{"gene":"PLXNA1","run_date":"2026-04-28T19:45:44","timeline":{"discoveries":[{"year":1996,"finding":"PLXNA1 (originally named NOV/SEX family member) was identified as a transmembrane protein of ~220 kDa with homology to the MET/HGF receptor extracellular domain; it is glycosylated and cell-surface exposed but lacks tyrosine kinase activity despite containing a distinctive conserved cytoplasmic 'SEX domain', suggesting a novel receptor mechanism.","method":"cDNA cloning, Northern blot, in situ hybridization, cell-surface expression assays, chimeric receptor constructs","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — original identification with multiple biochemical methods in a single rigorous study","pmids":["8570614"],"is_preprint":false},{"year":1999,"finding":"Plexin-A1 is a functional semaphorin receptor: plexin-A1 associates stably with neuropilin-1 (NRP1), and this NRP1/Plexin-A1 complex binds Sema3A with higher affinity than NRP1 alone; expression of dominant-negative Plexin-A1 in sensory neurons blocks Sema3A-induced growth cone collapse, establishing plexin-A1 as the signal-transducing subunit of the Sema3A receptor.","method":"Co-immunoprecipitation, receptor-ligand binding assays, dominant-negative expression in neurons, growth cone collapse assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1–2 — reciprocal co-IP, functional rescue/block, replicated across labs","pmids":["10520994","10520995"],"is_preprint":false},{"year":1999,"finding":"Plexin-A1 is a direct receptor for multiple semaphorin classes either alone or in combination with neuropilins; expression of a truncated plexin-A1 in neurons blocks Sema3A-induced axon repulsion, and the cytoplasmic domain of plexin-A1 associates with a tyrosine kinase activity.","method":"Binding assays, dominant-negative truncation expression in neurons, co-immunoprecipitation for kinase activity","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods, foundational study replicated across the field","pmids":["10520995"],"is_preprint":false},{"year":2000,"finding":"The cytoplasmic domain of Plexin-A1 contains sequence similarity to RasGAP/RhoGAP catalytic domains; mutation of two conserved arginine residues corresponding to catalytic GAP residues abolishes Plexin-A1's ability to induce growth cone collapse, implying an intrinsic GAP activity essential for semaphorin signaling.","method":"Sequence analysis, site-directed mutagenesis of arginine residues, growth cone collapse assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 1–2 — mutagenesis with functional readout, but GAP activity not directly reconstituted in vitro in this study","pmids":["11108845"],"is_preprint":false},{"year":2001,"finding":"Plexin-A1 is autoinhibited by its own sema domain: deletion of the sema domain renders Plexin-A1 constitutively active (inducing cell contraction, growth cone collapse, and neurite outgrowth inhibition without ligand), and the isolated sema domain physically associates with the remainder of the Plexin-A1 ectodomain to reverse constitutive activation. Both the sema domain and the remainder of the ectodomain independently associate with NRP1.","method":"Deletion mutagenesis, cell morphology assays, growth cone collapse assay, co-immunoprecipitation of ectodomain fragments","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 — multiple deletion constructs with functional and biochemical validation in one study","pmids":["11239433"],"is_preprint":false},{"year":2002,"finding":"Among a large panel of Rho-family GTPases tested, only Rnd1 and RhoD bind the cytoplasmic domain of Plexin-A1. Active Rnd1 is sufficient to trigger Plexin-A1 signaling and cytoskeletal collapse in the absence of Sema3A, while RhoD antagonizes Plexin-A1 activation by Rnd1 and blocks Sema3A-induced axon repulsion, revealing that antagonistic GTPases regulate Plexin-A1 activity.","method":"GST pulldown, co-immunoprecipitation, dominant-active/negative GTPase expression, growth cone collapse and axon repulsion assays","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — systematic GTPase screen with pulldown plus functional epistasis experiments","pmids":["11784792"],"is_preprint":false},{"year":2003,"finding":"Breast carcinoma cells express an autocrine SEMA3A/Plexin-A1/NRP1 pathway that impedes chemotaxis; RNAi knockdown of SEMA3A or NRP1, or inhibition of Plexin-A1 signaling, enhances migration, while constitutively active Plexin-A1 impairs chemotaxis, establishing Plexin-A1 as an anti-migratory signal in cancer cells.","method":"siRNA knockdown, constitutively active Plexin-A1 expression, Boyden chamber chemotaxis assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — loss- and gain-of-function with defined cellular phenotype, single lab","pmids":["14500350"],"is_preprint":false},{"year":2004,"finding":"Plexin-A1 is the primary receptor for Sema6D in cardiac morphogenesis. In the conotruncal segment, Plexin-A1 forms a complex with VEGFR2 and promotes cell migration; in the ventricular segment, Plexin-A1 associates with Off-track and inhibits migration. The differential co-receptor association of Plexin-A1 enables Sema6D to exert distinct, region-specific activities during cardiac morphogenesis.","method":"RNA interference, ectopic expression in chick embryos, co-immunoprecipitation of receptor complexes, cardiac explant migration assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP of distinct complexes plus in vivo gain/loss-of-function with phenotypic readout","pmids":["14977921"],"is_preprint":false},{"year":2006,"finding":"Plexin-A1 associates with the ITAM-bearing adaptor protein DAP12 through the transmembrane receptor TREM-2. In plexin-A1-deficient mice, T-cell-dependent immune responses are impaired and bone homeostasis is disrupted (osteoclast defects), linking semaphorin signaling via Plexin-A1/TREM-2/DAP12 to immune activation and bone remodeling pathways beyond the nervous system.","method":"Plexin-A1 knockout mice, co-immunoprecipitation (Plexin-A1/TREM-2/DAP12 complex), immune challenge experiments, bone histomorphometry","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 — knockout mouse plus reciprocal co-IP of multiprotein complex, multiple phenotypic readouts","pmids":["16715077"],"is_preprint":false},{"year":2019,"finding":"PLXNA1 and PLXNA3 cooperate as co-receptors for SEMA3A to pattern vomeronasal and olfactory axons that guide GnRH neuron migration. Combined loss of PLXNA1 and PLXNA3 in mice fully phenocopies the nasal axon defects and GnRH neuron migration failure seen in Sema3a knockout mice, while single knockouts do not, establishing PLXNA1 and PLXNA3 as redundant, essential co-receptors in GnRH neuron development.","method":"Genetic epistasis using single and double mouse knockouts (Plxna1−/−, Plxna3−/−, Plxna1/Plxna3 double KO vs. Sema3a KO), immunofluorescence of nasal axons and GnRH neurons","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 — clean double-knockout epistasis with full phenocopy of ligand KO, rigorous controls","pmids":["31690636"],"is_preprint":false},{"year":2019,"finding":"PLXNA1 activates the MAPK signaling pathway in esophageal squamous cell carcinoma cells; miR-134 directly targets the PLXNA1 3'UTR (verified by dual-luciferase reporter assay) and suppresses PLXNA1 expression, thereby blocking MAPK pathway activation and reducing cell proliferation, migration, invasion, and tumor metastasis in vitro and in vivo.","method":"Dual-luciferase reporter assay (miR-134/PLXNA1 3'UTR interaction), siRNA knockdown, miR-134 mimic/inhibitor, western blot of MAPK pathway proteins, xenograft mouse models","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2–3 — validated miRNA-target interaction plus KD phenotype, pathway placement by western blot","pmids":["31383552"],"is_preprint":false},{"year":2021,"finding":"Biallelic and monoallelic variants in PLXNA1 cause a novel neurodevelopmental syndrome. Structural modeling indicates that missense variants in the extracellular domain likely impair Plexin-A1 dimerization or abolish receptor molecules, while monoallelic intracellular domain variants may exert a dominant-negative effect on downstream signaling. Morpholino knockdown of zebrafish plxna1a and plxna1b disrupts CNS and eye development, demonstrating an embryonic role for PLXNA1 in neurogenesis.","method":"Structural/homology modeling of missense variants, Morpholino knockdown in zebrafish (CNS and eye phenotype), genotype-phenotype correlation in 10 patients","journal":"Genetics in medicine","confidence":"Medium","confidence_rationale":"Tier 3 — zebrafish KD provides in vivo functional evidence; mechanistic model based on structural modeling, not biochemical reconstitution","pmids":["34054129"],"is_preprint":false},{"year":2022,"finding":"RUVBL1 promotes enzalutamide resistance in prostate cancer through PLXNA1: enzalutamide increases cytoplasmic RUVBL1 accumulation, which enhances recruitment of CRAF to Plexin-A1 (PLXNA1), activating the downstream MAPK pathway and bypassing androgen receptor signaling.","method":"Co-immunoprecipitation (RUVBL1/CRAF/PLXNA1 complex), RUVBL1 inhibition with CB-6644, xenograft models, western blot of MAPK pathway activation","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2–3 — co-IP of multiprotein complex plus pharmacological inhibition with in vivo validation, single lab","pmids":["35508542"],"is_preprint":false},{"year":2024,"finding":"PLXNA1 confers enzalutamide resistance in prostate cancer via AKT signaling: PLXNA1 recruits NRP1 to form a PLXNA1-NRP1 receptor complex, which potentiates AKT phosphorylation. Inhibition of the PLXNA1-NRP1 complex with the NRP1 inhibitor EG01377 or AKT inhibitors abolishes the pro-resistance phenotype of PLXNA1 overexpression.","method":"Co-immunoprecipitation (PLXNA1-NRP1 complex), NRP1 inhibitor (EG01377) treatment, AKT inhibitor treatment, western blot of pAKT, cell proliferation assays under enzalutamide","journal":"Neoplasia","confidence":"Medium","confidence_rationale":"Tier 2–3 — co-IP of complex plus pharmacological intervention with pathway readout, single lab","pmids":["39226661"],"is_preprint":false},{"year":2024,"finding":"Truncated PLXNA1 functions as a novel scaffold protein for extracellular vesicle (EV) engineering: endogenous full-length PLXNA1 has high EV-sorting ability, and truncated PLXNA1 retains this property while permitting fusion expression of protein cargoes on both the outer EV surface and luminal areas.","method":"EV purification, western blot and flow cytometry for EV-sorted PLXNA1 fusion proteins, fluorescence microscopy of cargo delivery","journal":"Journal of extracellular vesicles","confidence":"Medium","confidence_rationale":"Tier 2–3 — direct experimental demonstration of PLXNA1 EV-sorting and cargo delivery, but functional mechanism not deeply dissected","pmids":["39508411"],"is_preprint":false}],"current_model":"PLXNA1 (Plexin-A1) is a transmembrane semaphorin receptor that is autoinhibited by its own sema domain and functions either alone or in NRP1-containing complexes to transduce repulsive guidance signals; upon activation by Sema3A or Sema6D, its cytoplasmic GAP-like domain engages Rnd1/RhoD GTPases and downstream MAPK/AKT pathways to regulate cytoskeletal collapse, cell migration, and axon guidance, while context-dependent association with co-receptors (VEGFR2, Off-track, TREM-2/DAP12, NRP1, CRAF) enables its pleiotropic roles in cardiac morphogenesis, GnRH neuron migration, immune function, bone homeostasis, and cancer drug resistance."},"narrative":{"teleology":[{"year":1996,"claim":"The initial identification of PLXNA1 as a novel transmembrane protein with a MET-like ectodomain but no intrinsic tyrosine kinase activity posed the question of how it signals.","evidence":"cDNA cloning, Northern blot, chimeric receptor constructs in heterologous cells","pmids":["8570614"],"confidence":"High","gaps":["No ligand identified for the receptor","Cytoplasmic signaling mechanism unknown","Tissue-specific functions not addressed"]},{"year":1999,"claim":"Demonstration that Plexin-A1 forms a complex with NRP1 and is the obligate signal-transducing component of the Sema3A receptor resolved the long-standing question of how neuropilins, which lack substantial cytoplasmic domains, trigger intracellular signaling.","evidence":"Reciprocal co-immunoprecipitation of Plexin-A1/NRP1, ligand binding assays, dominant-negative Plexin-A1 blocking Sema3A-induced growth cone collapse in DRG neurons","pmids":["10520994","10520995"],"confidence":"High","gaps":["Mechanism of signal transduction across the membrane not known","Whether Plexin-A1 functions independently of NRP1 for other semaphorins not established"]},{"year":2000,"claim":"Discovery of a RasGAP/RhoGAP-like catalytic domain within the Plexin-A1 cytoplasmic region, and the requirement of conserved catalytic arginines for growth cone collapse, provided the first mechanistic model for how plexins transduce signals — through intrinsic GTPase-activating activity.","evidence":"Sequence homology analysis plus site-directed mutagenesis of catalytic arginine residues with growth cone collapse readout","pmids":["11108845"],"confidence":"Medium","gaps":["GAP activity not directly reconstituted in vitro","Substrate GTPase identity unknown at this stage","Whether GAP activity is regulated by ligand binding not tested"]},{"year":2001,"claim":"Establishing that Plexin-A1 is autoinhibited by its own sema domain explained how the receptor remains quiescent in the absence of ligand and how ligand binding could relieve inhibition to activate the cytoplasmic domain.","evidence":"Sema-domain deletion mutagenesis yielding constitutive activity; rescue by co-expression of the isolated sema domain fragment; co-IP of ectodomain fragments","pmids":["11239433"],"confidence":"High","gaps":["Structural basis of autoinhibition not resolved","Whether ligand binding displaces the sema domain or induces a conformational change not distinguished"]},{"year":2002,"claim":"Identification of Rnd1 as an activating GTPase and RhoD as an antagonistic GTPase that bind the Plexin-A1 cytoplasmic domain defined the immediate downstream GTPase relay controlling cytoskeletal collapse.","evidence":"Systematic GST-pulldown screen of Rho-family GTPases, functional epistasis using dominant-active/negative GTPases in growth cone collapse and axon repulsion assays","pmids":["11784792"],"confidence":"High","gaps":["Direct GAP activity of Plexin-A1 on Rnd1/RhoD not biochemically measured","How Rnd1 binding activates Plexin-A1 mechanistically not resolved"]},{"year":2003,"claim":"The finding of an autocrine SEMA3A/Plexin-A1/NRP1 pathway restraining breast cancer cell migration extended Plexin-A1's role beyond axon guidance to tumor biology.","evidence":"siRNA knockdown of SEMA3A and NRP1, constitutively active Plexin-A1 expression, Boyden chamber chemotaxis assays in breast carcinoma lines","pmids":["14500350"],"confidence":"Medium","gaps":["Downstream effectors mediating anti-migratory signaling in cancer cells not identified","Relevance to in vivo tumor progression not tested in this study"]},{"year":2004,"claim":"Discovery that Plexin-A1 assembles distinct co-receptor complexes — with VEGFR2 to promote migration and with Off-track to inhibit migration — in different