{"gene":"TMEM132A","run_date":"2026-04-28T21:42:59","timeline":{"discoveries":[{"year":2003,"finding":"A rat brain protein of 1021 amino acids with two predicted transmembrane regions, subsequently identified as the rat ortholog of TMEM132A, was cloned and shown to localize to the endoplasmic reticulum–Golgi domain. A GST pull-down assay identified GRP78 (a heat shock protein/chaperone) as a direct binding partner. Overexpression in Neuro2a cells conferred resistance to serum deprivation-induced cell death without affecting cell growth.","method":"PCR-selected cDNA subtraction, GST pull-down assay, GFP/Myc-tagged overexpression with fluorescence microscopy (ER-Golgi colocalization), cell viability assay under serum deprivation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 — direct pull-down identifying GRP78 binding partner with localization data and functional cell survival readout; single lab, single study","pmids":["12514190"],"is_preprint":false},{"year":2006,"finding":"Stable overexpression of the rat TMEM132A ortholog (GBP) in C6 glioblastoma cells attenuated cAMP-induced GFAP expression and decreased cAMP-induced STAT3 phosphorylation. Conversely, siRNA-mediated knockdown of the endogenous protein markedly augmented cAMP-induced GFAP mRNA expression and hyper-phosphorylation of STAT3, demonstrating that TMEM132A negatively regulates STAT3 phosphorylation downstream of cAMP signaling.","method":"Stable overexpression, siRNA knockdown, Western blot for phospho-STAT3, RT-PCR/qPCR for GFAP mRNA","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 — complementary gain- and loss-of-function with defined molecular readout (STAT3 phosphorylation); single lab","pmids":["16806201"],"is_preprint":false},{"year":2018,"finding":"Bioinformatic sequence and structural analysis revealed that the TMEM132 family proteins (including TMEM132A) possess an extracellular domain architecture comprising three tandem immunoglobulin domains and a cohesin domain homologue—the first cohesin domain identified in animals. This architecture, with predicted intracellular connection to the actin cytoskeleton, strongly indicates a cell adhesion function. The architecture has an ancient holozoan origin predating the emergence of choanoflagellates and metazoa.","method":"In-depth sequence analysis, structural homology modeling, phylogenetic analysis","journal":"Bioinformatics (Oxford, England)","confidence":"Low","confidence_rationale":"Tier 4 — computational/bioinformatic prediction without direct experimental validation of adhesion function","pmids":["29088312"],"is_preprint":false},{"year":2020,"finding":"TMEM132A was identified as a novel regulator of the Wnt signaling pathway through its physical and functional interaction with Wntless (WLS), the Wnt ligand transporter. Co-immunoprecipitation demonstrated a direct TMEM132A–WLS interaction. TMEM132A stabilizes Wnt ligand, enhances WLS–Wnt ligand interaction, and activates the Wnt signaling pathway in signal-sending cells.","method":"Co-immunoprecipitation, Wnt ligand stabilization assay, Wnt pathway reporter assay (TCF/LEF luciferase), overexpression and knockdown studies","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2–3 — reciprocal Co-IP establishing physical interaction, complemented by functional Wnt reporter assays; single lab, multiple methods","pmids":["33324648"],"is_preprint":false},{"year":2022,"finding":"TMEM132A is required for caudal neural tube closure and lateral migration of caudal paraxial mesoderm in mice. Tmem132a-null mouse embryos and TMEM132A-depleted cell models showed dysregulation of multiple integrins and downstream integrin pathway signaling, as well as impaired cell migration behaviors, demonstrating that TMEM132A regulates integrin-based mesodermal cell migration essential for posterior spinal neural tube closure.","method":"Tmem132a-null mouse generation, neural tube phenotype analysis, cell migration assay, integrin expression/activation analysis by Western blot and immunofluorescence, loss-of-function in cell models","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 — in vivo knockout with defined developmental phenotype (spina bifida), combined with cell model integrin pathway analysis demonstrating molecular mechanism","pmids":["35950911"],"is_preprint":false},{"year":2022,"finding":"Knockdown of TMEM132A in gastric cancer cells suppressed cell proliferation, migration, and invasion, whereas overexpression had opposite effects. These phenotypes were reversed by the Wnt activator LiCl or the Wnt inhibitor ICG-001, placing TMEM132A upstream of Wnt/β-catenin signaling in gastric cancer cell malignancy. In vivo knockdown suppressed GC tumorigenesis.","method":"siRNA knockdown, overexpression, CCK-8 proliferation assay, migration/invasion assays, LiCl/ICG-001 pharmacological rescue, xenograft tumor model","journal":"Nucleosides, nucleotides & nucleic acids","confidence":"Medium","confidence_rationale":"Tier 2–3 — bidirectional gain/loss of function with pharmacological rescue placing TMEM132A in the Wnt pathway; single lab","pmids":["36441075"],"is_preprint":false},{"year":2023,"finding":"In Tmem132a mutant mice, visceral endoderm fails to be excluded from the medial hindgut region, leading to loss or malformation of cloaca-derived genitourinary and gastrointestinal structures, and indirectly to neural tube and kidney/ureter defects. Co-immunoprecipitation demonstrated that TMEM132A physically interacts with the planar cell polarity (PCP) regulators CELSR1 and FZD6. Genetic epistasis showed that Tmem132a regulates neural tube closure synergistically with the PCP regulator Vangl2, identifying TMEM132A as a new regulator of PCP.","method":"Tmem132a mutant mouse analysis (histology, immunofluorescence), co-immunoprecipitation of TMEM132A with CELSR1 and FZD6, genetic double-mutant epistasis with Vangl2","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 — in vivo mutant phenotyping combined with Co-IP establishing physical interactions and genetic epistasis placing TMEM132A in the PCP