{"gene":"PLXNA2","run_date":"2026-04-28T19:45:44","timeline":{"discoveries":[{"year":2006,"finding":"PLXNA2 was identified as a candidate schizophrenia susceptibility gene on chromosome 1q32; it encodes a transmembrane semaphorin receptor involved in axonal guidance during development, and genetic association spanning ~60 kb of the PLXNA2 gene was confirmed across multiple independent cohorts.","method":"Genome-wide association study with >25,000 SNPs; high-density SNP mapping; replication in independent case-control and family-based samples","journal":"Molecular psychiatry","confidence":"Low","confidence_rationale":"Tier 4 — genetic association only, no direct functional/mechanistic experiment on the protein","pmids":["16402134"],"is_preprint":false},{"year":2013,"finding":"PLXNA2 expression is directly and positively regulated by the TMPRSS2:ERG transcription factor fusion in prostate cancer cells, and PLXNA2 upregulation contributes to TMPRSS2:ERG-mediated enhancement of PC3c cell migration and invasion; PLXNA2 expression is also elevated in metastatic versus localized primary prostate cancer tumors.","method":"Ectopic TMPRSS2:ERG expression in PC3c cells; high-throughput microarray; siRNA knockdown of PLXNA2; migration and invasion assays; correlation analysis in PCa cohort","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2/3 — knockdown with defined cellular phenotype (migration/invasion) and transcriptional regulation shown, single lab","pmids":["23708657"],"is_preprint":false},{"year":2014,"finding":"Plxna2 (plexin A2) acts alongside Sema6a to maintain zebrafish eye vesicle cohesion during morphogenesis; Plxna2 is restricted to the ventral eye vesicle while sema6a is expressed throughout, and knockdown of either causes eye progenitors to fail to enter evaginating vesicles or delaminate from the eye epithelium; simultaneous knockdown of both rescues integrity, indicating a repulsion-neutralization mechanism.","method":"Morpholino knockdown in zebrafish; time-lapse microscopy; explant experiments; epistasis by double knockdown rescue","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis via double-knockdown rescue with live imaging, ortholog in zebrafish with domain/function consistent with mammalian PLXNA2","pmids":["24917502"],"is_preprint":false},{"year":2006,"finding":"Genetic polymorphisms in PLXNA2 (a semaphorin 3A receptor) are associated with vertebral fracture risk and bone mineral density in postmenopausal women, implicating PLXNA2 in neural regulation of bone metabolism via semaphorin 3A signaling.","method":"Resequencing of PLXNA2; SNP genotyping in postmenopausal cohort (n=560); association analysis","journal":"Osteoporosis international","confidence":"Low","confidence_rationale":"Tier 4 — genetic association only, no direct mechanistic experiment on the protein itself","pmids":["16932874"],"is_preprint":false},{"year":2007,"finding":"A PLXNA2 intronic SNP (rs2478813) shows allelic association with anxiety, depression, neuroticism, and psychological distress, and the mouse ortholog maps to a significant linkage region for anxiety, suggesting PLXNA2 influences psychiatric traits through its role in nervous system development and adult neurogenesis.","method":"Genetic association study in extreme discordant/concordant sibling pairs; Composite International Diagnostic Interview; Bonferroni-corrected association testing","journal":"Archives of general psychiatry","confidence":"Low","confidence_rationale":"Tier 4 — genetic association only, no direct mechanistic experiment","pmids":["17339520"],"is_preprint":false}],"current_model":"PLXNA2 encodes a transmembrane semaphorin receptor (plexin A2) that mediates repulsive axon guidance and cell migration signaling; in zebrafish, Plxna2 acts with Sema6a through a repulsion-neutralization mechanism to maintain eye vesicle epithelial cohesion during morphogenesis, and in human prostate cancer cells PLXNA2 is transcriptionally induced by the TMPRSS2:ERG fusion and functionally promotes cell migration and invasion downstream of ERG."