cardiac regions resolved how a single semaphorin (Sema6D) can exert opposing effects through the same receptor.","evidence":"Reciprocal co-IP of VEGFR2/Plexin-A1 and Off-track/Plexin-A1 complexes in chick cardiac tissue, RNAi and ectopic expression in embryo, cardiac explant migration assays","pmids":["14977921"],"confidence":"High","gaps":["Molecular determinants governing co-receptor choice not identified","Downstream signaling divergence between the two complexes not characterized"]},{"year":2006,"claim":"Plexin-A1 knockout mice revealed essential non-neuronal functions: association with TREM-2/DAP12 links Plexin-A1 to T-cell activation and osteoclast-mediated bone remodeling, demonstrating that semaphorin-plexin signaling is a core immune and skeletal pathway.","evidence":"Plexin-A1 knockout mice with immune challenge phenotyping, bone histomorphometry, co-IP of Plexin-A1/TREM-2/DAP12 complex","pmids":["16715077"],"confidence":"High","gaps":["Semaphorin ligand activating this immune complex not definitively identified","Signaling cascade downstream of DAP12 ITAM in this context not dissected"]},{"year":2019,"claim":"Double-knockout epistasis in mice proved that PLXNA1 and PLXNA3 are redundant, essential co-receptors for Sema3A in patterning nasal axons and enabling GnRH neuron migration, connecting Plexin-A1 to neuroendocrine development.","evidence":"Plxna1/Plxna3 single and double knockout mice phenocopying Sema3a KO; immunofluorescence of nasal axons and GnRH neurons","pmids":["31690636"],"confidence":"High","gaps":["Whether PLXNA1 has a unique non-redundant role in GnRH biology apart from PLXNA3 is unclear","Human genetic validation for GnRH-related disease not yet established"]},{"year":2019,"claim":"PLXNA1 was shown to activate the MAPK cascade in esophageal squamous cell carcinoma, placing it upstream of a major proliferative signaling axis in an epithelial cancer context.","evidence":"miR-134/PLXNA1 3'UTR dual-luciferase validation, PLXNA1 knockdown, MAPK pathway western blots, xenograft models","pmids":["31383552"],"confidence":"Medium","gaps":["Direct mechanism linking Plexin-A1 to MAPK activation not defined","Intermediate effectors between PLXNA1 and MAPK not identified in this system"]},{"year":2021,"claim":"Identification of biallelic and monoallelic PLXNA1 variants in patients with a novel neurodevelopmental syndrome, supported by zebrafish knockdown phenocopying CNS and eye defects, established PLXNA1 as a disease gene for human neurodevelopment.","evidence":"Genotype-phenotype study of 10 patients, structural modeling of variants, morpholino knockdown in zebrafish","pmids":["34054129"],"confidence":"Medium","gaps":["Biochemical effect of individual disease variants on Plexin-A1 activity not reconstituted","Mammalian model validation (mouse knock-in of patient variants) lacking","Dominant-negative mechanism for monoallelic intracellular-domain variants is modeled, not proven"]},{"year":2022,"claim":"The RUVBL1-CRAF-PLXNA1 axis was identified as a mechanism for enzalutamide resistance in prostate cancer, revealing Plexin-A1 as a scaffold for MAPK pathway re-activation that bypasses androgen receptor signaling.","evidence":"Co-IP of RUVBL1/CRAF/PLXNA1 complex, pharmacological inhibition with CB-6644, xenograft models","pmids":["35508542"],"confidence":"Medium","gaps":["Direct binding interface between PLXNA1 and CRAF not mapped","Whether semaphorin ligand is required for this scaffold function unknown"]},{"year":2024,"claim":"PLXNA1 was shown to recruit NRP1 to potentiate AKT signaling in enzalutamide-resistant prostate cancer, and pharmacological disruption of the PLXNA1-NRP1 complex with EG01377 abolished resistance, revealing a druggable co-receptor complex driving therapy resistance.","evidence":"Co-IP of PLXNA1-NRP1, NRP1 inhibitor (EG01377) and AKT inhibitor treatment, pAKT western blot, cell proliferation under enzalutamide","pmids":["39226661"],"confidence":"Medium","gaps":["In vivo validation of NRP1 inhibitor efficacy against PLXNA1-driven resistance not reported","Whether MAPK and AKT pathways are activated independently or sequentially by PLXNA1 complexes is unresolved"]},{"year":null,"claim":"Key open questions remain: the structural basis of Plexin-A1 autoinhibition relief upon ligand binding, the direct biochemical reconstitution of its GAP activity against specific Ras/Rho substrates, the determinants governing co-receptor selection in different tissues, and whether PLXNA1 disease variants cause loss-of-function or gain-of-function at the protein level.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structure of full-length Plexin-A1 in autoinhibited vs. activated states","GAP activity not reconstituted biochemically with purified components","Molecular rules dictating co-receptor selection (NRP1 vs. VEGFR2 vs. Off-track vs. TREM-2/DAP12) remain unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,5]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[1,2,7,8]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[12,13]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,4]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[14]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,5,7,10,12,13]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[7,9]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[1,2,9]}],"complexes":["Plexin-A1/NRP1 semaphorin receptor complex","Plexin-A1/VEGFR2 complex","Plexin-A1/TREM-2/DAP12 complex"],"partners":["NRP1","SEMA3A","SEMA6D","RND1","RHOD","TREM2","TYROBP","CRAF"],"other_free_text":[]},"mechanistic_narrative":"PLXNA1 (Plexin-A1) is a transmembrane semaphorin receptor that transduces repulsive guidance and morphogenetic signals by coupling ligand-induced relief of sema-domain autoinhibition to an intrinsic cytoplasmic GAP-like domain that engages Rnd1 and RhoD GTPases, ultimately triggering cytoskeletal collapse, growth cone retraction, and cell migration control [PMID:10520994, PMID:11239433, PMID:11784792, PMID:11108845]. PLXNA1 forms obligate or context-dependent complexes with neuropilin-1 (NRP1) to bind class-3 semaphorins such as Sema3A, and with alternative co-receptors (VEGFR2, Off-track, TREM-2/DAP12, CRAF) to activate MAPK or AKT cascades in cardiac morphogenesis, immune regulation, bone homeostasis, and cancer drug resistance [PMID:14977921, PMID:16715077, PMID:35508542, PMID:39226661]. In vivo, PLXNA1 cooperates redundantly with PLXNA3 to pattern nasal axons and guide GnRH neuron migration during development [PMID:31690636]. Biallelic and monoallelic PLXNA1 variants cause a neurodevelopmental syndrome with CNS and eye abnormalities [PMID:34054129]."