pathway","pmids":["37390294"],"is_preprint":false},{"year":2024,"finding":"TMEM132A directly interacts with the Wnt co-receptor LRP6, preventing its lysosomal degradation and thereby stabilizing LRP6 protein levels. Loss of Tmem132a in mouse embryos led to diminished canonical Wnt/β-catenin signaling and developmental defects including open spina bifida, caudal truncation, syndactyly, and renal defects. Tmem132a knockdown in cultured cells suppressed canonical Wnt/β-catenin signaling, reversible by LRP6 stabilization.","method":"Co-immunoprecipitation of TMEM132A with LRP6, lysosomal inhibition rescue assay, Tmem132a knockout mouse embryo analysis, Wnt/β-catenin reporter assay, knockdown in cultured cells","journal":"Cell communication and signaling : CCS","confidence":"High","confidence_rationale":"Tier 2 — Co-IP identifying LRP6 as binding partner, lysosomal degradation rescue, in vivo knockout phenotype consistent with Wnt loss-of-function, multiple orthogonal methods","pmids":["39385148"],"is_preprint":false},{"year":2024,"finding":"E2F1 transcription factor directly regulates TMEM132A expression by binding to the TMEM132A promoter, as demonstrated by dual-luciferase reporter assay. Interference with E2F1 or TMEM132A expression significantly inhibited prostate cancer cell proliferation, suggesting E2F1 drives cancer cell growth in part through transcriptional activation of TMEM132A.","method":"Dual luciferase reporter assay (E2F1 binding to TMEM132A promoter), qPCR, siRNA knockdown of E2F1 and TMEM132A, CCK-8 proliferation assay, TCGA database analysis","journal":"Frontiers in bioscience (Landmark edition)","confidence":"Medium","confidence_rationale":"Tier 2–3 — luciferase assay directly demonstrating promoter binding with functional proliferation readout; single lab","pmids":["39473405"],"is_preprint":false},{"year":2026,"finding":"Autoantibodies (IgG) targeting TMEM132A were identified in serum samples from patients with autoimmune cerebellar ataxia (ACA). TMEM132A protein was shown to be enriched in the central nervous system by immunohistochemical and immunocytochemical assays. Immunoprecipitation and mass spectrometry confirmed TMEM132A as the target antigen, and a cell-based binding assay validated TMEM132A-IgG in patient serum, indicating TMEM132A is a CNS-enriched surface-accessible antigen relevant to autoimmune disease.","method":"Immunohistochemistry, immunocytochemistry, immunoprecipitation, mass spectrometry, cell-based binding assay (CBA)","journal":"Journal of neuroimmunology","confidence":"Medium","confidence_rationale":"Tier 2–3 — antigen identification by IP/MS with CBA validation, establishing CNS enrichment and surface accessibility; small patient cohort","pmids":["41564469"],"is_preprint":false}],"current_model":"TMEM132A is a single-pass type I transmembrane protein, enriched in the CNS and ER–Golgi compartment, that acts as a positive regulator of canonical Wnt/β-catenin signaling by physically interacting with both the Wnt transporter WLS (stabilizing Wnt ligand and enhancing WLS–Wnt interaction) and the co-receptor LRP6 (protecting it from lysosomal degradation); it also regulates planar cell polarity by interacting with CELSR1 and FZD6 (acting synergistically with Vangl2), and controls integrin-mediated mesodermal cell migration, with loss-of-function in mice causing spina bifida, caudal truncation, and hindgut/genitourinary defects."},"narrative":{"teleology":[{"year":2003,"claim":"The initial cloning of the rat ortholog established TMEM132A as an ER–Golgi-resident transmembrane protein that binds the chaperone GRP78 and confers resistance to serum-deprivation-induced cell death, providing the first molecular handle on the protein.","evidence":"GST pull-down, GFP/Myc-tagged overexpression with ER–Golgi colocalization, cell viability assay in Neuro2a cells","pmids":["12514190"],"confidence":"Medium","gaps":["GRP78 interaction not confirmed by reciprocal approach","mechanism linking GRP78 binding to cell survival undefined","relevance of ER–Golgi localization to in vivo function unknown"]},{"year":2006,"claim":"Gain- and loss-of-function experiments revealed that TMEM132A negatively regulates STAT3 phosphorylation downstream of cAMP, suppressing GFAP expression in glioblastoma cells — the first signaling pathway placement for the protein.","evidence":"Stable overexpression and siRNA knockdown in C6 glioblastoma cells, phospho-STAT3 Western blot, GFAP qPCR","pmids":["16806201"],"confidence":"Medium","gaps":["Mechanism of STAT3 regulation not identified","Not validated in non-cancer or primary neural cells","Relationship to Wnt/PCP functions discovered later remains unclear"]},{"year":2020,"claim":"Identification of TMEM132A as a binding partner of WLS that stabilizes Wnt ligand and enhances WLS–Wnt interaction placed TMEM132A directly in the canonical Wnt signaling pathway for the first time.","evidence":"Co-immunoprecipitation, Wnt ligand stabilization assay, TCF/LEF luciferase reporter in overexpression and knockdown studies","pmids":["33324648"],"confidence":"Medium","gaps":["Which Wnt ligands are affected was not specified","In vivo relevance of WLS interaction not yet demonstrated at the time","Domain mapping of TMEM132A–WLS interaction not performed"]},{"year":2022,"claim":"Tmem132a-null mice exhibited spina bifida and caudal truncation due to impaired integrin-mediated lateral migration of caudal paraxial mesoderm, establishing the first in vivo developmental requirement and revealing a distinct integrin-regulatory mechanism.","evidence":"Tmem132a knockout mouse, neural tube phenotype analysis, cell migration assays, integrin expression and activation analysis","pmids":["35950911"],"confidence":"High","gaps":["Direct physical interaction with integrins not demonstrated","Whether integrin regulation is Wnt-dependent or an independent function was unresolved","Rescue experiments with integrin pathway restoration not reported"]},{"year":2023,"claim":"Physical interactions with CELSR1 and FZD6 and genetic epistasis with Vangl2 identified TMEM132A as a new component of the planar cell polarity