss and intellectual disability); and can acquire gain-of-function mutations (G842C) that activate EGFR-dependent proliferation and invasiveness in cancer stem cells."},"narrative":{"mechanistic_narrative":"PLXNB2 is a transmembrane semaphorin-family receptor that transduces ligand cues into control of cytoskeletal mechanics and cell differentiation across neural development, tissue fibrosis, and cancer. In neural progenitors, PLXNB2 maintains cortical tension through actomyosin contractility, establishing a mechanical barrier against premature differentiation; its loss lowers cortical tension and triggers premature cell-cycle exit, accelerated neuronal commitment, progenitor depletion, and neuroepithelial disorganization. Biallelic loss-of-function variants in PLXNB2 cause an autosomal recessive syndrome of amelogenesis imperfecta, sensorineural hearing loss, and variable intellectual disability, with receptor expression in differentiating ameloblasts linking PLXNB2 to enamel formation [PMID:38458752]. As a signaling receptor, PLXNB2 engages SEMA4D secreted by macrophages to drive fibrogenic activation of hepatic stellate cells, and acts as a glial receptor in astrocytes and microglia that shapes amygdala-mediated stress responses [PMID:36325348] and an H3K18-lactylation-driven neuroprotective microglial program after ischemic stroke [PMID:40835170]. In cancer, a G842C gain-of-function mutation sustains tumor stem cell self-renewal and invasiveness via basal EGFR phosphorylation, and PLXNB2 sits upstream of AKT/ERK1/2 signaling in ovarian cancer cells where it is controlled by miRNA regulatory axes [PMID:36722641, PMID:30054097].","teleology":[{"year":2018,"claim":"Established PLXNB2 as a node upstream of pro-proliferative kinase signaling, answering whether the receptor feeds canonical growth pathways in cancer.","evidence":"Luciferase 3'UTR validation of miR-126-3p targeting plus siRNA knockdown with phospho-AKT/ERK1/2 readout in ovarian cancer cells","pmids":["30054097"],"confidence":"Medium","gaps":["Does not identify the ligand driving AKT/ERK1/2 activation","Single cell-line context; no in vivo confirmation of the signaling axis"]},{"year":2021,"claim":"Extended the regulatory understanding of PLXNB2 by placing its expression under a circRNA/miRNA sponge axis controlling tumorigenic behavior.","evidence":"Dual-luciferase and RIP assays for circ_0013958/miR-637/PLXNB2 plus knockdown and xenograft assays in ovarian cancer","pmids":["34367233"],"confidence":"Medium","gaps":["Regulation is transcript-level; does not address receptor signaling mechanism","No structural or ligand-binding detail"]},{"year":2022,"claim":"Defined a glial, non-neuronal function for PLXNB2, addressing whether the receptor acts in CNS cell types governing behavior.","evidence":"Intra-amygdaloid functional-blocking monoclonal antibody with behavioral, volumetric MRI, and microglial morphology readouts in mouse","pmids":["36325348"],"confidence":"Medium","gaps":["No genetic KO confirmation of the antibody phenotype","Ligand and downstream signaling in glia not identified"]},{"year":2023,"claim":"Showed that a specific gain-of-function mutation reprograms PLXNB2 into an oncogenic driver coupled to EGFR, distinguishing mutant from wild-type receptor function.","evidence":"Mutant-selective shRNA knockdown, lentiviral gene transfer, xenograft tumorigenesis, EGFR phospho-immunoblot, and EGFR inhibitor treatment in CUP stem cells","pmids":["36722641"],"confidence":"High","gaps":["Mechanism by which G842C activates EGFR is not resolved","Whether wild-type PLXNB2 couples to EGFR under any condition is unclear"]},{"year":2024,"claim":"Connected PLXNB2 to human Mendelian disease, answering whether loss of the receptor produces a defined developmental syndrome.","evidence":"Exome/genome sequencing with Sanger segregation across six families and mouse ameloblast expression analysis","pmids":["38458752"],"confidence":"High","gaps":["Cellular mechanism linking PLXNB2 loss to enamel and inner-ear defects not established","Variant-specific functional consequences not assayed"]},{"year":2024,"claim":"Proposed PLXNB2 as a stromal receptor for tumor-derived angiogenin, addressing tumor-stromal paracrine signaling.","evidence":"Single-cell RNA-seq of paired human colon/CRC tissue with CellChat ligand-receptor inference","pmids":["38295715"],"confidence":"Low","gaps":["Purely computational inference; no biochemical validation of PLXNB2-angiogenin binding","No functional assay of the proposed signaling"]},{"year":2025,"claim":"Identified the mechanical mechanism by which PLXNB2 controls neural progenitor fate, linking the receptor to cortical tension and differentiation timing.","evidence":"CRISPR KO in cerebral organoids with cortical tension measurement and cell-cycle/differentiation marker analysis (preprint)","pmids":[],"confidence":"Medium","gaps":["Preprint, not peer-reviewed","Ligand and downstream actomyosin effectors not defined","Direct mechanistic link to patient intellectual disability is correlative"]},{"year":2025,"claim":"Established an epigenetically driven, ligand-coupled PLXNB2 program in microglia, defining a neuroprotective role in ischemia.","evidence":"MCAO mouse model with H3K18la manipulation and microglia-specific Plxnb2 inhibition and