},"prefetch_data":{"uniprot":{"accession":"Q9UIW2","full_name":"Plexin-A1","aliases":["Semaphorin receptor NOV"],"length_aa":1896,"mass_kda":211.1,"function":"Coreceptor for SEMA3A, SEMA3C, SEMA3F and SEMA6D. Necessary for signaling by class 3 semaphorins and subsequent remodeling of the cytoskeleton. Plays a role in axon guidance, invasive growth and cell migration. Class 3 semaphorins bind to a complex composed of a neuropilin and a plexin. The plexin modulates the affinity of the complex for specific semaphorins, and its cytoplasmic domain is required for the activation of down-stream signaling events in the cytoplasm. Acts as coreceptor of TREM2 for SEMA6D in dendritic cells and is involved in the generation of immune responses and skeletal homeostasis","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9UIW2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PLXNA1","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/PLXNA1","total_profiled":1310},"omim":[{"mim_id":"620997","title":"SEMAPHORIN 3G; SEMA3G","url":"https://www.omim.org/entry/620997"},{"mim_id":"619955","title":"DWORSCHAK-PUNETHA NEURODEVELOPMENTAL SYNDROME; DWOPNED","url":"https://www.omim.org/entry/619955"},{"mim_id":"607414","title":"FEZ FAMILY ZINC FINGER PROTEIN 2; FEZF2","url":"https://www.omim.org/entry/607414"},{"mim_id":"601471","title":"FACIAL PARESIS, HEREDITARY CONGENITAL, 1; HCFP1","url":"https://www.omim.org/entry/601471"},{"mim_id":"601055","title":"PLEXIN A1; PLXNA1","url":"https://www.omim.org/entry/601055"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"},{"location":"Centrosome","reliability":"Additional"},{"location":"Basal body","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PLXNA1"},"hgnc":{"alias_symbol":["NOV"],"prev_symbol":["PLXN1"]},"alphafold":{"accession":"Q9UIW2","domains":[{"cath_id":"2.130.10.10","chopping":"232-480","consensus_level":"medium","plddt":88.8857,"start":232,"end":480},{"cath_id":"2.60.40.10","chopping":"520-673","consensus_level":"medium","plddt":90.3084,"start":520,"end":673},{"cath_id":"2.60.40","chopping":"709-853","consensus_level":"medium","plddt":87.0274,"start":709,"end":853},{"cath_id":"2.60.40.10","chopping":"866-1043","consensus_level":"medium","plddt":92.3583,"start":866,"end":1043},{"cath_id":"2.60.40.10","chopping":"1048-1148","consensus_level":"medium","plddt":90.065,"start":1048,"end":1148},{"cath_id":"2.60.40.10","chopping":"1152-1239","consensus_level":"medium","plddt":80.8148,"start":1152,"end":1239},{"cath_id":"1.10.506.10","chopping":"1302-1333_1435-1479_1679-1840","consensus_level":"medium","plddt":86.2503,"start":1302,"end":1840},{"cath_id":"-","chopping":"1338-1399_1846-1896","consensus_level":"medium","plddt":87.6596,"start":1338,"end":1896},{"cath_id":"3.10.20.90","chopping":"1498-1604_1651-1655","consensus_level":"medium","plddt":84.9352,"start":1498,"end":1655}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UIW2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UIW2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UIW2-F1-predicted_aligned_error_v6.png","plddt_mean":84.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PLXNA1","jax_strain_url":"https://www.jax.org/strain/search?query=PLXNA1"},"sequence":{"accession":"Q9UIW2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UIW2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UIW2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UIW2"}},"corpus_meta":[{"pmid":"27620848","id":"PMC_27620848","title":"Genome-based 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phenocopies the full spectrum of nasal axon and GnRH neuron defects seen in SEMA3A knockout mice, establishing that PLXNA1 acts in the SEMA3A-NRP signaling axis to guide GnRH neuron migration.\",\n      \"method\": \"Genetic epistasis: double knockout mouse models (Plxna1/Plxna3 combined KO vs SEMA3A KO), histological analysis of nasal axon patterning and GnRH neuron positioning\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean double-KO epistasis with defined cellular phenotype, replicated comparison to SEMA3A KO\",\n      \"pmids\": [\"31690636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Biallelic loss-of-function variants in the extracellular domains of PLXNA1 impair receptor dimerization or abolish receptor expression, while monoallelic variants in the intracellular domains cause a dominant-negative effect on downstream signaling, resulting in a neurodevelopmental syndrome with brain and eye anomalies; zebrafish morpholino knockdown of plxna1a and plxna1b confirmed an embryonic role in CNS and eye development.\",\n      \"method\": \"Structural modeling of missense variants, Morpholino knockdown in zebrafish with phenotypic readout (CNS and eye development), genotype-phenotype correlation in human patients\",\n      \"journal\": \"Genetics in medicine : official journal of the American College of Medical Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — zebrafish KD with defined phenotype plus structural modeling; single study\",\n      \"pmids\": [\"34054129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RUVBL1 promotes enzalutamide resistance in prostate cancer by enhancing recruitment of CRAF to PLXNA1, leading to activation of the downstream MAPK pathway; PLXNA1 thus acts as a scaffold for CRAF to activate MAPK signaling in the cytoplasm.\",\n      \"method\": \"Co-immunoprecipitation of RUVBL1-PLXNA1-CRAF complex, xenograft models, pharmacological inhibition (CB-6644), KD/OE with MAPK pathway readout\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP identifying complex, supported by xenograft and pharmacological rescue; single lab\",\n      \"pmids\": [\"35508542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PLXNA1 recruits NRP1 to form a PLXNA1-NRP1 receptor complex that potentiates AKT phosphorylation, thereby activating the AKT signaling pathway and conferring enzalutamide resistance in prostate cancer; inhibiting the PLXNA1-NRP1 complex with the NRP1 inhibitor EG01377 or AKT inhibitors abolished the pro-resistance phenotype.\",\n      \"method\": \"Co-immunoprecipitation of PLXNA1-NRP1 complex, AKT phosphorylation assays, pharmacological inhibition with EG01377 and AKT inhibitors, KD/OE with proliferation readout\",\n      \"journal\": \"Neoplasia (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP establishing complex, functional rescue with specific inhibitors; single lab\",\n      \"pmids\": [\"39226661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PLXNA1 activates the MAPK signaling pathway in esophageal squamous cell carcinoma cells; silencing of PLXNA1 (downstream target of miR-134) suppressed MAPK pathway activation and reduced cell proliferation, migration, invasion, and tumor metastasis in vitro and in vivo.\",\n      \"method\": \"siRNA knockdown of PLXNA1, dual-luciferase reporter assay (confirming miR-134 targeting of PLXNA1), Western blotting for MAPK pathway proteins, in vivo xenograft/lymph node metastasis models\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — KD with defined pathway readout plus in vivo validation; single lab\",\n      \"pmids\": [\"31383552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Full-length PLXNA1 has high EV-sorting ability and localizes to extracellular vesicles; truncated PLXNA1 retains this EV-sorting function and can serve as a scaffold protein to display fused proteins of interest on both the outer surface and luminal compartments of extracellular vesicles.\",\n      \"method\": \"Genetic fusion constructs, extracellular vesicle fractionation and characterization, live-cell imaging, functional EV cargo delivery assays\",\n      \"journal\": \"Journal of extracellular vesicles\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization to EVs with functional consequence (cargo delivery); single lab\",\n      \"pmids\": [\"39508411\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PLXNA1 (Plexin-A1) is a transmembrane receptor that acts as a co-receptor with neuropilins for semaphorin SEMA3A to guide axon patterning and GnRH neuron migration during development; in cancer contexts, PLXNA1 functions as a scaffold recruiting CRAF and NRP1 to activate downstream MAPK and AKT signaling pathways, thereby promoting cell proliferation and drug resistance.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nLooking at the corpus, I need to identify papers actually about the canonical PLXNA1 protein.\n\n**Classification:**\n- Papers [1]-[100] in the main corpus: The vast majority (papers 1-30, 32-33, 35-50, 52-100 in the retrieved set) are about bacterial taxonomy - clearly EXCLUDE (symbol collision/irrelevant).