{"gene":"TMEM132A","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2020,"finding":"TMEM132A physically interacts with the Wnt ligand transporting protein Wntless (WLS), stabilizes Wnt ligand, enhances WLS-Wnt ligand interaction, and activates the Wnt signaling pathway in signal-sending cells.","method":"Co-immunoprecipitation (physical interaction), functional assays (Wnt ligand stabilization, pathway activation readouts)","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction demonstrated and multiple functional readouts reported, but from a single lab; full methods not detailed in abstract","pmids":["33324648"],"is_preprint":false},{"year":2022,"finding":"TMEM132A regulates several integrins and downstream integrin pathway activation, and is required for lateral migration of the caudal paraxial mesoderm and spinal neural tube closure in mice; loss of TMEM132A in null mice impairs mesodermal cell migration behaviors.","method":"Tmem132a-null mouse genetic model, cell migration assays, integrin pathway activation readouts (loss-of-function with defined cellular phenotype)","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean knockout mouse with defined phenotype and integrin pathway readout, single lab","pmids":["35950911"],"is_preprint":false},{"year":2023,"finding":"TMEM132A physically interacts with planar cell polarity (PCP) regulators CELSR1 and FZD6, mediates intercellular interaction, and genetically interacts synergistically with PCP regulator Vangl2 for neural tube closure, placing TMEM132A as a regulator of PCP signaling.","method":"Co-immunoprecipitation (physical interaction with CELSR1 and FZD6), genetic epistasis (double mutant with Vangl2), Tmem132a mutant mouse phenotypic analysis","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and genetic epistasis in mouse, single lab","pmids":["37390294"],"is_preprint":false},{"year":2024,"finding":"TMEM132A interacts with the Wnt co-receptor LRP6, stabilizes LRP6, and prevents its lysosomal degradation, thereby promoting canonical Wnt/β-catenin signaling; loss of Tmem132a in mice leads to diminished Wnt/β-catenin signaling and developmental malformations resembling Wnt/β-catenin mutant phenotypes.","method":"Co-immunoprecipitation (TMEM132A–LRP6 interaction), lysosomal degradation assays, Tmem132a knockout mouse model, knockdown in cultured cells with Wnt/β-catenin reporter readout","journal":"Cell communication and signaling : CCS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, degradation assay, and in vivo genetic model with pathway readout in single lab; multiple orthogonal methods","pmids":["39385148"],"is_preprint":false},{"year":2024,"finding":"E2F1 directly regulates TMEM132A expression by binding to the TMEM132A promoter, as demonstrated by dual-luciferase reporter assay; TMEM132A is a transcriptional target of E2F1 and its expression affects prostate cancer cell proliferation.","method":"Dual-luciferase reporter assay (E2F1 binding to TMEM132A promoter), qPCR, CCK8 proliferation assay, knockdown/overexpression in cancer cell lines","journal":"Frontiers in bioscience (Landmark edition)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — luciferase reporter assay in a single lab with limited mechanistic depth; no chromatin immunoprecipitation or structural validation","pmids":["39473405"],"is_preprint":false},{"year":2026,"finding":"TMEM132A knockdown in breast cancer cell lines reduces expression of Wnt pathway components (Wnt3a, β-catenin, c-Myc, Cyclin D1) and decreases nuclear accumulation of β-catenin, while TMEM132A overexpression promotes nuclear β-catenin accumulation, establishing that TMEM132A activates canonical Wnt/β-catenin signaling in breast cancer cells.","method":"Nuclear/cytoplasmic fractionation assays, knockdown and overexpression in breast cancer cell lines (MDA-MB-231, MCF-7), Wnt inhibitor C59 rescue experiment, proliferation/migration/invasion/apoptosis assays","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — subcellular fractionation with functional consequence, pharmacological rescue, multiple cell lines; single lab","pmids":["42203132"],"is_preprint":false}],"current_model":"TMEM132A is a single-pass type I transmembrane protein that promotes canonical Wnt/β-catenin signaling by interacting with and stabilizing the co-receptor LRP6 (preventing lysosomal degradation) and by binding the Wnt transporter WLS to enhance Wnt ligand stability and secretion; additionally, TMEM132A interacts with PCP regulators CELSR1 and FZD6 and genetically cooperates with Vangl2 to regulate planar cell polarity, mesodermal integrin-dependent cell migration, and neural tube closure in vivo."