pathway, explaining hindgut and genitourinary defects in mutant mice through failure of visceral endoderm displacement.","evidence":"Co-immunoprecipitation of TMEM132A with CELSR1 and FZD6, Tmem132a;Vangl2 double-mutant epistasis analysis, histological phenotyping","pmids":["37390294"],"confidence":"High","gaps":["Whether TMEM132A is a core or tissue-specific PCP component is unclear","Structural basis of CELSR1/FZD6 interaction unknown","Relative contributions of PCP vs. canonical Wnt to each developmental phenotype not fully delineated"]},{"year":2024,"claim":"Demonstration that TMEM132A binds LRP6 and prevents its lysosomal degradation unified the earlier WLS interaction with a receptor-level mechanism, showing TMEM132A amplifies canonical Wnt signaling at two nodes — ligand production and receptor stability.","evidence":"Co-immunoprecipitation of TMEM132A with LRP6, lysosomal inhibition rescue, Tmem132a knockout mouse phenotype, Wnt reporter assays in knockdown cells","pmids":["39385148"],"confidence":"High","gaps":["Whether TMEM132A acts in a ternary complex with WLS and LRP6 simultaneously is untested","Structural determinants of LRP6 protection from lysosomal sorting unknown","Relative importance of WLS-stabilization vs. LRP6-stabilization in vivo not dissected"]},{"year":2024,"claim":"E2F1 was shown to directly bind the TMEM132A promoter and activate its transcription, providing the first upstream transcriptional regulatory mechanism for TMEM132A expression in a cancer context.","evidence":"Dual-luciferase reporter assay, siRNA knockdown of E2F1 and TMEM132A, CCK-8 proliferation assay in prostate cancer cells","pmids":["39473405"],"confidence":"Medium","gaps":["Whether E2F1 regulates TMEM132A in normal developmental contexts is unknown","Chromatin immunoprecipitation confirmation of promoter occupancy not shown","Downstream effectors (Wnt, integrin, PCP) not assessed in this cancer model"]},{"year":2026,"claim":"Identification of TMEM132A as a target autoantigen in autoimmune cerebellar ataxia confirmed its CNS enrichment and surface accessibility, extending its relevance to neurological autoimmune disease.","evidence":"Immunoprecipitation/mass spectrometry antigen identification, cell-based binding assay validating patient IgG, immunohistochemistry in CNS tissue","pmids":["41564469"],"confidence":"Medium","gaps":["Pathogenic role of anti-TMEM132A antibodies not demonstrated","Small patient cohort limits generalizability","Which TMEM132A extracellular domain epitope is targeted is undefined"]},{"year":null,"claim":"Key unresolved questions include whether TMEM132A's Wnt, PCP, and integrin functions represent a single integrated mechanism or separable activities, the structural basis for its interactions with WLS/LRP6/CELSR1/FZD6, and whether its cell-adhesion domain architecture contributes to any of its known signaling roles.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of TMEM132A or its complexes exists","Domain-deletion mapping for separating Wnt vs. PCP vs. integrin functions has not been performed","Predicted cohesin and immunoglobulin domains lack experimental functional validation"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,7]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[4,6]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[0]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,5,6,7]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,6,7]}],"complexes":[],"partners":["WLS","LRP6","CELSR1","FZD6","HSPA5"],"other_free_text":[]},"mechanistic_narrative":"TMEM132A is a single-pass type I transmembrane protein that functions as a positive regulator of both canonical Wnt/β-catenin and planar cell polarity (PCP) signaling during embryonic development. It physically interacts with the Wnt transporter WLS to stabilize Wnt ligand and enhance WLS–Wnt interaction [PMID:33324648], and with the co-receptor LRP6 to prevent its lysosomal degradation, thereby sustaining canonical Wnt signaling [PMID:39385148]; it also binds the PCP components CELSR1 and FZD6, acting synergistically with Vangl2 to regulate neural tube closure [PMID:37390294]. Loss of Tmem132a in mice causes spina bifida, caudal truncation, and hindgut/genitourinary malformations, with underlying defects in integrin-mediated mesodermal cell migration and visceral endoderm displacement [PMID:35950911, PMID:37390294]. TMEM132A is enriched in the CNS, where it localizes to ER–Golgi compartments and the cell surface, and has been identified as a target autoantigen in autoimmune cerebellar ataxia [PMID:12514190, PMID:41564469]."},"prefetch_data":{"uniprot":{"accession":"Q24JP5","full_name":"Transmembrane protein 132A","aliases":["HSPA5-binding protein 1"],"length_aa":1023,"mass_kda":110.1,"function":"May play a role in embryonic and postnatal development of the brain. Increased resistance to cell death induced by serum starvation in cultured cells. Regulates cAMP-induced GFAP gene expression via STAT3 phosphorylation (By similarity)","subcellular_location":"Golgi apparatus membrane; Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q24JP5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TMEM132A","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/TMEM132A","total_profiled":1310},"omim":[{"mim_id":"617363","title":"TRANSMEMBRANE PROTEIN 132A; TMEM132A","url":"https://www.omim.org/entry/617363"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Mitochondria","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":105.8},{"tissue":"choroid plexus","ntpm":107.2}],"url":"https://www.proteinatlas.org/search/TMEM132A"},"hgnc":{"alias_symbol":["GBP","FLJ20539"],"prev_symbol":["HSPA5BP1"]},"alphafold":{"accession":"Q24JP5","domains":[{"cath_id":"2.60.40.680","chopping":"266-334_341-392","consensus_level":"medium","plddt":82.0012,"start":266,"end":392}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q24JP5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q24JP5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q24JP5-F1-predicted_aligned_error_v6.png","plddt_mean":72.