\n- Paper [34] describes \"circ-PLXNA1\" - a circRNA from the PLXNA1 locus in duck - EXCLUDE (alt-locus product, case B).\n- Papers [24], [38], [39], [45], [51], [80], [81], [87] describe PLXNA1 protein - KEEP.\n\n**Additional curated papers:**\n- [4] PMID:10520995 - Plexins as semaphorin receptors, includes plexin-A1 - KEEP\n- [8] PMID:10520994 - Plexin-neuropilin-1 complexes as Sema3A receptors - KEEP\n- [12] PMID:14977921 - Sema6D/Plexin-A1/OTK/VEGFR2 in cardiac morphogenesis - KEEP\n- [14] PMID:16715077 - Plexin-A1/DAP12 in immune responses - KEEP\n- [17] PMID:11239433 - PlexinA1 autoinhibition by sema domain - KEEP\n- [19] PMID:11108845 - Plexin-A1 GAP activity, Rho GTPase binding - KEEP\n- [22] PMID:8570614 - Original identification of plexin family (NOV/SEX/OCT/SEP) - KEEP\n- [23] PMID:11784792 - Rnd1/RhoD regulation of Plexin-A1 - KEEP\n- [16] PMID:14500350 - SEMA3A/plexin-A1/NP1 autocrine pathway in carcinoma - KEEP\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"PLXNA1 (originally named NOV/SEX family member) was identified as a transmembrane protein of ~220 kDa with homology to the MET/HGF receptor extracellular domain; it is glycosylated and cell-surface exposed but lacks tyrosine kinase activity despite containing a distinctive conserved cytoplasmic 'SEX domain', suggesting a novel receptor mechanism.\",\n      \"method\": \"cDNA cloning, Northern blot, in situ hybridization, cell-surface expression assays, chimeric receptor constructs\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — original identification with multiple biochemical methods in a single rigorous study\",\n      \"pmids\": [\"8570614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Plexin-A1 is a functional semaphorin receptor: plexin-A1 associates stably with neuropilin-1 (NRP1), and this NRP1/Plexin-A1 complex binds Sema3A with higher affinity than NRP1 alone; expression of dominant-negative Plexin-A1 in sensory neurons blocks Sema3A-induced growth cone collapse, establishing plexin-A1 as the signal-transducing subunit of the Sema3A receptor.\",\n      \"method\": \"Co-immunoprecipitation, receptor-ligand binding assays, dominant-negative expression in neurons, growth cone collapse assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — reciprocal co-IP, functional rescue/block, replicated across labs\",\n      \"pmids\": [\"10520994\", \"10520995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Plexin-A1 is a direct receptor for multiple semaphorin classes either alone or in combination with neuropilins; expression of a truncated plexin-A1 in neurons blocks Sema3A-induced axon repulsion, and the cytoplasmic domain of plexin-A1 associates with a tyrosine kinase activity.\",\n      \"method\": \"Binding assays, dominant-negative truncation expression in neurons, co-immunoprecipitation for kinase activity\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, foundational study replicated across the field\",\n      \"pmids\": [\"10520995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The cytoplasmic domain of Plexin-A1 contains sequence similarity to RasGAP/RhoGAP catalytic domains; mutation of two conserved arginine residues corresponding to catalytic GAP residues abolishes Plexin-A1's ability to induce growth cone collapse, implying an intrinsic GAP activity essential for semaphorin signaling.\",\n      \"method\": \"Sequence analysis, site-directed mutagenesis of arginine residues, growth cone collapse assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — mutagenesis with functional readout, but GAP activity not directly reconstituted in vitro in this study\",\n      \"pmids\": [\"11108845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Plexin-A1 is autoinhibited by its own sema domain: deletion of the sema domain renders Plexin-A1 constitutively active (inducing cell contraction, growth cone collapse, and neurite outgrowth inhibition without ligand), and the isolated sema domain physically associates with the remainder of the Plexin-A1 ectodomain to reverse constitutive activation. Both the sema domain and the remainder of the ectodomain independently associate with NRP1.\",\n      \"method\": \"Deletion mutagenesis, cell morphology assays, growth cone collapse assay, co-immunoprecipitation of ectodomain fragments\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple deletion constructs with functional and biochemical validation in one study\",\n      \"pmids\": [\"11239433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Among a large panel of Rho-family GTPases tested, only Rnd1 and RhoD bind the cytoplasmic domain of Plexin-A1. Active Rnd1 is sufficient to trigger Plexin-A1 signaling and cytoskeletal collapse in the absence of Sema3A, while RhoD antagonizes Plexin-A1 activation by Rnd1 and blocks Sema3A-induced axon repulsion, revealing that antagonistic GTPases regulate Plexin-A1 activity.\",\n      \"method\": \"GST pulldown, co-immunoprecipitation, dominant-active/negative GTPase expression, growth cone collapse and axon repulsion assays\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — systematic GTPase screen with pulldown plus functional epistasis experiments\",\n      \"pmids\": [\"11784792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Breast carcinoma cells express an autocrine SEMA3A/Plexin-A1/NRP1 pathway that impedes chemotaxis; RNAi knockdown of SEMA3A or NRP1, or inhibition of Plexin-A1 signaling, enhances migration, while constitutively active Plexin-A1 impairs chemotaxis, establishing Plexin-A1 as an anti-migratory signal in cancer cells.\",\n      \"method\": \"siRNA knockdown, constitutively active Plexin-A1 expression, Boyden chamber chemotaxis assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss- and gain-of-function with defined cellular phenotype, single lab\",\n      \"pmids\": [\"14500350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Plexin-A1 is the primary receptor for Sema6D in cardiac morphogenesis. In the conotruncal segment, Plexin-A1 forms a complex with VEGFR2 and promotes cell migration; in the ventricular segment, Plexin-A1 associates with Off-track and inhibits migration. The differential co-receptor association of Plexin-A1 enables Sema6D to exert distinct, region-specific activities during cardiac morphogenesis.\",\n      \"method\": \"RNA interference, ectopic expression in chick embryos, co-immunoprecipitation of receptor complexes, cardiac explant migration assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP of distinct complexes plus in vivo gain/loss-of-function with phenotypic readout\",\n      \"pmids\": [\"14977921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Plexin-A1 associates with the ITAM-bearing adaptor protein DAP12 through the transmembrane receptor TREM-2. In plexin-A1-deficient mice, T-cell-dependent immune responses are impaired and bone homeostasis is disrupted (osteoclast defects), linking semaphorin signaling via Plexin-A1/TREM-2/DAP12 to immune activation and bone remodeling pathways beyond the nervous system.\",\n      \"method\": \"Plexin-A1 knockout mice, co-immunoprecipitation (Plexin-A1/TREM-2/DAP12 complex), immune challenge experiments, bone histomorphometry\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — knockout mouse plus reciprocal co-IP of multiprotein complex, multiple phenotypic readouts\",\n      \"pmids\": [\"16715077\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PLXNA1 and PLXNA3 cooperate as co-receptors for SEMA3A to pattern vomeronasal and olfactory axons that guide GnRH neuron migration. Combined loss of PLXNA1 and PLXNA3 in mice fully phenocopies the nasal axon defects and GnRH neuron migration failure seen in Sema3a knockout mice, while single knockouts do not, establishing PLXNA1 and PLXNA3 as redundant, essential co-receptors in GnRH neuron development.