},"narrative":{"mechanistic_narrative":"TMEM132A is a single-pass transmembrane protein that functions as a positive regulator of canonical Wnt/β-catenin signaling during development and in cancer cells [PMID:33324648, PMID:39385148, PMID:42203132]. It supports the pathway at two levels: in signal-sending cells it physically binds the Wnt cargo transporter WLS, stabilizes Wnt ligand, and enhances ligand secretion [PMID:33324648], while in signal-receiving cells it interacts with the co-receptor LRP6, protecting it from lysosomal degradation to sustain downstream β-catenin activation [PMID:39385148]. Consistent with this, TMEM132A loss diminishes Wnt/β-catenin signaling and produces developmental malformations resembling Wnt mutant phenotypes in mice [PMID:39385148], and its knockdown in breast cancer cells reduces Wnt3a, β-catenin, c-Myc, and Cyclin D1 levels and lowers nuclear β-catenin accumulation [PMID:42203132]. Beyond canonical Wnt, TMEM132A engages the planar cell polarity machinery, interacting with CELSR1 and FZD6 and cooperating genetically with Vangl2 to control neural tube closure [PMID:37390294], and it regulates integrin signaling required for caudal paraxial mesoderm migration in vivo [PMID:35950911]. TMEM132A expression is driven transcriptionally by E2F1, linking it to proliferative control in cancer [PMID:39473405].","teleology":[{"year":2020,"claim":"Established a first molecular role for TMEM132A in Wnt biology by showing it acts in signal-sending cells to stabilize and secrete Wnt ligand via the transporter WLS.","evidence":"Co-immunoprecipitation and Wnt ligand stabilization/pathway activation assays","pmids":["33324648"],"confidence":"Medium","gaps":["Single lab without independent replication","Structural basis of the TMEM132A–WLS interaction not defined","Whether ligand-side and receptor-side functions occur in the same cell unresolved"]},{"year":2022,"claim":"Placed TMEM132A in cell migration and morphogenesis by demonstrating it regulates integrins and is required for mesodermal migration and neural tube closure.","evidence":"Tmem132a-null mouse, cell migration assays, integrin pathway readouts","pmids":["35950911"],"confidence":"Medium","gaps":["Direct biochemical link between TMEM132A and specific integrins not established","Relationship between the migration phenotype and Wnt signaling unclear"]},{"year":2023,"claim":"Extended TMEM132A function to non-canonical signaling by showing physical and genetic links to the planar cell polarity pathway.","evidence":"Co-IP with CELSR1 and FZD6, genetic epistasis with Vangl2 in mouse mutants","pmids":["37390294"],"confidence":"Medium","gaps":["Mechanism of how TMEM132A modulates PCP complex assembly unknown","Single lab","How canonical Wnt and PCP roles are coordinated unresolved"]},{"year":2024,"claim":"Defined a receptor-side mechanism: TMEM132A stabilizes LRP6 by blocking its lysosomal degradation, directly promoting canonical Wnt/β-catenin output.","evidence":"Co-IP, lysosomal degradation assays, knockout mouse and Wnt/β-catenin reporter readouts","pmids":["39385148"],"confidence":"Medium","gaps":["Trafficking step at which TMEM132A intercepts LRP6 not defined","Whether TMEM132A directly competes with a degradation adaptor unknown"]},{"year":2024,"claim":"Identified an upstream transcriptional input, showing E2F1 drives TMEM132A expression and linking it to cancer cell proliferation.","evidence":"Dual-luciferase reporter assay, qPCR, proliferation assays in prostate cancer cells","pmids":["39473405"],"confidence":"Low","gaps":["No ChIP confirmation of direct promoter occupancy","Functional link to Wnt signaling in this context not tested","Single lab, limited mechanistic depth"]},{"year":2026,"claim":"Confirmed TMEM132A activates canonical Wnt/β-catenin signaling in a cancer setting with pharmacological dependency on Wnt.","evidence":"Knockdown/overexpression with nuclear/cytoplasmic fractionation and C59 Wnt inhibitor rescue in breast cancer lines","pmids":["42203132"],"confidence":"Medium","gaps":["Whether the LRP6 or WLS axis underlies the cancer effect not distinguished","In vivo tumor relevance not established"]},{"year":null,"claim":"How TMEM132A integrates its canonical Wnt, PCP, and integrin-dependent migration roles into a unified molecular mechanism remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of