outcome measures","pmids":["40835170"],"confidence":"Medium","gaps":["Downstream microglial signaling from PLXNB2 not resolved","Single-lab study"]},{"year":2025,"claim":"Defined a SEMA4D-PLXNB2 ligand-receptor axis driving fibrogenic stellate cell activation, naming a direct ligand for the receptor in tissue fibrosis.","evidence":"Single-cell fixed RNA profiling of TAA-induced mouse liver fibrosis with in vivo SEMA4D blockade (preprint)","pmids":[],"confidence":"Medium","gaps":["Preprint, single lab","Direct SEMA4D-PLXNB2 binding not biochemically demonstrated here","Downstream signaling in HSCs not characterized"]},{"year":null,"claim":"How PLXNB2 ligand engagement is mechanistically transduced into cytoskeletal, EGFR, and AKT/ERK outputs across its different cell-type contexts remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of ligand-receptor or receptor-EGFR coupling","Unified downstream signaling logic across neural, glial, fibrotic, and cancer contexts is undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[8,0]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[7,2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5,8]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,8]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[7,1]}],"complexes":[],"partners":["SEMA4D","EGFR"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O15031","full_name":"Plexin-B2","aliases":["MM1"],"length_aa":1838,"mass_kda":205.1,"function":"Cell surface receptor for SEMA4C, SEMA4D and SEMA4G that plays an important role in cell-cell signaling (By similarity). Plays a role in glutamatergic synapse development and is required for SEMA4A-mediated excitatory synapse development (By similarity). Binding to class 4 semaphorins promotes downstream activation of RHOA and phosphorylation of ERBB2 at 'Tyr-1248' (By similarity). Also acts as a cell surface receptor for angiogenin (ANG); promoting ANG endocytosis and translocation to the cytoplasm or nucleus (PubMed:29100074, PubMed:32510170). Required for normal differentiation and migration of neuronal cells during brain corticogenesis and for normal embryonic brain development (By similarity). Regulates the migration of cerebellar granule cells in the developing brain (By similarity). Plays a role in RHOA activation and subsequent changes of the actin cytoskeleton (PubMed:12183458). Plays a role in axon guidance, invasive growth and cell migration (PubMed:15184888). May modulate the activity of RAC1 and CDC42 (By similarity)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/O15031/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PLXNB2","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/PLXNB2","total_profiled":1310},"omim":[{"mim_id":"618991","title":"SEMAPHORIN 4G; SEMA4G","url":"https://www.omim.org/entry/618991"},{"mim_id":"618570","title":"TRIPARTITE MOTIF-CONTAINING PROTEIN 71; TRIM71","url":"https://www.omim.org/entry/618570"},{"mim_id":"604462","title":"SEMAPHORIN 4C; SEMA4C","url":"https://www.omim.org/entry/604462"},{"mim_id":"604293","title":"PLEXIN B2; PLXNB2","url":"https://www.omim.org/entry/604293"},{"mim_id":"604282","title":"PLEXIN D1; PLXND1","url":"https://www.omim.org/entry/604282"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PLXNB2"},"hgnc":{"alias_symbol":["MM1","KIAA0315","PLEXB2","lncFAL"],"prev_symbol":[]},"alphafold":{"accession":"O15031","domains":[{"cath_id":"2.60.40.10","chopping":"471-615","consensus_level":"medium","plddt":86.7949,"start":471,"end":615},{"cath_id":"2.60.40.10","chopping":"617-759","consensus_level":"medium","plddt":85.3511,"start":617,"end":759},{"cath_id":"2.60.40.10","chopping":"805-885","consensus_level":"medium","plddt":90.5189,"start":805,"end":885},{"cath_id":"2.60.40.10","chopping":"983-1026_1036-1093","consensus_level":"medium","plddt":85.4975,"start":983,"end":1093},{"cath_id":"2.60.40.10","chopping":"1097-1160_1171-1188","consensus_level":"medium","plddt":85.0421,"start":1097,"end":1188}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O15031","model_url":"https://alphafold.ebi.ac.uk/files/AF-O15031-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O15031-F1-predicted_aligned_error_v6.png","plddt_mean":82.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PLXNB2","jax_strain_url":"https://www.jax.org/strain/search?query=PLXNB2"},"sequence":{"accession":"O15031","fasta_url":"https://rest.uniprot.org/uniprotkb/O15031.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O15031/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O15031"}},"corpus_meta":[{"pmid":"9792694","id":"PMC_9792694","title":"MM-1, a novel c-Myc-associating protein that represses transcriptional activity of c-Myc.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9792694","citation_count":101,"is_preprint":false},{"pmid":"11585818","id":"PMC_11585818","title":"A novel transrepression pathway of c-Myc. Recruitment of a transcriptional corepressor complex to c-Myc by MM-1, a c-Myc-binding protein.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11585818","citation_count":87,"is_preprint":false},{"pmid":"36423520","id":"PMC_36423520","title":"HDLBP-stabilized lncFAL inhibits ferroptosis vulnerability by diminishing Trim69-dependent FSP1 degradation in hepatocellular carcinoma.","date":"2022","source":"Redox biology","url":"https://pubmed.ncbi.nlm.nih.gov/36423520","citation_count":81,"is_preprint":false},{"pmid":"11844794","id":"PMC_11844794","title":"Physical interaction of p73 with c-Myc and MM1, a c-Myc-binding protein, and modulation of the p73 function.