},"narrative":{"teleology":[{"year":2006,"claim":"Genetic association studies linked PLXNA2 polymorphisms to schizophrenia susceptibility and bone metabolism traits, establishing PLXNA2 as a candidate gene with pleiotropic effects but without direct mechanistic insight into protein function.","evidence":"Genome-wide and targeted SNP association studies in human cohorts","pmids":["16402134","16932874"],"confidence":"Low","gaps":["No functional experiments on the PLXNA2 protein were performed","Association signals have not been linked to specific molecular mechanisms","Not independently replicated with functional validation"]},{"year":2013,"claim":"Establishing a functional role in cancer biology, PLXNA2 was shown to be a direct transcriptional target of TMPRSS2:ERG that promotes prostate cancer cell migration and invasion, linking semaphorin receptor signaling to oncogenic phenotypes.","evidence":"Ectopic TMPRSS2:ERG expression, microarray, siRNA knockdown of PLXNA2, migration/invasion assays in PC3c cells","pmids":["23708657"],"confidence":"Medium","gaps":["Downstream signaling pathway from PLXNA2 to migration/invasion not delineated","Semaphorin ligand dependence of the pro-migratory function not tested","Single cell line; generalizability to other cancer contexts unknown"]},{"year":2014,"claim":"A repulsion-neutralization mechanism was established whereby Plxna2 and Sema6a counterbalance each other to maintain epithelial cohesion during zebrafish eye morphogenesis, providing the first in vivo epistatic dissection of PLXNA2 function in tissue organization.","evidence":"Morpholino knockdown in zebrafish with time-lapse imaging; double-knockdown epistasis rescue","pmids":["24917502"],"confidence":"Medium","gaps":["Mechanism by which Plxna2–Sema6a interaction regulates cell adhesion at the molecular level is unresolved","Whether mammalian PLXNA2 performs an analogous tissue-cohesion role has not been tested","Morpholino-based evidence; genetic mutant confirmation not reported"]},{"year":null,"claim":"The intracellular signaling cascades downstream of PLXNA2 activation — including GAP activity regulation, cytoskeletal effectors, and co-receptor partnerships — remain largely uncharacterized by direct experimental evidence in mammalian systems.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of PLXNA2 in complex with semaphorin ligands","Intrinsic GAP activity and GTPase substrates not experimentally defined","Specific co-receptors (neuropilins) required for PLXNA2 signaling not functionally dissected"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2]}],"complexes":[],"partners":["SEMA6A"],"other_free_text":[]},"mechanistic_narrative":"PLXNA2 encodes plexin A2, a transmembrane semaphorin receptor that mediates repulsive cell signaling during development. In zebrafish, Plxna2 acts with Sema6a through a repulsion-neutralization mechanism to maintain eye vesicle epithelial cohesion; loss of either gene disrupts eye progenitor integration, and simultaneous knockdown rescues tissue integrity [PMID:24917502]. In human prostate cancer cells, PLXNA2 is transcriptionally induced by the TMPRSS2:ERG fusion oncoprotein and functionally promotes cell migration and invasion downstream of ERG signaling [PMID:23708657]."},"prefetch_data":{"uniprot":{"accession":"O75051","full_name":"Plexin-A2","aliases":["Semaphorin receptor OCT"],"length_aa":1894,"mass_kda":211.1,"function":"Coreceptor for SEMA3A and SEMA6A. Necessary for signaling by SEMA6A and 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 (By similarity)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/O75051/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PLXNA2","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PLXNA2","total_profiled":1310},"omim":[{"mim_id":"616186","title":"H19/IGF2-IMPRINTING CONTROL REGION","url":"https://www.omim.org/entry/616186"},{"mim_id":"608873","title":"SEMAPHORIN 6B; SEMA6B","url":"https://www.omim.org/entry/608873"},{"mim_id":"605885","title":"SEMAPHORIN 6A; SEMA6A","url":"https://www.omim.org/entry/605885"},{"mim_id":"604280","title":"PLEXIN A4; PLXNA4","url":"https://www.omim.org/entry/604280"},{"mim_id":"601866","title":"SEMAPHORIN 