TMEM132A or its complexes","Membrane topology and trafficking itinerary not mapped","Whether ligand-side WLS and receptor-side LRP6 functions are separable not determined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[0,3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,3]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,3,5]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,2]}],"complexes":[],"partners":["WLS","LRP6","CELSR1","FZD6"],"other_free_text":[]}},"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":"33324648","id":"PMC_33324648","title":"TMEM132A, a Novel Wnt Signaling Pathway Regulator Through Wntless (WLS) Interaction.","date":"2020","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/33324648","citation_count":33,"is_preprint":false},{"pmid":"35950911","id":"PMC_35950911","title":"TMEM132A ensures mouse caudal neural tube closure and regulates integrin-based mesodermal migration.","date":"2022","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/35950911","citation_count":14,"is_preprint":false},{"pmid":"36441075","id":"PMC_36441075","title":"Knockdown of TMEM132A restrains the malignant phenotype of gastric cancer cells via inhibiting Wnt signaling.","date":"2022","source":"Nucleosides, nucleotides & nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/36441075","citation_count":7,"is_preprint":false},{"pmid":"39385148","id":"PMC_39385148","title":"TMEM132A regulates Wnt/β-catenin signaling through stabilizing LRP6 during mouse embryonic development.","date":"2024","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/39385148","citation_count":6,"is_preprint":false},{"pmid":"38947398","id":"PMC_38947398","title":"Multidimensional analysis of TMEM132A in pan-cancer: unveiling its potential as a biomarker for treatment response prediction.","date":"2024","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/38947398","citation_count":6,"is_preprint":false},{"pmid":"37390294","id":"PMC_37390294","title":"TMEM132A regulates mouse hindgut morphogenesis and caudal development.","date":"2023","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/37390294","citation_count":5,"is_preprint":false},{"pmid":"39473405","id":"PMC_39473405","title":"Study of the Role of E2F1 and TMEM132A in Prostate Cancer Development.","date":"2024","source":"Frontiers in bioscience (Landmark edition)","url":"https://pubmed.ncbi.nlm.nih.gov/39473405","citation_count":5,"is_preprint":false},{"pmid":"41564469","id":"PMC_41564469","title":"TMEM132A autoimmunity in patients with suspected autoimmune cerebellar ataxia.","date":"2026","source":"Journal of neuroimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/41564469","citation_count":0,"is_preprint":false},{"pmid":"41874757","id":"PMC_41874757","title":"TMEM132A is associated with metabolic reprogramming, macrophage-oriented immune remodeling, and breast cancer progression.","date":"2026","source":"Clinical and experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41874757","citation_count":0,"is_preprint":false},{"pmid":"42035383","id":"PMC_42035383","title":"A pan-cancer analysis of TMEM132A in human tumors.","date":"2026","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/42035383","citation_count":0,"is_preprint":false},{"pmid":"42203132","id":"PMC_42203132","title":"TMEM132A affects proliferation, invasion, and apoptosis via the β-catenin-dependent Wnt signaling in breast cancer.","date":"2026","source":"Biochimica et biophysica acta. Molecular cell research","url":"https://pubmed.ncbi.nlm.nih.gov/42203132","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7613,"output_tokens":1584,"usd":0.0233,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8418,"output_tokens":2250,"usd":0.04917,"stage2_stop_reason":"end_turn"},"total_usd":0.07247,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2020,\n      \"finding\": \"TMEM132A physically interacts with the Wnt ligand transporting protein Wntless (WLS), stabilizes Wnt ligand, enhances WLS-Wnt ligand interaction, and activates the Wnt signaling pathway in signal-sending cells.\",\n      \"method\": \"Co-immunoprecipitation (physical interaction), functional assays (Wnt ligand stabilization, pathway activation readouts)\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction demonstrated and multiple functional readouts reported, but from a single lab; full methods not detailed in abstract\",\n      \"pmids\": [\"33324648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TMEM132A regulates several integrins and downstream integrin pathway activation, and is required for lateral migration of the caudal paraxial mesoderm and spinal neural tube closure in mice; loss of TMEM132A in null mice impairs mesodermal cell migration behaviors.