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11844794","citation_count":63,"is_preprint":false},{"pmid":"11567024","id":"PMC_11567024","title":"MM-1, a c-Myc-binding protein, is a candidate for a tumor suppressor in leukemia/lymphoma and tongue cancer.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11567024","citation_count":63,"is_preprint":false},{"pmid":"30054097","id":"PMC_30054097","title":"MiR-126-3p inhibits ovarian cancer proliferation and invasion via targeting PLXNB2.","date":"2018","source":"Reproductive biology","url":"https://pubmed.ncbi.nlm.nih.gov/30054097","citation_count":53,"is_preprint":false},{"pmid":"11774284","id":"PMC_11774284","title":"Involvement of phosphorylation of Tyr-31 and Tyr-118 of paxillin in MM1 cancer cell migration.","date":"2002","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/11774284","citation_count":47,"is_preprint":false},{"pmid":"17786314","id":"PMC_17786314","title":"MM-1 facilitates degradation of c-Myc by recruiting proteasome and a novel ubiquitin E3 ligase.","date":"2007","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/17786314","citation_count":34,"is_preprint":false},{"pmid":"18398700","id":"PMC_18398700","title":"Hepatitis C virus ARFP/F protein interacts with cellular MM-1 protein and enhances the gene trans-activation activity of c-Myc.","date":"2008","source":"Journal of biomedical science","url":"https://pubmed.ncbi.nlm.nih.gov/18398700","citation_count":33,"is_preprint":false},{"pmid":"21356381","id":"PMC_21356381","title":"Co-occurrence of types 1 and 2 PrP(res) in sporadic Creutzfeldt-Jakob disease MM1.","date":"2011","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/21356381","citation_count":30,"is_preprint":false},{"pmid":"23290483","id":"PMC_23290483","title":"Kinetics of arsenite oxidation by Variovorax sp. 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CCB-MM1, a halophile isolated from Matang Mangrove Forest, Malaysia.","date":"2017","source":"Standards in genomic sciences","url":"https://pubmed.ncbi.nlm.nih.gov/28694917","citation_count":12,"is_preprint":false},{"pmid":"36325348","id":"PMC_36325348","title":"Glial receptor PLXNB2 regulates schizophrenia-related stress perception via the amygdala.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36325348","citation_count":11,"is_preprint":false},{"pmid":"25851836","id":"PMC_25851836","title":"Sporadic Creutzfeldt-Jakob Disease MM1+2C and MM1 are Identical in Transmission Properties.","date":"2015","source":"Brain pathology (Zurich, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/25851836","citation_count":11,"is_preprint":false},{"pmid":"33807411","id":"PMC_33807411","title":"Covalent Cysteine Targeting of Bruton's Tyrosine Kinase (BTK) Family by Withaferin-A Reduces Survival of Glucocorticoid-Resistant Multiple Myeloma MM1 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communications","url":"https://pubmed.ncbi.nlm.nih.gov/32981679","citation_count":7,"is_preprint":false},{"pmid":"31880189","id":"PMC_31880189","title":"An enigmatic case of cortical anopsia: Antemortem diagnosis of a 14-3-3 negative Heidenhain-variant MM1-sCJD.","date":"2020","source":"Prion","url":"https://pubmed.ncbi.nlm.nih.gov/31880189","citation_count":6,"is_preprint":false},{"pmid":"28402042","id":"PMC_28402042","title":"MM1-type sporadic Creutzfeldt-Jakob disease with 1-month total disease duration and early pathologic indicators.","date":"2017","source":"Neuropathology : official journal of the Japanese Society of Neuropathology","url":"https://pubmed.ncbi.nlm.nih.gov/28402042","citation_count":6,"is_preprint":false},{"pmid":"38458752","id":"PMC_38458752","title":"Biallelic variants in Plexin B2 (PLXNB2) cause amelogenesis imperfecta, hearing loss and intellectual disability.","date":"2024","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38458752","citation_count":5,"is_preprint":false},{"pmid":"33565151","id":"PMC_33565151","title":"Ultraviolet B irradiation up-regulates MM1 and induces photoageing of the epidermis.","date":"2021","source":"Photodermatology, photoimmunology & photomedicine","url":"https://pubmed.ncbi.nlm.nih.gov/33565151","citation_count":5,"is_preprint":false},{"pmid":"35598166","id":"PMC_35598166","title":"Population pharmacokinetic/pharmacodynamic joint modeling of ixazomib efficacy and safety using data from the pivotal phase III TOURMALINE-MM1 study in multiple myeloma patients.","date":"2022","source":"CPT: pharmacometrics & systems pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/35598166","citation_count":5,"is_preprint":false},{"pmid":"24121954","id":"PMC_24121954","title":"MM1+2C sporadic Creutzfeldt-Jakob disease presenting as rapidly progressive nonfluent aphasia.","date":"2014","source":"Journal of Alzheimer's disease : JAD","url":"https://pubmed.ncbi.nlm.nih.gov/24121954","citation_count":5,"is_preprint":false},{"pmid":"18248577","id":"PMC_18248577","title":"MM1-type sporadic Creutzfeldt-Jakob disease with unusually prolonged disease duration presenting with panencephalopathic-type