\",\n      \"method\": \"Genetic epistasis using single and double mouse knockouts (Plxna1−/−, Plxna3−/−, Plxna1/Plxna3 double KO vs. Sema3a KO), immunofluorescence of nasal axons and GnRH neurons\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean double-knockout epistasis with full phenocopy of ligand KO, rigorous controls\",\n      \"pmids\": [\"31690636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PLXNA1 activates the MAPK signaling pathway in esophageal squamous cell carcinoma cells; miR-134 directly targets the PLXNA1 3'UTR (verified by dual-luciferase reporter assay) and suppresses PLXNA1 expression, thereby blocking MAPK pathway activation and reducing cell proliferation, migration, invasion, and tumor metastasis in vitro and in vivo.\",\n      \"method\": \"Dual-luciferase reporter assay (miR-134/PLXNA1 3'UTR interaction), siRNA knockdown, miR-134 mimic/inhibitor, western blot of MAPK pathway proteins, xenograft mouse models\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — validated miRNA-target interaction plus KD phenotype, pathway placement by western blot\",\n      \"pmids\": [\"31383552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Biallelic and monoallelic variants in PLXNA1 cause a novel neurodevelopmental syndrome. Structural modeling indicates that missense variants in the extracellular domain likely impair Plexin-A1 dimerization or abolish receptor molecules, while monoallelic intracellular domain variants may exert a dominant-negative effect on downstream signaling. Morpholino knockdown of zebrafish plxna1a and plxna1b disrupts CNS and eye development, demonstrating an embryonic role for PLXNA1 in neurogenesis.\",\n      \"method\": \"Structural/homology modeling of missense variants, Morpholino knockdown in zebrafish (CNS and eye phenotype), genotype-phenotype correlation in 10 patients\",\n      \"journal\": \"Genetics in medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — zebrafish KD provides in vivo functional evidence; mechanistic model based on structural modeling, not biochemical reconstitution\",\n      \"pmids\": [\"34054129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RUVBL1 promotes enzalutamide resistance in prostate cancer through PLXNA1: enzalutamide increases cytoplasmic RUVBL1 accumulation, which enhances recruitment of CRAF to Plexin-A1 (PLXNA1), activating the downstream MAPK pathway and bypassing androgen receptor signaling.\",\n      \"method\": \"Co-immunoprecipitation (RUVBL1/CRAF/PLXNA1 complex), RUVBL1 inhibition with CB-6644, xenograft models, western blot of MAPK pathway activation\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — co-IP of multiprotein complex plus pharmacological inhibition with in vivo validation, single lab\",\n      \"pmids\": [\"35508542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PLXNA1 confers enzalutamide resistance in prostate cancer via AKT signaling: PLXNA1 recruits NRP1 to form a PLXNA1-NRP1 receptor complex, which potentiates AKT phosphorylation. Inhibition of the PLXNA1-NRP1 complex with the NRP1 inhibitor EG01377 or AKT inhibitors abolishes the pro-resistance phenotype of PLXNA1 overexpression.\",\n      \"method\": \"Co-immunoprecipitation (PLXNA1-NRP1 complex), NRP1 inhibitor (EG01377) treatment, AKT inhibitor treatment, western blot of pAKT, cell proliferation assays under enzalutamide\",\n      \"journal\": \"Neoplasia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — co-IP of complex plus pharmacological intervention with pathway readout, single lab\",\n      \"pmids\": [\"39226661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Truncated PLXNA1 functions as a novel scaffold protein for extracellular vesicle (EV) engineering: endogenous full-length PLXNA1 has high EV-sorting ability, and truncated PLXNA1 retains this property while permitting fusion expression of protein cargoes on both the outer EV surface and luminal areas.\",\n      \"method\": \"EV purification, western blot and flow cytometry for EV-sorted PLXNA1 fusion proteins, fluorescence microscopy of cargo delivery\",\n      \"journal\": \"Journal of extracellular vesicles\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — direct experimental demonstration of PLXNA1 EV-sorting and cargo delivery, but functional mechanism not deeply dissected\",\n      \"pmids\": [\"39508411\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PLXNA1 (Plexin-A1) is a transmembrane semaphorin receptor that is autoinhibited by its own sema domain and functions either alone or in NRP1-containing complexes to transduce repulsive guidance signals; upon activation by Sema3A or Sema6D, its cytoplasmic GAP-like domain engages Rnd1/RhoD GTPases and downstream MAPK/AKT pathways to regulate cytoskeletal collapse, cell migration, and axon guidance, while context-dependent association with co-receptors (VEGFR2, Off-track, TREM-2/DAP12, NRP1, CRAF) enables its pleiotropic roles in cardiac morphogenesis, GnRH neuron migration, immune function, bone homeostasis, and cancer drug resistance.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PLXNA1 (Plexin-A1) is a transmembrane semaphorin receptor that cooperates with neuropilins (NRP1/NRP2) to transduce SEMA3A signals required for axon guidance and GnRH neuron migration during development; combined loss of PLXNA1 and PLXNA3 phenocopies SEMA3A knockout defects in nasal axon patterning and GnRH neuron positioning [PMID:31690636]. Biallelic loss-of-function variants in PLXNA1 extracellular domains impair receptor dimerization while monoallelic intracellular-domain variants exert dominant-negative effects on downstream signaling, causing a neurodevelopmental syndrome with brain and eye anomalies [PMID:34054129]. In cancer cells, PLXNA1 functions as a signaling scaffold that recruits CRAF to activate the MAPK pathway and partners with NRP1 to potentiate AKT phosphorylation, promoting cell proliferation and drug resistance in prostate and esophageal carcinomas [PMID:35508542, PMID:39226661, PMID:31383552].\",\n  \"teleology\": [\n    {\n      \"year\": 2019,\n      \"claim\": \"Establishing that PLXNA1 is a functional co-receptor in the SEMA3A-neuropilin axis required for GnRH neuron migration resolved how semaphorin signals are transduced through plexin receptors during neuroendocrine development.\",\n      \"evidence\": \"Plxna1/Plxna3 double-KO mice phenocopied SEMA3A-KO nasal axon and GnRH neuron defects\",\n      \"pmids\": [\"31690636\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Relative contributions of PLXNA1 versus PLXNA3 to SEMA3A signaling are not fully resolved\",\n        \"Intracellular signaling cascades downstream of PLXNA1 in GnRH neurons not characterized\",\n        \"Whether PLXNA1 mediates SEMA3A-independent signals in this context is unknown\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrating that PLXNA1 silencing suppresses MAPK pathway activation and metastasis in esophageal squamous cell carcinoma established PLXNA1 as a pro-oncogenic signaling hub beyond its canonical neurodevelopmental role.\",\n      \"evidence\": \"siRNA knockdown of PLXNA1 with Western blot MAPK readout and in vivo xenograft/metastasis models\",\n      \"pmids\": [\"31383552\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct mechanism by which PLXNA1 activates MAPK in ESCC cells not identified\",\n        \"Whether semaphorin ligands are involved in PLXNA1-driven MAPK activation in cancer is unclear\",\n        \"Single-lab study without independent replication\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linking biallelic and monoallelic PLXNA1 variants to a neurodevelopmental syndrome with brain and eye anomalies established PLXNA1 as a disease gene and revealed that extracellular-domain variants disrupt dimerization while intracellular-domain variants act dominant-negatively.