\",\n      \"method\": \"Tmem132a-null mouse genetic model, cell migration assays, integrin pathway activation readouts (loss-of-function with defined cellular phenotype)\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean knockout mouse with defined phenotype and integrin pathway readout, single lab\",\n      \"pmids\": [\"35950911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TMEM132A physically interacts with planar cell polarity (PCP) regulators CELSR1 and FZD6, mediates intercellular interaction, and genetically interacts synergistically with PCP regulator Vangl2 for neural tube closure, placing TMEM132A as a regulator of PCP signaling.\",\n      \"method\": \"Co-immunoprecipitation (physical interaction with CELSR1 and FZD6), genetic epistasis (double mutant with Vangl2), Tmem132a mutant mouse phenotypic analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and genetic epistasis in mouse, single lab\",\n      \"pmids\": [\"37390294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TMEM132A interacts with the Wnt co-receptor LRP6, stabilizes LRP6, and prevents its lysosomal degradation, thereby promoting canonical Wnt/β-catenin signaling; loss of Tmem132a in mice leads to diminished Wnt/β-catenin signaling and developmental malformations resembling Wnt/β-catenin mutant phenotypes.\",\n      \"method\": \"Co-immunoprecipitation (TMEM132A–LRP6 interaction), lysosomal degradation assays, Tmem132a knockout mouse model, knockdown in cultured cells with Wnt/β-catenin reporter readout\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, degradation assay, and in vivo genetic model with pathway readout in single lab; multiple orthogonal methods\",\n      \"pmids\": [\"39385148\"],\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 assay; TMEM132A is a transcriptional target of E2F1 and its expression affects prostate cancer cell proliferation.\",\n      \"method\": \"Dual-luciferase reporter assay (E2F1 binding to TMEM132A promoter), qPCR, CCK8 proliferation assay, knockdown/overexpression in cancer cell lines\",\n      \"journal\": \"Frontiers in bioscience (Landmark edition)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — luciferase reporter assay in a single lab with limited mechanistic depth; no chromatin immunoprecipitation or structural validation\",\n      \"pmids\": [\"39473405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TMEM132A knockdown in breast cancer cell lines reduces expression of Wnt pathway components (Wnt3a, β-catenin, c-Myc, Cyclin D1) and decreases nuclear accumulation of β-catenin, while TMEM132A overexpression promotes nuclear β-catenin accumulation, establishing that TMEM132A activates canonical Wnt/β-catenin signaling in breast cancer cells.\",\n      \"method\": \"Nuclear/cytoplasmic fractionation assays, knockdown and overexpression in breast cancer cell lines (MDA-MB-231, MCF-7), Wnt inhibitor C59 rescue experiment, proliferation/migration/invasion/apoptosis assays\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — subcellular fractionation with functional consequence, pharmacological rescue, multiple cell lines; single lab\",\n      \"pmids\": [\"42203132\"],\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 interacting with and stabilizing the co-receptor LRP6 (preventing lysosomal degradation) and by binding the Wnt transporter WLS to enhance Wnt ligand stability and secretion; additionally, TMEM132A interacts with PCP regulators CELSR1 and FZD6 and genetically cooperates with Vangl2 to regulate planar cell polarity, mesodermal integrin-dependent cell migration, and neural tube closure in vivo.