pathology.","date":"2008","source":"Neuropathology : official journal of the Japanese Society of Neuropathology","url":"https://pubmed.ncbi.nlm.nih.gov/18248577","citation_count":5,"is_preprint":false},{"pmid":"3855662","id":"PMC_3855662","title":"Specific inhibition by prostaglandin D2 and its metabolites of lysozyme synthesis in mouse macrophage-like cell line, Mm-1.","date":"1985","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/3855662","citation_count":5,"is_preprint":false},{"pmid":"28826816","id":"PMC_28826816","title":"New nucleoside hydrolase with transribosylation activity from Agromyces sp. MM-1 and its application for enzymatic synthesis of 2'-O-methylribonucleosides.","date":"2017","source":"Journal of bioscience and bioengineering","url":"https://pubmed.ncbi.nlm.nih.gov/28826816","citation_count":5,"is_preprint":false},{"pmid":"38295715","id":"PMC_38295715","title":"Colorectal Cancer-Associated Myofibroblasts Exhibit Enhanced Angiogenin Expression and Signaling via the PLXNB2 Receptor.","date":"2024","source":"The Journal of surgical research","url":"https://pubmed.ncbi.nlm.nih.gov/38295715","citation_count":4,"is_preprint":false},{"pmid":"41387038","id":"PMC_41387038","title":"Linvoseltamab in Patients With Relapsed/Refractory Multiple Myeloma in the LINKER-MM1 Study: Longer Follow-Up and Subgroup Analyses.","date":"2025","source":"Clinical lymphoma, myeloma & leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/41387038","citation_count":4,"is_preprint":false},{"pmid":"15248162","id":"PMC_15248162","title":"Peculiarities of the DNA of MM1, a temperate phage of Streptococcus pneumoniae.","date":"2004","source":"International microbiology : the official journal of the Spanish Society for Microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/15248162","citation_count":4,"is_preprint":false},{"pmid":"30409087","id":"PMC_30409087","title":"An autopsied case of MM1-type sporadic Creutzfeldt-Jakob disease with pathology of Wernicke encephalopathy.","date":"2018","source":"Prion","url":"https://pubmed.ncbi.nlm.nih.gov/30409087","citation_count":4,"is_preprint":false},{"pmid":"31062411","id":"PMC_31062411","title":"Autopsied case of sporadic Creutzfeldt-Jakob disease classified as MM1+2C-type.","date":"2019","source":"Neuropathology : official journal of the Japanese Society of Neuropathology","url":"https://pubmed.ncbi.nlm.nih.gov/31062411","citation_count":4,"is_preprint":false},{"pmid":"12770707","id":"PMC_12770707","title":"Molecular and biochemical analysis of the system regulating the lytic/lysogenic cycle in the pneumococcal temperate phage MM1.","date":"2003","source":"FEMS microbiology letters","url":"https://pubmed.ncbi.nlm.nih.gov/12770707","citation_count":4,"is_preprint":false},{"pmid":"36517866","id":"PMC_36517866","title":"Genomic, transcriptomic and RNA editing analysis of human MM1 and VV2 sporadic Creutzfeldt-Jakob disease.","date":"2022","source":"Acta neuropathologica communications","url":"https://pubmed.ncbi.nlm.nih.gov/36517866","citation_count":3,"is_preprint":false},{"pmid":"33689784","id":"PMC_33689784","title":"Metabolic strategies of dormancy of a marine bacterium Microbulbifer aggregans CCB-MM1: Its alternative electron transfer chain and sulfate-reducing pathway.","date":"2021","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/33689784","citation_count":3,"is_preprint":false},{"pmid":"11693803","id":"PMC_11693803","title":"Mammary fetal gland: identification of new oncofetal antigens by monoclonal antibodies B72.3, MM1.80 and 4.36.","date":"2001","source":"Tumori","url":"https://pubmed.ncbi.nlm.nih.gov/11693803","citation_count":3,"is_preprint":false},{"pmid":"8981658","id":"PMC_8981658","title":"Implications of automated creatine kinase (CK)-MM1,2,3/CK-MB1,2 isoform analysis as an early marker for the detection of myocardial tissue damage.","date":"1996","source":"Scandinavian journal of clinical and laboratory investigation","url":"https://pubmed.ncbi.nlm.nih.gov/8981658","citation_count":3,"is_preprint":false},{"pmid":"24450104","id":"PMC_24450104","title":"[A case of MM1+2 Creutzfeldt-Jakob disease with a longitudinal study of EEG and MRI].","date":"2013","source":"Rinsho byori. The Japanese journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/24450104","citation_count":3,"is_preprint":false},{"pmid":"32367540","id":"PMC_32367540","title":"Identification of intracerebral hemorrhage in the early-phase of MM1+2C-type sporadic Creutzfeldt-Jakob disease: A case report.","date":"2020","source":"Neuropathology : official journal of the Japanese Society of Neuropathology","url":"https://pubmed.ncbi.nlm.nih.gov/32367540","citation_count":2,"is_preprint":false},{"pmid":"34796964","id":"PMC_34796964","title":"An assimilatory sulfite reductase, CysI, negatively regulates the dormancy of Microbulbifer aggregans CCB-MM1T.","date":"2021","source":"Journal of basic microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/34796964","citation_count":2,"is_preprint":false},{"pmid":"37632633","id":"PMC_37632633","title":"Expression analysis, clinical significance and potential function of PLXNB2 in acute myeloid leukaemia.","date":"2023","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/37632633","citation_count":1,"is_preprint":false},{"pmid":"33472525","id":"PMC_33472525","title":"System