4D; SEMA4D","url":"https://www.omim.org/entry/601866"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"pancreas","ntpm":33.1}],"url":"https://www.proteinatlas.org/search/PLXNA2"},"hgnc":{"alias_symbol":["OCT","FLJ11751","FLJ30634","KIAA0463"],"prev_symbol":["PLXN2"]},"alphafold":{"accession":"O75051","domains":[{"cath_id":"3.30.1680.10","chopping":"517-553","consensus_level":"medium","plddt":91.0816,"start":517,"end":553},{"cath_id":"2.60.40.10","chopping":"561-655","consensus_level":"high","plddt":88.6681,"start":561,"end":655},{"cath_id":"2.60.40.10","chopping":"703-803","consensus_level":"high","plddt":88.804,"start":703,"end":803},{"cath_id":"-","chopping":"812-847","consensus_level":"medium","plddt":82.7381,"start":812,"end":847},{"cath_id":"2.60.40.10","chopping":"860-1037","consensus_level":"medium","plddt":89.9902,"start":860,"end":1037},{"cath_id":"2.60.40,2.60.40","chopping":"1042-1134","consensus_level":"high","plddt":85.2251,"start":1042,"end":1134},{"cath_id":"2.60.40.10","chopping":"1145-1229","consensus_level":"high","plddt":81.2119,"start":1145,"end":1229},{"cath_id":"1.10.506.10","chopping":"1439-1494_1682-1786_1795-1842","consensus_level":"medium","plddt":87.4433,"start":1439,"end":1842},{"cath_id":"3.10.20.90","chopping":"1497-1600_1644-1654","consensus_level":"medium","plddt":83.0286,"start":1497,"end":1654}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75051","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75051-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75051-F1-predicted_aligned_error_v6.png","plddt_mean":84.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PLXNA2","jax_strain_url":"https://www.jax.org/strain/search?query=PLXNA2"},"sequence":{"accession":"O75051","fasta_url":"https://rest.uniprot.org/uniprotkb/O75051.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75051/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75051"}},"corpus_meta":[{"pmid":"10742100","id":"PMC_10742100","title":"Quantitative 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it encodes a transmembrane semaphorin receptor involved in axonal guidance during development, and genetic association spanning ~60 kb of the PLXNA2 gene was confirmed across multiple independent cohorts.\",\n      \"method\": \"Genome-wide association study with >25,000 SNPs; high-density SNP mapping; replication in independent case-control and family-based samples\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — genetic association only, no direct functional/mechanistic experiment on the protein\",\n      \"pmids\": [\"16402134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PLXNA2 expression is directly and positively regulated by the TMPRSS2:ERG transcription factor fusion in prostate cancer cells, and PLXNA2 upregulation contributes to TMPRSS2:ERG-mediated enhancement of PC3c cell migration and invasion; PLXNA2 expression is also elevated in metastatic versus localized primary prostate cancer tumors.\",\n      \"method\": \"Ectopic TMPRSS2:ERG expression in PC3c cells; high-throughput microarray; siRNA knockdown of PLXNA2; migration and invasion assays; correlation analysis in PCa cohort\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — knockdown with defined cellular phenotype (migration/invasion) and transcriptional regulation shown, single lab\",\n      \"pmids\": [\"23708657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Plxna2 (plexin A2) acts alongside Sema6a to maintain zebrafish eye vesicle cohesion during morphogenesis; Plxna2 is restricted to the ventral eye vesicle while sema6a is expressed throughout, and knockdown of either causes eye progenitors to fail to enter evaginating vesicles or delaminate from the eye epithelium; simultaneous knockdown of both rescues integrity, indicating a repulsion-neutralization mechanism.\",\n      \"method\": \"Morpholino knockdown in zebrafish; time-lapse microscopy; explant experiments; epistasis by double knockdown rescue\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis via double-knockdown rescue with live imaging, ortholog in zebrafish with domain/function consistent with mammalian PLXNA2\",\n      \"pmids\": [\"24917502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Genetic polymorphisms in PLXNA2 (a semaphorin 3A receptor) are associated with vertebral fracture risk and bone mineral density in postmenopausal women, implicating PLXNA2 in neural regulation of bone metabolism via semaphorin 3A signaling.\",\n      \"method\": \"Resequencing of PLXNA2; SNP genotyping in postmenopausal cohort (n=560); association analysis\",\n      \"journal\": \"Osteoporosis international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — genetic association only, no direct mechanistic experiment on the protein itself\",\n      \"pmids\": [\"16932874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"A PLXNA2 intronic SNP (rs2478813) shows allelic association with anxiety, depression, neuroticism, and psychological distress, and the mouse ortholog maps to a significant linkage region for anxiety, suggesting PLXNA2 influences psychiatric traits through its role in nervous system development and adult neurogenesis.