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TMEM132A is a single-pass transmembrane protein that functions as a positive regulator of canonical Wnt/\\u03b2-catenin signaling during development and in cancer cells [#0, #3, #5]. It supports the pathway at two levels: in signal-sending cells it physically binds the Wnt cargo transporter WLS, stabilizes Wnt ligand, and enhances ligand secretion [#0], while in signal-receiving cells it interacts with the co-receptor LRP6, protecting it from lysosomal degradation to sustain downstream \\u03b2-catenin activation [#3]. Consistent with this, TMEM132A loss diminishes Wnt/\\u03b2-catenin signaling and produces developmental malformations resembling Wnt mutant phenotypes in mice [#3], and its knockdown in breast cancer cells reduces Wnt3a, \\u03b2-catenin, c-Myc, and Cyclin D1 levels and lowers nuclear \\u03b2-catenin accumulation [#5]. Beyond canonical Wnt, TMEM132A engages the planar cell polarity machinery, interacting with CELSR1 and FZD6 and cooperating genetically with Vangl2 to control neural tube closure [#2], and it regulates integrin signaling required for caudal paraxial mesoderm migration in vivo [#1]. TMEM132A expression is driven transcriptionally by E2F1, linking it to proliferative control in cancer [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2020,\n      \"claim\": \"Established a first molecular role for TMEM132A in Wnt biology by showing it acts in signal-sending cells to stabilize and secrete Wnt ligand via the transporter WLS.\",\n      \"evidence\": \"Co-immunoprecipitation and Wnt ligand stabilization/pathway activation assays\",\n      \"pmids\": [\"33324648\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab without independent replication\", \"Structural basis of the TMEM132A\\u2013WLS interaction not defined\", \"Whether ligand-side and receptor-side functions occur in the same cell unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed TMEM132A in cell migration and morphogenesis by demonstrating it regulates integrins and is required for mesodermal migration and neural tube closure.\",\n      \"evidence\": \"Tmem132a-null mouse, cell migration assays, integrin pathway readouts\",\n      \"pmids\": [\"35950911\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical link between TMEM132A and specific integrins not established\", \"Relationship between the migration phenotype and Wnt signaling unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended TMEM132A function to non-canonical signaling by showing physical and genetic links to the planar cell polarity pathway.\",\n      \"evidence\": \"Co-IP with CELSR1 and FZD6, genetic epistasis with Vangl2 in mouse mutants\",\n      \"pmids\": [\"37390294\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of how TMEM132A modulates PCP complex assembly unknown\", \"Single lab\", \"How canonical Wnt and PCP roles are coordinated unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a receptor-side mechanism: TMEM132A stabilizes LRP6 by blocking its lysosomal degradation, directly promoting canonical Wnt/\\u03b2-catenin output.\",\n      \"evidence\": \"Co-IP, lysosomal degradation assays, knockout mouse and Wnt/\\u03b2-catenin reporter readouts\",\n      \"pmids\": [\"39385148\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Trafficking step at which TMEM132A intercepts LRP6 not defined\", \"Whether TMEM132A directly competes with a degradation adaptor unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified an upstream transcriptional input, showing E2F1 drives TMEM132A expression and linking it to cancer cell proliferation.\",\n      \"evidence\": \"Dual-luciferase reporter assay, qPCR, proliferation assays in prostate cancer cells\",\n      \"pmids\": [\"39473405\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No ChIP confirmation of direct promoter occupancy\", \"Functional link to Wnt signaling in this context not tested\", \"Single lab, limited mechanistic depth\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Confirmed TMEM132A activates canonical Wnt/\\u03b2-catenin signaling in a cancer setting with pharmacological dependency on Wnt.\",\n      \"evidence\": \"Knockdown/overexpression with nuclear/cytoplasmic fractionation and C59 Wnt inhibitor rescue in breast cancer lines\",\n      \"pmids\": [\"42203132\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the LRP6 or WLS axis underlies the cancer effect not distinguished\", \"In vivo tumor relevance not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TMEM132A integrates its canonical Wnt, PCP, and integrin-dependent migration roles into a unified molecular mechanism remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of TMEM132A or its complexes\", \"Membrane topology and trafficking itinerary not mapped\", \"Whether ligand-side WLS and receptor-side LRP6 functions are separable not determined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3, 5]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"WLS\", \"LRP6\", \"CELSR1\", \"FZD6\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":5,"faith_pct":80.0}}