degeneration in an MM1-type sporadic Creutzfeldt-Jakob disease case with an unusually prolonged akinetic mutism state.","date":"2021","source":"Prion","url":"https://pubmed.ncbi.nlm.nih.gov/33472525","citation_count":1,"is_preprint":false},{"pmid":"37393646","id":"PMC_37393646","title":"Evaluation of murine OX40L-murine IgG1(MM1) fusion protein on immunogenicity against L. mexicana infection in BALB/c mice.","date":"2023","source":"Comparative immunology, microbiology and infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/37393646","citation_count":0,"is_preprint":false},{"pmid":"36063412","id":"PMC_36063412","title":"Chronological Changes in the Expression Pattern of Hippocampal Prion Proteins During Disease Progression in Sporadic Creutzfeldt-Jakob Disease MM1 Subtype.","date":"2022","source":"Journal of neuropathology and experimental neurology","url":"https://pubmed.ncbi.nlm.nih.gov/36063412","citation_count":0,"is_preprint":false},{"pmid":"31839058","id":"PMC_31839058","title":"[Effect of Pomalidomide on Activity of Myeloma Cell Line MM1.S and Expression of CRBN].","date":"2019","source":"Zhongguo shi yan xue ye xue za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/31839058","citation_count":0,"is_preprint":false},{"pmid":"41599720","id":"PMC_41599720","title":"Kinetics of MM1.S Multiple Myeloma Cells in a 3D Polymer Particle Culture System with Bone Marrow Stromal Cells and Bortezomib.","date":"2026","source":"Pharmaceuticals (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/41599720","citation_count":0,"is_preprint":false},{"pmid":"2093552","id":"PMC_2093552","title":"[Serum isoforms of creatine kinase MM (MM3/MM1 ratio) in the diagnosis of acute myocardial infarction].","date":"1990","source":"Zhonghua xin xue guan bing za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/2093552","citation_count":0,"is_preprint":false},{"pmid":"16328889","id":"PMC_16328889","title":"Molecular cloning, expression and chromosomal localization of mouse MM-1.","date":"2005","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/16328889","citation_count":0,"is_preprint":false},{"pmid":"41990421","id":"PMC_41990421","title":"Virulent phages MM-1 and MM-2 attack enterohemorrhagic Escherichia coli and Salmonella enterica strains.","date":"2026","source":"International journal of medical microbiology : IJMM","url":"https://pubmed.ncbi.nlm.nih.gov/41990421","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.19.677444","title":"Cortical tension as a mechanical barrier to safeguard against premature differentiation during neurogenesis","date":"2025-09-20","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.19.677444","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.14.659695","title":"Proximity labelling-based identification of vascular homing peptide receptors","date":"2025-06-15","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.14.659695","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.17.676758","title":"Proteomic and Kinetic Characterization of Prion Seeding in Distinct Human CJD Strains Unveils Early Diagnostic Biomarkers","date":"2025-09-17","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.17.676758","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.25.661599","title":"SORLA upregulation suppresses global pathological effects in aged tauopathy mouse brain","date":"2025-06-29","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.25.661599","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.12.657772","title":"A single-cell fixed RNA profiling of liver fibrosis progression and regression reveals SEMA4D and LMCD1 as key mediators of fibrogenesis","date":"2025-06-12","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.12.657772","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.11.01.621584","title":"Targeted Alpha Therapy with [  <sup>225</sup>  Ac]Ac-Macropa-Isatuximab for CD38-positive Hematological Malignancies","date":"2024-11-03","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.01.621584","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":40056,"output_tokens":3323,"usd":0.085006,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9903,"output_tokens":2999,"usd":0.062245,"stage2_stop_reason":"end_turn"},"total_usd":0.147251,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify papers about the canonical PLXNB2 protein (Plexin B2, a large transmembrane semaphorin receptor). I must exclude:\n- Papers about MM-1/MM1 as the c-Myc binding protein (PFDN5/prefoldin subunit 5) — this is a different gene, alias collision\n- Papers about CJD MM1 subtype (prion disease classification)\n- Papers about bacterial MM1 strains\n- Papers about creatine kinase MM isoforms\n- Papers about hamster melanoma MM1\n- Papers about lncFAL (non-coding RNA product)\n- Papers about circRNA products\n\nPapers clearly about PLXNB2 (Plexin B2 protein):\n- PMID 36325348: PLXNB2 in schizophrenia/stress/amygdala\n- PMID 38458752: biallelic PLXNB2 variants causing amelogenesis imperfecta, hearing loss, ID\n- PMID 36722641: mutated PLXNB2 G842C in CUP stem cells, EGFR signaling\n- PMID 30054097: miR-126-3p targeting PLXNB2 in ovarian cancer (luciferase validation)\n- PMID 34367233: circRNA/miR-637/PLXNB2 axis (luciferase validation)\n- PMID 38295715: PLXNB2 as