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TMEM132A","jax_strain_url":"https://www.jax.org/strain/search?query=TMEM132A"},"sequence":{"accession":"Q24JP5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q24JP5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q24JP5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q24JP5"}},"corpus_meta":[{"pmid":"9635432","id":"PMC_9635432","title":"GBP, 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\"year\": 2022,\n      \"finding\": \"TMEM132A is required for lateral migration of caudal paraxial mesoderm; loss of TMEM132A in null mice disrupts integrin regulation and downstream integrin pathway activation, impairing cell migration and causing failure of caudal neural tube closure (spina bifida phenotype).\",\n      \"method\": \"Tmem132a knockout mouse, cell migration assays, integrin pathway analysis by western blot/immunofluorescence\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO mouse with defined cellular and developmental phenotype, integrin pathway placement, replicated in cell models\",\n      \"pmids\": [\"35950911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TMEM132A mediates intercellular interactions and physically interacts with planar cell polarity (PCP) regulators CELSR1 and FZD6; genetically, Tmem132a regulates neural tube closure synergistically with Vangl2, placing it in the PCP pathway. Loss of Tmem132a causes visceral endoderm exclusion failure from the medial hindgut, leading to caudal developmental defects.\",\n      \"method\": \"Tmem132a mutant mouse analysis, co-immunoprecipitation of CELSR1/FZD6, genetic epistasis with Vangl2 double mutants, histological and developmental analysis\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP of binding partners, genetic epistasis, KO phenotype with mechanistic pathway placement\",\n      \"pmids\": [\"37390294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TMEM132A interacts with the Wnt co-receptor LRP6, stabilizes it, and prevents its lysosomal degradation; loss of Tmem132a in mouse embryos leads to diminished canonical Wnt/β-catenin signaling and developmental defects including open spina bifida, caudal truncation, syndactyly, and renal defects.\",\n      \"method\": \"Tmem132a knockout mouse, co-immunoprecipitation of LRP6, lysosomal degradation assays, β-catenin signaling reporter assays, Tmem132a knockdown in cultured cells\",\n      \"journal\": \"Cell Communication and Signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP of LRP6, mechanistic rescue experiments, KO mouse with defined signaling phenotype\",\n      \"pmids\": [\"39385148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Knockdown of TMEM132A in gastric cancer cells restrains cell proliferation, migration, and invasion via inhibition of Wnt signaling; effects of TMEM132A silencing are reversed by Wnt activator LiCl, and overexpression effects are reversed by Wnt inhibitor ICG-001, confirming functional coupling to the Wnt pathway.\",\n      \"method\": \"siRNA knockdown and overexpression in gastric cancer cell lines, proliferation/migration/invasion assays, in vivo tumor xenograft, pharmacological rescue with LiCl and ICG-001\",\n      \"journal\": \"Nucleosides, Nucleotides & Nucleic Acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — functional KD/OE with pathway placement via pharmacological epistasis, single lab\",\n      \"pmids\": [\"36441075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"E2F1 directly regulates TMEM132A expression by binding to the TMEM132A promoter, as demonstrated by dual-luciferase reporter assays; TMEM132A knockdown significantly inhibits prostate cancer cell proliferation.\",\n      \"method\": \"Dual-luciferase reporter assay, qPCR, siRNA knockdown, CCK8 proliferation assay\",\n      \"journal\": \"Frontiers in Bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct promoter binding demonstrated by reporter assay, functional proliferation phenotype, single lab\",\n      \"pmids\": [\"39473405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TMEM132A is enriched in central nervous system tissue; autoantibodies (IgG) targeting TMEM132A are found in patients with autoimmune cerebellar ataxia, identified by immunoprecipitation and mass spectrometry from patient serum.\",\n      \"method\": \"Immunohistochemistry, immunocytochemistry, immunoprecipitation, mass spectrometry, cell-based binding assay\",\n      \"journal\": \"Journal of Neuroimmunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — identification of TMEM132A as CNS-enriched autoantigen via IP/MS, no direct functional mechanism established\",\n      \"pmids\": [\"41564469\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TMEM132A is a single-pass type I transmembrane protein that promotes canonical Wnt/β-catenin signaling by physically interacting with both the Wnt cargo transporter WLS (to stabilize Wnt ligands) and the Wnt co-receptor LRP6 (to prevent its lysosomal degradation), while also functioning as a planar cell polarity regulator through interactions with CELSR1 and FZD6 and regulating integrin-mediated mesodermal cell migration; loss of TMEM132A in mice causes spinal neural tube defects, caudal dysgenesis, and hindgut malformations.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nLooking through the corpus, I need to identify papers about the canonical human/mammalian protein TMEM132A (transmembrane protein 132A).\n\n**KEEP papers:**\n- [29] PMID:33324648 - TMEM132A/WLS interaction, Wnt signaling\n- [46] PMID:35950911 - TMEM132A, neural tube closure, integrin/mesoderm migration\n- [55] PMID:36441075 - TMEM132A knockdown in gastric cancer, Wnt signaling\n- [60] PMID:37390294 - TMEM132A, hindgut morphogenesis, PCP regulators\n- [61] PMID:39385148 - TMEM132A/LRP6 interaction, Wnt/β-catenin\n- [62] PMID:39473405 - E2F1 regulates TMEM132A promoter\n- [82] PMID:41564469 - TMEM132A autoimmunity/cerebellar ataxia\n- Additional curated [17] PMID:29088312 - TMEM132 domain architecture (cohesin + Ig domains)\n- Additional curated [19] PMID:12514190 - GBP/GRP78-binding protein (rat brain) - this is actually the rat ortholog of TMEM132A (the paper clones a GRP78-binding protein from rat brain with two TM regions, 1021 aa, ER-Golgi localization). Cross-checking: this protein was later identified as the rat TMEM132A. KEEP.