\",\n      \"method\": \"Genetic association study in extreme discordant/concordant sibling pairs; Composite International Diagnostic Interview; Bonferroni-corrected association testing\",\n      \"journal\": \"Archives of general psychiatry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — genetic association only, no direct mechanistic experiment\",\n      \"pmids\": [\"17339520\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PLXNA2 encodes a transmembrane semaphorin receptor (plexin A2) that mediates repulsive axon guidance and cell migration signaling; in zebrafish, Plxna2 acts with Sema6a through a repulsion-neutralization mechanism to maintain eye vesicle epithelial cohesion during morphogenesis, and in human prostate cancer cells PLXNA2 is transcriptionally induced by the TMPRSS2:ERG fusion and functionally promotes cell migration and invasion downstream of ERG.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PLXNA2 encodes plexin A2, a transmembrane semaphorin receptor that mediates repulsive cell signaling during development. In zebrafish, Plxna2 acts with Sema6a through a repulsion-neutralization mechanism to maintain eye vesicle epithelial cohesion; loss of either gene disrupts eye progenitor integration, and simultaneous knockdown rescues tissue integrity [PMID:24917502]. In human prostate cancer cells, PLXNA2 is transcriptionally induced by the TMPRSS2:ERG fusion oncoprotein and functionally promotes cell migration and invasion downstream of ERG signaling [PMID:23708657].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Genetic association studies linked PLXNA2 polymorphisms to schizophrenia susceptibility and bone metabolism traits, establishing PLXNA2 as a candidate gene with pleiotropic effects but without direct mechanistic insight into protein function.\",\n      \"evidence\": \"Genome-wide and targeted SNP association studies in human cohorts\",\n      \"pmids\": [\"16402134\", \"16932874\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No functional experiments on the PLXNA2 protein were performed\", \"Association signals have not been linked to specific molecular mechanisms\", \"Not independently replicated with functional validation\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Establishing a functional role in cancer biology, PLXNA2 was shown to be a direct transcriptional target of TMPRSS2:ERG that promotes prostate cancer cell migration and invasion, linking semaphorin receptor signaling to oncogenic phenotypes.\",\n      \"evidence\": \"Ectopic TMPRSS2:ERG expression, microarray, siRNA knockdown of PLXNA2, migration/invasion assays in PC3c cells\",\n      \"pmids\": [\"23708657\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream signaling pathway from PLXNA2 to migration/invasion not delineated\", \"Semaphorin ligand dependence of the pro-migratory function not tested\", \"Single cell line; generalizability to other cancer contexts unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"A repulsion-neutralization mechanism was established whereby Plxna2 and Sema6a counterbalance each other to maintain epithelial cohesion during zebrafish eye morphogenesis, providing the first in vivo epistatic dissection of PLXNA2 function in tissue organization.\",\n      \"evidence\": \"Morpholino knockdown in zebrafish with time-lapse imaging; double-knockdown epistasis rescue\",\n      \"pmids\": [\"24917502\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which Plxna2–Sema6a interaction regulates cell adhesion at the molecular level is unresolved\", \"Whether mammalian PLXNA2 performs an analogous tissue-cohesion role has not been tested\", \"Morpholino-based evidence; genetic mutant confirmation not reported\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The intracellular signaling cascades downstream of PLXNA2 activation — including GAP activity regulation, cytoskeletal effectors, and co-receptor partnerships — remain largely uncharacterized by direct experimental evidence in mammalian systems.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of PLXNA2 in complex with semaphorin ligands\", \"Intrinsic GAP activity and GTPase substrates not experimentally defined\", \"Specific co-receptors (neuropilins) required for PLXNA2 signaling not functionally dissected\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SEMA6A\"],\n    \"other_free_text\": []\n  }\n}\n```"}