angiogenin receptor in colorectal cancer myofibroblasts\n- PMID 40835170: H3K18la-regulated plxnb2 in microglia after ischemic stroke\n- PMID 37632633: PLXNB2 expression/function in AML (mostly expression-based, limited mechanism)\n- bio_10.1101_2025.09.19.677444: Plexin-B2 controls actomyosin contractility/cortical tension in neurogenesis\n- bio_10.1101_2025.06.14.659695: PLXNB2 proximity-labeled near NRP-1 in RPARPAR peptide context\n- bio_10.1101_2025.06.12.657772: SEMA4D activates Plxnb2+ HSCs in liver fibrosis\n- PMID 36517866: genomic/transcriptomic CJD analysis — mentions PLXNB2 only tangentially, not mechanistic about the protein\n- bio_10.1101_2025.06.25.661599: PlxnB1/B2 induction in glia in tauopathy — expression context\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2022,\n      \"finding\": \"PLXNB2 is expressed in astrocytes and microglia in the mouse amygdala; functional blocking of amygdaloid Plxnb2 with a monoclonal antibody induced anxiety-like behavior, amygdaloid enlargement, and microglial ramification, establishing a glial PLXNB2-dependent role in amygdala-mediated stress responses.\",\n      \"method\": \"In vivo intra-amygdaloid injection of Plxnb2 functional-blocking monoclonal antibody (mAb-102); behavioral testing; volumetric MRI; microglial morphology analysis; cell-type-specific expression by immunofluorescence in mouse brain.\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional blocking in vivo with multiple orthogonal readouts (behavior, morphology, imaging) in a single lab; no genetic KO confirmation.\",\n      \"pmids\": [\"36325348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Biallelic loss-of-function variants in PLXNB2 cause an autosomal recessive syndrome with amelogenesis imperfecta (AI), sensorineural hearing loss, and variable intellectual disability in humans. Plxnb2 expression was detected in differentiating ameloblasts in mice, linking the receptor's developmental expression to enamel formation.\",\n      \"method\": \"Exome/genome sequencing with Sanger segregation in six families; RNA expression analysis in C57Bl/6 mouse ameloblasts.\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — replicated across six independent families with multiple variant classes (missense, nonsense, splicing, deletion), supported by mouse expression data.\",\n      \"pmids\": [\"38458752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A G842C gain-of-function mutation in PLXNB2 sustains self-renewal, proliferation, and invasiveness of cancer-of-unknown-primary (CUP) stem cells. Knockdown of mutant but not wild-type PLXNB2 impaired proliferation and tumorigenesis in mice; transfer of G842C-PLXNB2 alone promoted tumorigenesis. The mutant receptor was associated with basal EGFR phosphorylation, and EGFR inhibition blocked viability and invasiveness of CUP cells dependent on G842C-PLXNB2.\",\n      \"method\": \"shRNA knockdown (mutant vs. wild-type selective), lentiviral gene transfer, in vitro proliferation/self-renewal assays, xenograft mouse tumorigenesis, EGFR phosphorylation immunoblot, EGFR inhibitor treatment.\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (KD, OE, in vivo, pharmacological inhibition) all converging on mutant-specific PLXNB2/EGFR mechanism in a single rigorous study.\",\n      \"pmids\": [\"36722641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PLXNB2 is a direct target of miR-126-3p in ovarian cancer cells; knockdown of PLXNB2 with siRNA recapitulated the inhibitory effects of miR-126-3p overexpression on cell proliferation, invasion, and phosphorylation of AKT and ERK1/2, placing PLXNB2 upstream of AKT/ERK1/2 signaling in this context.\",\n      \"method\": \"Luciferase reporter assay confirming miR-126-3p binding to PLXNB2 3′UTR; siRNA knockdown of PLXNB2; proliferation, invasion, and cell cycle assays; phospho-immunoblot for AKT and ERK1/2.\",\n      \"journal\": \"Reproductive biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct 3′UTR validation and KD phenotype replicated by two orthogonal perturbations (miRNA OE and siRNA KD), single lab.\",\n      \"pmids\": [\"30054097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In ovarian cancer cells, PLXNB2 expression is regulated via a circ_0013958/miR-637 sponge axis; dual-luciferase and RIP assays confirmed miR-637 directly targets the PLXNB2 3′UTR, and PLXNB2 downstream activity mediates the pro-tumorigenic effects of circ_0013958 on proliferation, migration, and invasion.\",\n      \"method\": \"Dual-luciferase reporter assay; RNA immunoprecipitation (RIP); siRNA knockdown; in vitro proliferation/invasion/apoptosis assays; xenograft tumor assay.\",\n      \"journal\": \"Frontiers in genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — luciferase and RIP validate direct miR-637/PLXNB2 interaction; rescue experiments support pathway placement, single lab.\",\n      \"pmids\": [\"34367233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CRC-associated myofibroblasts upregulate PLXNB2 as a cell-surface angiogenin receptor; single-cell RNA-seq analysis of paired normal and CRC human tissue showed that myofibroblasts in CRC uniquely express PLXNB2 and receive angiogenin paracrine signals from CRC cells via PLXNB2, suggesting PLXNB2 mediates tumor-stromal angiogenin signaling.