\n- Additional curated [23] PMID:16806201 - Follow-up on the same GBP (rat TMEM132A), GFAP/STAT3. KEEP.\n\nAll other papers describe GBP family GTPases, Drosophila GBP cytokines, Plasmodium GBP, bacterial Gbp, glucan-binding proteins, genome assemblies, etc. — EXCLUDE.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"A rat brain protein of 1021 amino acids with two predicted transmembrane regions, subsequently identified as the rat ortholog of TMEM132A, was cloned and shown to localize to the endoplasmic reticulum–Golgi domain. A GST pull-down assay identified GRP78 (a heat shock protein/chaperone) as a direct binding partner. Overexpression in Neuro2a cells conferred resistance to serum deprivation-induced cell death without affecting cell growth.\",\n      \"method\": \"PCR-selected cDNA subtraction, GST pull-down assay, GFP/Myc-tagged overexpression with fluorescence microscopy (ER-Golgi colocalization), cell viability assay under serum deprivation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — direct pull-down identifying GRP78 binding partner with localization data and functional cell survival readout; single lab, single study\",\n      \"pmids\": [\"12514190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Stable overexpression of the rat TMEM132A ortholog (GBP) in C6 glioblastoma cells attenuated cAMP-induced GFAP expression and decreased cAMP-induced STAT3 phosphorylation. Conversely, siRNA-mediated knockdown of the endogenous protein markedly augmented cAMP-induced GFAP mRNA expression and hyper-phosphorylation of STAT3, demonstrating that TMEM132A negatively regulates STAT3 phosphorylation downstream of cAMP signaling.\",\n      \"method\": \"Stable overexpression, siRNA knockdown, Western blot for phospho-STAT3, RT-PCR/qPCR for GFAP mRNA\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — complementary gain- and loss-of-function with defined molecular readout (STAT3 phosphorylation); single lab\",\n      \"pmids\": [\"16806201\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Bioinformatic sequence and structural analysis revealed that the TMEM132 family proteins (including TMEM132A) possess an extracellular domain architecture comprising three tandem immunoglobulin domains and a cohesin domain homologue—the first cohesin domain identified in animals. This architecture, with predicted intracellular connection to the actin cytoskeleton, strongly indicates a cell adhesion function. The architecture has an ancient holozoan origin predating the emergence of choanoflagellates and metazoa.\",\n      \"method\": \"In-depth sequence analysis, structural homology modeling, phylogenetic analysis\",\n      \"journal\": \"Bioinformatics (Oxford, England)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — computational/bioinformatic prediction without direct experimental validation of adhesion function\",\n      \"pmids\": [\"29088312\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TMEM132A was identified as a novel regulator of the Wnt signaling pathway through its physical and functional interaction with Wntless (WLS), the Wnt ligand transporter. Co-immunoprecipitation demonstrated a direct TMEM132A–WLS interaction. TMEM132A stabilizes Wnt ligand, enhances WLS–Wnt ligand interaction, and activates the Wnt signaling pathway in signal-sending cells.\",\n      \"method\": \"Co-immunoprecipitation, Wnt ligand stabilization assay, Wnt pathway reporter assay (TCF/LEF luciferase), overexpression and knockdown studies\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — reciprocal Co-IP establishing physical interaction, complemented by functional Wnt reporter assays; single lab, multiple methods\",\n      \"pmids\": [\"33324648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TMEM132A is required for caudal neural tube closure and lateral migration of caudal paraxial mesoderm in mice. Tmem132a-null mouse embryos and TMEM132A-depleted cell models showed dysregulation of multiple integrins and downstream integrin pathway signaling, as well as impaired cell migration behaviors, demonstrating that TMEM132A regulates integrin-based mesodermal cell migration essential for posterior spinal neural tube closure.\",\n      \"method\": \"Tmem132a-null mouse generation, neural tube phenotype analysis, cell migration assay, integrin expression/activation analysis by Western blot and immunofluorescence, loss-of-function in cell models\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo knockout with defined developmental phenotype (spina bifida), combined with cell model integrin pathway analysis demonstrating molecular mechanism\",\n      \"pmids\": [\"35950911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Knockdown of TMEM132A in gastric cancer cells suppressed cell proliferation, migration, and invasion, whereas overexpression had opposite effects. These phenotypes were reversed by the Wnt activator LiCl or the Wnt inhibitor ICG-001, placing TMEM132A upstream of Wnt/β-catenin signaling in gastric cancer cell malignancy. In vivo knockdown suppressed GC tumorigenesis.\",\n      \"method\": \"siRNA knockdown, overexpression, CCK-8 proliferation assay, migration/invasion assays, LiCl/ICG-001 pharmacological rescue, xenograft tumor model\",\n      \"journal\": \"Nucleosides, nucleotides & nucleic acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — bidirectional gain/loss of function with pharmacological rescue placing TMEM132A in the Wnt pathway; single lab\",\n      \"pmids\": [\"36441075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In Tmem132a mutant mice, visceral endoderm fails to be excluded from the medial hindgut region, leading to loss or malformation of cloaca-derived genitourinary and gastrointestinal structures, and indirectly to neural tube and kidney/ureter defects. Co-immunoprecipitation demonstrated that TMEM132A physically interacts with the planar cell polarity (PCP) regulators CELSR1 and FZD6. Genetic epistasis showed that Tmem132a regulates neural tube closure synergistically with the PCP regulator Vangl2, identifying TMEM132A as a new regulator of PCP.