\",\n      \"evidence\": \"Structural modeling of patient variants, zebrafish morpholino knockdown of plxna1a/b with CNS and eye phenotyping, genotype-phenotype correlation\",\n      \"pmids\": [\"34054129\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Zebrafish morpholino knockdown lacks genetic knockout confirmation\",\n        \"Dominant-negative mechanism of intracellular variants not biochemically reconstituted\",\n        \"Downstream signaling pathways disrupted in patient cells not directly measured\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identifying PLXNA1 as a scaffold that recruits CRAF (via RUVBL1) to activate MAPK signaling provided a molecular mechanism for PLXNA1-driven drug resistance in prostate cancer.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation of RUVBL1-PLXNA1-CRAF, xenograft models, pharmacological rescue with CB-6644\",\n      \"pmids\": [\"35508542\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether PLXNA1-CRAF interaction is direct or entirely RUVBL1-dependent is unresolved\",\n        \"Structural basis of the ternary complex is unknown\",\n        \"Single-lab finding without independent replication\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showing that PLXNA1 recruits NRP1 to potentiate AKT phosphorylation expanded the scaffold model to a second major signaling axis and revealed a druggable receptor complex driving enzalutamide resistance.\",\n      \"evidence\": \"Co-immunoprecipitation of PLXNA1-NRP1, AKT phosphorylation assays, pharmacological rescue with EG01377 and AKT inhibitors\",\n      \"pmids\": [\"39226661\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether PLXNA1-NRP1-AKT and PLXNA1-CRAF-MAPK axes operate independently or converge is unknown\",\n        \"Ligand dependence (semaphorin or VEGF) for the PLXNA1-NRP1 complex in cancer cells is untested\",\n        \"Single-lab study\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrating that PLXNA1 is efficiently sorted into extracellular vesicles and can scaffold heterologous cargo revealed an unanticipated cell-biological role and biotechnological application.\",\n      \"evidence\": \"EV fractionation, genetic fusion constructs, live-cell imaging, functional EV cargo delivery assays\",\n      \"pmids\": [\"39508411\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular determinants driving PLXNA1 EV sorting are not identified\",\n        \"Physiological significance of endogenous PLXNA1 on EVs is unknown\",\n        \"Single-lab observation\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PLXNA1's developmental semaphorin-dependent signaling and cancer scaffold functions are integrated — including whether shared ligands or post-translational modifications switch between these modes — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of full-length PLXNA1 in complex with its signaling partners\",\n        \"GAP activity of the PLXNA1 intracellular domain toward R-Ras family GTPases not characterized in the cancer scaffold context\",\n        \"In vivo relevance of PLXNA1 EV sorting is untested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 3, 4]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"NRP1\",\n      \"NRP2\",\n      \"PLXNA3\",\n      \"CRAF\",\n      \"RUVBL1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"PLXNA1 (Plexin-A1) is a transmembrane semaphorin receptor that transduces repulsive guidance and morphogenetic signals by coupling ligand-induced relief of sema-domain autoinhibition to an intrinsic cytoplasmic GAP-like domain that engages Rnd1 and RhoD GTPases, ultimately triggering cytoskeletal collapse, growth cone retraction, and cell migration control [PMID:10520994, PMID:11239433, PMID:11784792, PMID:11108845]. PLXNA1 forms obligate or context-dependent complexes with neuropilin-1 (NRP1) to bind class-3 semaphorins such as Sema3A, and with alternative co-receptors (VEGFR2, Off-track, TREM-2/DAP12, CRAF) to activate MAPK or AKT cascades in cardiac morphogenesis, immune regulation, bone homeostasis, and cancer drug resistance [PMID:14977921, PMID:16715077, PMID:35508542, PMID:39226661]. In vivo, PLXNA1 cooperates redundantly with PLXNA3 to pattern nasal axons and guide GnRH neuron migration during development [PMID:31690636]. Biallelic and monoallelic PLXNA1 variants cause a neurodevelopmental syndrome with CNS and eye abnormalities [PMID:34054129].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"The initial identification of PLXNA1 as a novel transmembrane protein with a MET-like ectodomain but no intrinsic tyrosine kinase activity posed the question of how it signals.\",\n      \"evidence\": \"cDNA cloning, Northern blot, chimeric receptor constructs in heterologous cells\",\n      \"pmids\": [\"8570614\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No ligand identified for the receptor\",\n        \"Cytoplasmic signaling mechanism unknown\",\n        \"Tissue-specific functions not addressed\"\n      ]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Demonstration that Plexin-A1 forms a complex with NRP1 and is the obligate signal-transducing component of the Sema3A receptor resolved the long-standing question of how neuropilins, which lack substantial cytoplasmic domains, trigger intracellular signaling.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation of Plexin-A1/NRP1, ligand binding assays, dominant-negative Plexin-A1 blocking Sema3A-induced growth cone collapse in DRG neurons\",\n      \"pmids\": [\"10520994\", \"10520995\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism of signal transduction across the membrane not known\",\n        \"Whether Plexin-A1 functions independently of NRP1 for other semaphorins not established\"\n      ]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Discovery of a RasGAP/RhoGAP-like catalytic domain within the Plexin-A1 cytoplasmic region, and the requirement of conserved catalytic arginines for growth cone collapse, provided the first mechanistic model for how plexins transduce signals — through intrinsic GTPase-activating activity.\",\n      \"evidence\": \"Sequence homology analysis plus site-directed mutagenesis of catalytic arginine residues with growth cone collapse readout\",\n      \"pmids\": [\"11108845\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"GAP activity not directly reconstituted in vitro\",\n        \"Substrate GTPase identity unknown at this stage\",\n        \"Whether GAP activity is regulated by ligand binding not tested\"\n      ]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Establishing that Plexin-A1 is autoinhibited by its own sema domain explained how the receptor remains quiescent in the absence of ligand and how ligand binding could relieve inhibition to activate the cytoplasmic domain.\",\n      \"evidence\": \"Sema-domain deletion mutagenesis yielding constitutive activity; rescue by co-expression of the isolated sema domain fragment; co-IP of ectodomain fragments\",\n      \"pmids\": [\"11239433\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of autoinhibition not resolved\",\n        \"Whether ligand binding displaces the sema domain or induces a conformational change not distinguished\"\n      ]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identification of Rnd1 as an activating GTPase and RhoD as an antagonistic GTPase that bind the Plexin-A1 cytoplasmic domain defined the immediate downstream GTPase relay controlling cytoskeletal collapse.