\",\n      \"method\": \"Single-cell RNA sequencing of paired normal human colon and CRC tissue; CellChat ligand-receptor interaction analysis; PLXNB2 expression quantification across cell populations.\",\n      \"journal\": \"The Journal of surgical research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — based solely on computational inference from scRNA-seq; no direct biochemical or functional validation of PLXNB2-angiogenin interaction performed.\",\n      \"pmids\": [\"38295715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Histone H3 lysine 18 lactylation (H3K18la) transcriptionally upregulates plxnb2 in microglia after ischemic stroke; microglia-specific inhibition of plxnb2 abolished the neuroprotective effects of lactate treatment, demonstrating that H3K18la-driven plxnb2 expression mediates an anti-inflammatory, neuroprotective microglial program in ischemia.\",\n      \"method\": \"Middle cerebral artery occlusion mouse model; H3K18la ChIP/lactate manipulation; microglia-specific Plxnb2 inhibition; histological and behavioral outcome measures.\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic/pharmacological inhibition of plxnb2 with defined neuroprotective readout; H3K18la-plxnb2 link supported by epigenetic manipulation, single lab.\",\n      \"pmids\": [\"40835170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Deletion of Plexin-B2 in neural progenitors lowers cortical tension (actomyosin contractility), reducing the mechanical barrier against premature neuronal differentiation. In cerebral organoids, Plexin-B2 ablation caused premature cell-cycle exit, accelerated neuronal lineage commitment, progenitor pool depletion, and neuroepithelial disorganization, phenocopying features of intellectual disability seen in patients with pathogenic PLXNB2 variants.\",\n      \"method\": \"Genetic deletion (CRISPR/KO) in cerebral organoids; cortical tension measurements; cell-cycle and differentiation marker analysis; comparison to patient phenotype.\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with multiple mechanistic readouts (tension, cell-cycle, differentiation) in organoid model; preprint, not yet peer-reviewed.\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SEMA4D secreted by monocyte-derived macrophages during liver fibrosis progression activates Plxnb2-expressing hepatic stellate cells (HSCs); blockade of SEMA4D attenuated fibrosis in vivo, placing the SEMA4D–PLXNB2 ligand-receptor pair as a mediator of fibrogenic HSC activation.\",\n      \"method\": \"Single-cell fixed RNA profiling (FLEX) of TAA-induced mouse liver fibrosis; ligand-receptor interaction analysis; in vivo SEMA4D blockade with fibrosis readout.\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — scRNA-seq identifies SEMA4D→Plxnb2 axis and in vivo blockade confirms functional relevance; preprint, single lab.\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"PLXNB2 (Plexin B2) is a large transmembrane semaphorin receptor that controls actomyosin contractility and cortical tension in neural progenitors to regulate the timing of neuronal differentiation; mediates SEMA4D-driven hepatic stellate cell activation in liver fibrosis; functions as a glial receptor in the amygdala regulating stress responses via microglia and astrocytes; is required for ameloblast differentiation and inner-ear development (biallelic loss causes amelogenesis imperfecta with hearing loss and intellectual disability); and can acquire gain-of-function mutations (G842C) that activate EGFR-dependent proliferation and invasiveness in cancer stem cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PLXNB2 is a transmembrane semaphorin-family receptor that transduces ligand cues into control of cytoskeletal mechanics and cell differentiation across neural development, tissue fibrosis, and cancer [#7, #8]. In neural progenitors, PLXNB2 maintains cortical tension through actomyosin contractility, establishing a mechanical barrier against premature differentiation; its loss lowers cortical tension and triggers premature cell-cycle exit, accelerated neuronal commitment, progenitor depletion, and neuroepithelial disorganization [#7]. Biallelic loss-of-function variants in PLXNB2 cause an autosomal recessive syndrome of amelogenesis imperfecta, sensorineural hearing loss, and variable intellectual disability, with receptor expression in differentiating ameloblasts linking PLXNB2 to enamel formation [#1]. As a signaling receptor, PLXNB2 engages SEMA4D secreted by macrophages to drive fibrogenic activation of hepatic stellate cells [#8], and acts as a glial receptor in astrocytes and microglia that shapes amygdala-mediated stress responses [#0] and an H3K18-lactylation-driven neuroprotective microglial program after ischemic stroke [#6]. In cancer, a G842C gain-of-function mutation sustains tumor stem cell self-renewal and invasiveness via basal EGFR phosphorylation, and PLXNB2 sits upstream of AKT/ERK1/2 signaling in ovarian cancer cells where it is controlled by miRNA regulatory axes [#2, #3].\",\n  \"teleology\": [\n    {\n      \"year\": 2018,\n      \"claim\": \"Established PLXNB2 as a node upstream of pro-proliferative kinase signaling, answering whether the receptor feeds canonical growth pathways in cancer.