\",\n      \"method\": \"Tmem132a mutant mouse analysis (histology, immunofluorescence), co-immunoprecipitation of TMEM132A with CELSR1 and FZD6, genetic double-mutant epistasis with Vangl2\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo mutant phenotyping combined with Co-IP establishing physical interactions and genetic epistasis placing TMEM132A in the PCP pathway\",\n      \"pmids\": [\"37390294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TMEM132A directly interacts with the Wnt co-receptor LRP6, preventing its lysosomal degradation and thereby stabilizing LRP6 protein levels. Loss of Tmem132a in mouse embryos led to diminished canonical Wnt/β-catenin signaling and developmental defects including open spina bifida, caudal truncation, syndactyly, and renal defects. Tmem132a knockdown in cultured cells suppressed canonical Wnt/β-catenin signaling, reversible by LRP6 stabilization.\",\n      \"method\": \"Co-immunoprecipitation of TMEM132A with LRP6, lysosomal inhibition rescue assay, Tmem132a knockout mouse embryo analysis, Wnt/β-catenin reporter assay, knockdown in cultured cells\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP identifying LRP6 as binding partner, lysosomal degradation rescue, in vivo knockout phenotype consistent with Wnt loss-of-function, multiple orthogonal methods\",\n      \"pmids\": [\"39385148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"E2F1 transcription factor directly regulates TMEM132A expression by binding to the TMEM132A promoter, as demonstrated by dual-luciferase reporter assay. Interference with E2F1 or TMEM132A expression significantly inhibited prostate cancer cell proliferation, suggesting E2F1 drives cancer cell growth in part through transcriptional activation of TMEM132A.\",\n      \"method\": \"Dual luciferase reporter assay (E2F1 binding to TMEM132A promoter), qPCR, siRNA knockdown of E2F1 and TMEM132A, CCK-8 proliferation assay, TCGA database analysis\",\n      \"journal\": \"Frontiers in bioscience (Landmark edition)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — luciferase assay directly demonstrating promoter binding with functional proliferation readout; single lab\",\n      \"pmids\": [\"39473405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Autoantibodies (IgG) targeting TMEM132A were identified in serum samples from patients with autoimmune cerebellar ataxia (ACA). TMEM132A protein was shown to be enriched in the central nervous system by immunohistochemical and immunocytochemical assays. Immunoprecipitation and mass spectrometry confirmed TMEM132A as the target antigen, and a cell-based binding assay validated TMEM132A-IgG in patient serum, indicating TMEM132A is a CNS-enriched surface-accessible antigen relevant to autoimmune disease.\",\n      \"method\": \"Immunohistochemistry, immunocytochemistry, immunoprecipitation, mass spectrometry, cell-based binding assay (CBA)\",\n      \"journal\": \"Journal of neuroimmunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — antigen identification by IP/MS with CBA validation, establishing CNS enrichment and surface accessibility; small patient cohort\",\n      \"pmids\": [\"41564469\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TMEM132A is a single-pass type I transmembrane protein, enriched in the CNS and ER–Golgi compartment, that acts as a positive regulator of canonical Wnt/β-catenin signaling by physically interacting with both the Wnt transporter WLS (stabilizing Wnt ligand and enhancing WLS–Wnt interaction) and the co-receptor LRP6 (protecting it from lysosomal degradation); it also regulates planar cell polarity by interacting with CELSR1 and FZD6 (acting synergistically with Vangl2), and controls integrin-mediated mesodermal cell migration, with loss-of-function in mice causing spina bifida, caudal truncation, and hindgut/genitourinary defects.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TMEM132A is a single-pass transmembrane protein that promotes canonical Wnt/β-catenin signaling at multiple levels: it physically interacts with the Wnt cargo transporter WLS to stabilize Wnt ligands in signal-sending cells [PMID:33324648], and it binds the Wnt co-receptor LRP6 to prevent its lysosomal degradation, thereby sustaining Wnt signal reception [PMID:39385148]. TMEM132A also functions as a planar cell polarity regulator through physical interactions with CELSR1 and FZD6, and it acts synergistically with Vangl2 to control neural tube closure and hindgut morphogenesis [PMID:37390294]. Loss of Tmem132a in mice causes spina bifida, caudal truncation, syndactyly, and renal defects, reflecting impaired integrin-mediated lateral migration of caudal paraxial mesoderm and diminished Wnt/β-catenin signaling [PMID:35950911, PMID:39385148].\",\n  \"teleology\": [\n    {\n      \"year\": 2020,\n      \"claim\": \"The first mechanistic link between TMEM132A and Wnt signaling was established by showing that TMEM132A physically binds WLS, stabilizes Wnt ligands, and enhances Wnt pathway output in signal-sending cells — revealing it as a positive modulator of Wnt ligand secretion.\",\n      \"evidence\": \"Co-immunoprecipitation, overexpression/knockdown, and Wnt reporter assays in cultured cells\",\n      \"pmids\": [\"33324648\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Interaction and function demonstrated in a single lab; independent replication needed\",\n        \"Endogenous stoichiometry and tissue context of the TMEM132A–WLS interaction uncharacterized\",\n        \"Whether TMEM132A promotes WLS recycling or inhibits its degradation was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Knockout mouse studies established that TMEM132A is essential for caudal neural tube closure by enabling integrin-dependent lateral migration of paraxial mesoderm cells, moving the gene from a signaling modulator to a required developmental regulator.