\",\n      \"evidence\": \"Systematic GST-pulldown screen of Rho-family GTPases, functional epistasis using dominant-active/negative GTPases in growth cone collapse and axon repulsion assays\",\n      \"pmids\": [\"11784792\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct GAP activity of Plexin-A1 on Rnd1/RhoD not biochemically measured\",\n        \"How Rnd1 binding activates Plexin-A1 mechanistically not resolved\"\n      ]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"The finding of an autocrine SEMA3A/Plexin-A1/NRP1 pathway restraining breast cancer cell migration extended Plexin-A1's role beyond axon guidance to tumor biology.\",\n      \"evidence\": \"siRNA knockdown of SEMA3A and NRP1, constitutively active Plexin-A1 expression, Boyden chamber chemotaxis assays in breast carcinoma lines\",\n      \"pmids\": [\"14500350\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Downstream effectors mediating anti-migratory signaling in cancer cells not identified\",\n        \"Relevance to in vivo tumor progression not tested in this study\"\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Discovery that Plexin-A1 assembles distinct co-receptor complexes — with VEGFR2 to promote migration and with Off-track to inhibit migration — in different cardiac regions resolved how a single semaphorin (Sema6D) can exert opposing effects through the same receptor.\",\n      \"evidence\": \"Reciprocal co-IP of VEGFR2/Plexin-A1 and Off-track/Plexin-A1 complexes in chick cardiac tissue, RNAi and ectopic expression in embryo, cardiac explant migration assays\",\n      \"pmids\": [\"14977921\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular determinants governing co-receptor choice not identified\",\n        \"Downstream signaling divergence between the two complexes not characterized\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Plexin-A1 knockout mice revealed essential non-neuronal functions: association with TREM-2/DAP12 links Plexin-A1 to T-cell activation and osteoclast-mediated bone remodeling, demonstrating that semaphorin-plexin signaling is a core immune and skeletal pathway.\",\n      \"evidence\": \"Plexin-A1 knockout mice with immune challenge phenotyping, bone histomorphometry, co-IP of Plexin-A1/TREM-2/DAP12 complex\",\n      \"pmids\": [\"16715077\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Semaphorin ligand activating this immune complex not definitively identified\",\n        \"Signaling cascade downstream of DAP12 ITAM in this context not dissected\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Double-knockout epistasis in mice proved that PLXNA1 and PLXNA3 are redundant, essential co-receptors for Sema3A in patterning nasal axons and enabling GnRH neuron migration, connecting Plexin-A1 to neuroendocrine development.\",\n      \"evidence\": \"Plxna1/Plxna3 single and double knockout mice phenocopying Sema3a KO; immunofluorescence of nasal axons and GnRH neurons\",\n      \"pmids\": [\"31690636\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether PLXNA1 has a unique non-redundant role in GnRH biology apart from PLXNA3 is unclear\",\n        \"Human genetic validation for GnRH-related disease not yet established\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"PLXNA1 was shown to activate the MAPK cascade in esophageal squamous cell carcinoma, placing it upstream of a major proliferative signaling axis in an epithelial cancer context.\",\n      \"evidence\": \"miR-134/PLXNA1 3'UTR dual-luciferase validation, PLXNA1 knockdown, MAPK pathway western blots, xenograft models\",\n      \"pmids\": [\"31383552\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct mechanism linking Plexin-A1 to MAPK activation not defined\",\n        \"Intermediate effectors between PLXNA1 and MAPK not identified in this system\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identification of biallelic and monoallelic PLXNA1 variants in patients with a novel neurodevelopmental syndrome, supported by zebrafish knockdown phenocopying CNS and eye defects, established PLXNA1 as a disease gene for human neurodevelopment.\",\n      \"evidence\": \"Genotype-phenotype study of 10 patients, structural modeling of variants, morpholino knockdown in zebrafish\",\n      \"pmids\": [\"34054129\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Biochemical effect of individual disease variants on Plexin-A1 activity not reconstituted\",\n        \"Mammalian model validation (mouse knock-in of patient variants) lacking\",\n        \"Dominant-negative mechanism for monoallelic intracellular-domain variants is modeled, not proven\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The RUVBL1-CRAF-PLXNA1 axis was identified as a mechanism for enzalutamide resistance in prostate cancer, revealing Plexin-A1 as a scaffold for MAPK pathway re-activation that bypasses androgen receptor signaling.\",\n      \"evidence\": \"Co-IP of RUVBL1/CRAF/PLXNA1 complex, pharmacological inhibition with CB-6644, xenograft models\",\n      \"pmids\": [\"35508542\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct binding interface between PLXNA1 and CRAF not mapped\",\n        \"Whether semaphorin ligand is required for this scaffold function unknown\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"PLXNA1 was shown to recruit NRP1 to potentiate AKT signaling in enzalutamide-resistant prostate cancer, and pharmacological disruption of the PLXNA1-NRP1 complex with EG01377 abolished resistance, revealing a druggable co-receptor complex driving therapy resistance.\",\n      \"evidence\": \"Co-IP of PLXNA1-NRP1, NRP1 inhibitor (EG01377) and AKT inhibitor treatment, pAKT western blot, cell proliferation under enzalutamide\",\n      \"pmids\": [\"39226661\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"In vivo validation of NRP1 inhibitor efficacy against PLXNA1-driven resistance not reported\",\n        \"Whether MAPK and AKT pathways are activated independently or sequentially by PLXNA1 complexes is unresolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions remain: the structural basis of Plexin-A1 autoinhibition relief upon ligand binding, the direct biochemical reconstitution of its GAP activity against specific Ras/Rho substrates, the determinants governing co-receptor selection in different tissues, and whether PLXNA1 disease variants cause loss-of-function or gain-of-function at the protein level.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No high-resolution structure of full-length Plexin-A1 in autoinhibited vs. activated states\",\n        \"GAP activity not reconstituted biochemically with purified components\",\n        \"Molecular rules dictating co-receptor selection (NRP1 vs. VEGFR2 vs. Off-track vs. TREM-2/DAP12) remain unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [1, 2, 7, 8]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [12, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 5, 7, 10, 12, 13]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [7, 9]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [1, 2, 9]}\n    ],\n    \"complexes\": [\n      \"Plexin-A1/NRP1 semaphorin receptor complex\",\n      \"Plexin-A1/VEGFR2 complex\",\n      \"Plexin-A1/TREM-2/DAP12 complex\"\n    ],\n    \"partners\": [\n      \"NRP1\",\n      \"SEMA3A\",\n      \"SEMA6D\",\n      \"RND1\",\n      \"RHOD\",\n      \"TREM2\",\n      \"TYROBP\",\n      \"CRAF\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}