\",\n      \"evidence\": \"Luciferase 3'UTR validation of miR-126-3p targeting plus siRNA knockdown with phospho-AKT/ERK1/2 readout in ovarian cancer cells\",\n      \"pmids\": [\"30054097\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not identify the ligand driving AKT/ERK1/2 activation\", \"Single cell-line context; no in vivo confirmation of the signaling axis\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended the regulatory understanding of PLXNB2 by placing its expression under a circRNA/miRNA sponge axis controlling tumorigenic behavior.\",\n      \"evidence\": \"Dual-luciferase and RIP assays for circ_0013958/miR-637/PLXNB2 plus knockdown and xenograft assays in ovarian cancer\",\n      \"pmids\": [\"34367233\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Regulation is transcript-level; does not address receptor signaling mechanism\", \"No structural or ligand-binding detail\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined a glial, non-neuronal function for PLXNB2, addressing whether the receptor acts in CNS cell types governing behavior.\",\n      \"evidence\": \"Intra-amygdaloid functional-blocking monoclonal antibody with behavioral, volumetric MRI, and microglial morphology readouts in mouse\",\n      \"pmids\": [\"36325348\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No genetic KO confirmation of the antibody phenotype\", \"Ligand and downstream signaling in glia not identified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed that a specific gain-of-function mutation reprograms PLXNB2 into an oncogenic driver coupled to EGFR, distinguishing mutant from wild-type receptor function.\",\n      \"evidence\": \"Mutant-selective shRNA knockdown, lentiviral gene transfer, xenograft tumorigenesis, EGFR phospho-immunoblot, and EGFR inhibitor treatment in CUP stem cells\",\n      \"pmids\": [\"36722641\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which G842C activates EGFR is not resolved\", \"Whether wild-type PLXNB2 couples to EGFR under any condition is unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected PLXNB2 to human Mendelian disease, answering whether loss of the receptor produces a defined developmental syndrome.\",\n      \"evidence\": \"Exome/genome sequencing with Sanger segregation across six families and mouse ameloblast expression analysis\",\n      \"pmids\": [\"38458752\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular mechanism linking PLXNB2 loss to enamel and inner-ear defects not established\", \"Variant-specific functional consequences not assayed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Proposed PLXNB2 as a stromal receptor for tumor-derived angiogenin, addressing tumor-stromal paracrine signaling.\",\n      \"evidence\": \"Single-cell RNA-seq of paired human colon/CRC tissue with CellChat ligand-receptor inference\",\n      \"pmids\": [\"38295715\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Purely computational inference; no biochemical validation of PLXNB2-angiogenin binding\", \"No functional assay of the proposed signaling\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified the mechanical mechanism by which PLXNB2 controls neural progenitor fate, linking the receptor to cortical tension and differentiation timing.\",\n      \"evidence\": \"CRISPR KO in cerebral organoids with cortical tension measurement and cell-cycle/differentiation marker analysis (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"Ligand and downstream actomyosin effectors not defined\", \"Direct mechanistic link to patient intellectual disability is correlative\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established an epigenetically driven, ligand-coupled PLXNB2 program in microglia, defining a neuroprotective role in ischemia.\",\n      \"evidence\": \"MCAO mouse model with H3K18la manipulation and microglia-specific Plxnb2 inhibition and outcome measures\",\n      \"pmids\": [\"40835170\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream microglial signaling from PLXNB2 not resolved\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a SEMA4D-PLXNB2 ligand-receptor axis driving fibrogenic stellate cell activation, naming a direct ligand for the receptor in tissue fibrosis.\",\n      \"evidence\": \"Single-cell fixed RNA profiling of TAA-induced mouse liver fibrosis with in vivo SEMA4D blockade (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, single lab\", \"Direct SEMA4D-PLXNB2 binding not biochemically demonstrated here\", \"Downstream signaling in HSCs not characterized\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PLXNB2 ligand engagement is mechanistically transduced into cytoskeletal, EGFR, and AKT/ERK outputs across its different cell-type contexts remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of ligand-receptor or receptor-EGFR coupling\", \"Unified downstream signaling logic across neural, glial, fibrotic, and cancer contexts is undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [8, 0]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [7, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 8]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [7, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SEMA4D\", \"EGFR\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":3,"faith_pct":100.0}}