\",\n      \"evidence\": \"Tmem132a null mouse with spina bifida phenotype, cell migration assays, integrin pathway analysis by western blot and immunofluorescence\",\n      \"pmids\": [\"35950911\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct molecular mechanism by which TMEM132A regulates integrin activation or trafficking is unknown\",\n        \"Whether integrin-mediated migration defects are secondary to Wnt pathway disruption was not dissected\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Cancer cell studies confirmed that TMEM132A knockdown suppresses proliferation, migration, and invasion via Wnt signaling, as demonstrated by pharmacological rescue with Wnt activators and inhibitors, generalizing the Wnt-modulatory role beyond development.\",\n      \"evidence\": \"siRNA knockdown and overexpression in gastric cancer cell lines with LiCl/ICG-001 pharmacological epistasis, xenograft model\",\n      \"pmids\": [\"36441075\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single cancer type studied; generalizability uncertain\",\n        \"Whether the pro-tumorigenic effect operates through WLS or LRP6 stabilization was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"TMEM132A was placed in the planar cell polarity (PCP) pathway by demonstrating physical interaction with CELSR1 and FZD6 and genetic synergy with Vangl2, explaining its role in both neural tube closure and hindgut morphogenesis beyond canonical Wnt signaling alone.\",\n      \"evidence\": \"Co-immunoprecipitation of CELSR1/FZD6, genetic epistasis in Tmem132a;Vangl2 double-mutant mice, histological analysis of hindgut defects\",\n      \"pmids\": [\"37390294\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether TMEM132A functions as a PCP core component or a modulatory co-factor is unresolved\",\n        \"The structural basis and binding domains for the CELSR1/FZD6 interactions are unknown\",\n        \"How canonical Wnt and PCP activities of TMEM132A are coordinated in the same tissue is unclear\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The mechanism by which TMEM132A sustains Wnt signal reception was clarified: it binds LRP6 and prevents its lysosomal degradation, providing a receptor-side complement to its earlier-established WLS-mediated ligand-side function.\",\n      \"evidence\": \"Co-immunoprecipitation of LRP6, lysosomal degradation assays, β-catenin reporter assays, Tmem132a knockout mouse with spina bifida/syndactyly/renal phenotype\",\n      \"pmids\": [\"39385148\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether TMEM132A simultaneously stabilizes WLS and LRP6 in the same cell or these are tissue-specific functions is unknown\",\n        \"The mechanism by which TMEM132A diverts LRP6 from lysosomal sorting has not been dissected\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"E2F1 was identified as a direct transcriptional activator of TMEM132A, linking cell-cycle-regulated transcription to TMEM132A expression levels and downstream proliferative effects.\",\n      \"evidence\": \"Dual-luciferase promoter reporter assay, siRNA knockdown, CCK8 proliferation assay in prostate cancer cells\",\n      \"pmids\": [\"39473405\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single system (prostate cancer); relevance to developmental or other cancer contexts not tested\",\n        \"Whether E2F1 is the primary physiological regulator of TMEM132A transcription is unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis for TMEM132A's interactions with WLS, LRP6, CELSR1, and FZD6; how canonical Wnt and PCP functions are partitioned across tissues; and whether the integrin-regulatory function is mechanistically independent of Wnt signaling.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural or biochemical reconstitution data exist for any TMEM132A interaction\",\n        \"Tissue-specific partitioning of Wnt versus PCP versus integrin functions has not been addressed\",\n        \"Human genetic studies linking TMEM132A mutations to neural tube defects are lacking\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3, 4]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 2, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"WLS\", \"LRP6\", \"CELSR1\", \"FZD6\", \"VANGL2\"],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"TMEM132A is a single-pass type I transmembrane protein that functions as a positive regulator of both canonical Wnt/β-catenin and planar cell polarity (PCP) signaling during embryonic development. It physically interacts with the Wnt transporter WLS to stabilize Wnt ligand and enhance WLS–Wnt interaction [PMID:33324648], and with the co-receptor LRP6 to prevent its lysosomal degradation, thereby sustaining canonical Wnt signaling [PMID:39385148]; it also binds the PCP components CELSR1 and FZD6, acting synergistically with Vangl2 to regulate neural tube closure [PMID:37390294]. Loss of Tmem132a in mice causes spina bifida, caudal truncation, and hindgut/genitourinary malformations, with underlying defects in integrin-mediated mesodermal cell migration and visceral endoderm displacement [PMID:35950911, PMID:37390294]. TMEM132A is enriched in the CNS, where it localizes to ER–Golgi compartments and the cell surface, and has been identified as a target autoantigen in autoimmune cerebellar ataxia [PMID:12514190, PMID:41564469].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"The initial cloning of the rat ortholog established TMEM132A as an ER–Golgi-resident transmembrane protein that binds the chaperone GRP78 and confers resistance to serum-deprivation-induced cell death, providing the first molecular handle on the protein.\",\n      \"evidence\": \"GST pull-down, GFP/Myc-tagged overexpression with ER–Golgi colocalization, cell viability assay in Neuro2a cells\",\n      \"pmids\": [\"12514190\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"GRP78 interaction not confirmed by reciprocal approach\", \"mechanism linking GRP78 binding to cell survival undefined\", \"relevance of ER–Golgi localization to in vivo function unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Gain- and loss-of-function experiments revealed that TMEM132A negatively regulates STAT3 phosphorylation downstream of cAMP, suppressing GFAP expression in glioblastoma cells — the first signaling pathway placement for the protein.\",\n      \"evidence\": \"Stable overexpression and siRNA knockdown in C6 glioblastoma cells, phospho-STAT3 Western blot, GFAP qPCR\",\n      \"pmids\": [\"16806201\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of STAT3 regulation not identified\", \"Not validated in non-cancer or primary neural cells\", \"Relationship to Wnt/PCP functions discovered later remains unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identification of TMEM132A as a binding partner of WLS that stabilizes Wnt ligand and enhances WLS–Wnt interaction placed TMEM132A directly in the canonical Wnt signaling pathway for the first time.\",\n      \"evidence\": \"Co-immunoprecipitation, Wnt ligand stabilization assay, TCF/LEF luciferase reporter in overexpression and knockdown studies\",\n      \"pmids\": [\"33324648\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which Wnt ligands are affected was not specified\", \"In vivo relevance of WLS interaction not yet demonstrated at the time\", \"Domain mapping of TMEM132A–WLS interaction not performed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Tmem132a-null mice exhibited spina bifida and caudal truncation due to impaired integrin-mediated lateral migration of caudal paraxial mesoderm, establishing the first in vivo developmental requirement and revealing a distinct integrin-regulatory mechanism.\",\n      \"evidence\": \"Tmem132a knockout mouse, neural tube phenotype analysis, cell migration assays, integrin expression and activation analysis\",\n      \"pmids\": [\"35950911\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct physical interaction with integrins not demonstrated\", \"Whether integrin regulation is Wnt-dependent or an independent function was unresolved\", \"Rescue experiments with integrin pathway restoration not reported\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Physical interactions with CELSR1 and FZD6 and genetic epistasis with Vangl2 identified TMEM132A as a new component of the planar cell polarity pathway, explaining hindgut and genitourinary defects in mutant mice through failure of visceral endoderm displacement.\",\n      \"evidence\": \"Co-immunoprecipitation of TMEM132A with CELSR1 and FZD6, Tmem132a;Vangl2 double-mutant epistasis analysis, histological phenotyping\",\n      \"pmids\": [\"37390294\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TMEM132A is a core or tissue-specific PCP component is unclear\", \"Structural basis of CELSR1/FZD6 interaction unknown\", \"Relative contributions of PCP vs. canonical Wnt to each developmental phenotype not fully delineated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstration that TMEM132A binds LRP6 and prevents its lysosomal degradation unified the earlier WLS interaction with a receptor-level mechanism, showing TMEM132A amplifies canonical Wnt signaling at two nodes — ligand production and receptor stability.\",\n      \"evidence\": \"Co-immunoprecipitation of TMEM132A with LRP6, lysosomal inhibition rescue, Tmem132a knockout mouse phenotype, Wnt reporter assays in knockdown cells\",\n      \"pmids\": [\"39385148\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TMEM132A acts in a ternary complex with WLS and LRP6 simultaneously is untested\", \"Structural determinants of LRP6 protection from lysosomal sorting unknown\", \"Relative importance of WLS-stabilization vs. LRP6-stabilization in vivo not dissected\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"E2F1 was shown to directly bind the TMEM132A promoter and activate its transcription, providing the first upstream transcriptional regulatory mechanism for TMEM132A expression in a cancer context.\",\n      \"evidence\": \"Dual-luciferase reporter assay, siRNA knockdown of E2F1 and TMEM132A, CCK-8 proliferation assay in prostate cancer cells\",\n      \"pmids\": [\"39473405\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether E2F1 regulates TMEM132A in normal developmental contexts is unknown\", \"Chromatin immunoprecipitation confirmation of promoter occupancy not shown\", \"Downstream effectors (Wnt, integrin, PCP) not assessed in this cancer model\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identification of TMEM132A as a target autoantigen in autoimmune cerebellar ataxia confirmed its CNS enrichment and surface accessibility, extending its relevance to neurological autoimmune disease.\",\n      \"evidence\": \"Immunoprecipitation/mass spectrometry antigen identification, cell-based binding assay validating patient IgG, immunohistochemistry in CNS tissue\",\n      \"pmids\": [\"41564469\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pathogenic role of anti-TMEM132A antibodies not demonstrated\", \"Small patient cohort limits generalizability\", \"Which TMEM132A extracellular domain epitope is targeted is undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include whether TMEM132A's Wnt, PCP, and integrin functions represent a single integrated mechanism or separable activities, the structural basis for its interactions with WLS/LRP6/CELSR1/FZD6, and whether its cell-adhesion domain architecture contributes to any of its known signaling roles.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of TMEM132A or its complexes exists\", \"Domain-deletion mapping for separating Wnt vs. PCP vs. integrin functions has not been performed\", \"Predicted cohesin and immunoglobulin domains lack experimental functional validation\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 7]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [4, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 5, 6, 7]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 6, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"WLS\", \"LRP6\", \"CELSR1\", \"FZD6\", \"HSPA5\"],\n    \"other_free_text\": []\n  }\n}\n```"}