{"gene":"PLEKHA6","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2000,"finding":"The PH domain of PLEKHA6 (referred to as PEPP3) was identified as a novel phosphoinositide-binding module that may interact with PtdIns3P in vitro, based on its sequence similarity to PEPP1 and PEPP2 which were shown to bind PtdIns3P.","method":"In vitro phosphoinositide-binding assay using expressed PH domains; sequence-based PPBM motif search in EST databases","journal":"The Biochemical journal","confidence":"Low","confidence_rationale":"Tier 3 / Weak — binding for PEPP3 specifically was inferred from homology to PEPP1/PEPP2; the paper states PEPP3 'may also interact with PtdIns3P' without direct experimental confirmation for PEPP3 itself","pmids":["11001876"],"is_preprint":false},{"year":2021,"finding":"PLEKHA6 interacts with PDZD11 through its WW domains (binding to the PDZD11 N-terminus), and this WW-PLEKHA6–PDZD11 complex is required for efficient anterograde targeting of the Menkes copper ATPase ATP7A to the cell periphery under elevated copper conditions, thereby promoting copper extrusion.","method":"Pull-down experiments; CRISPR-KO of PLEKHA5/6/7 in kidney epithelial cells; immunofluorescence microscopy; measurement of bioavailable and total cellular copper; metallothionein-1 expression assay; cell viability assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal pull-down, CRISPR-KO with defined cellular phenotype (ATP7A mislocalization, elevated copper), multiple orthogonal functional readouts in a single rigorous study","pmids":["34613798"],"is_preprint":false},{"year":2021,"finding":"The subcellular localization of PLEKHA6 is cooperatively determined by its WW domains, PH domain, and C-terminal region: the C-terminal region of PLEKHA6 promotes its localization at adherens junctions in epithelial cells, while WW-mediated interaction with PDZD11 is required for cytoplasmic microtubule association.","method":"Expression of mutant and chimeric WW-PLEKHA proteins in cultured cells; immunofluorescence microscopy","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — domain-deletion and chimeric constructs in live cells with imaging readout, single lab, multiple constructs tested","pmids":["34568338"],"is_preprint":false},{"year":2018,"finding":"A chromosomal translocation creating a PLEKHA6-NTRK3 fusion gene results in a chimeric protein that activates the RAS-RAF-MEK-ERK (MAPK) signaling pathway and promotes cell growth when overexpressed in NIH 3T3 cells.","method":"Whole genome sequencing to identify the fusion; overexpression of PLEKHA6-NTRK3 fusion construct in NIH 3T3 cells with MAPK pathway activation assay and cell growth assay","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional cell-based assay with defined pathway readout (MAPK activation, proliferation), single lab, single method per readout","pmids":["30098202"],"is_preprint":false},{"year":2025,"finding":"Knockdown of PLEKHA6 in A549 lung adenocarcinoma cells suppresses β-catenin and VE-cadherin expression, impairs proliferation, migration, and colony formation, and enhances apoptosis and cell cycle arrest, placing PLEKHA6 as a positive regulator of Wnt/β-catenin signaling in LUAD cells.","method":"siRNA/shRNA knockdown in A549 cells; Western blot for β-catenin and VE-cadherin; proliferation, migration, colony formation, apoptosis, and cell cycle assays","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — loss-of-function with multiple cellular phenotype readouts and molecular target identification (β-catenin), single lab","pmids":["40814363"],"is_preprint":false}],"current_model":"PLEKHA6 is a PH- and WW-domain-containing scaffold protein that interacts with PDZD11 via its WW domains to promote anterograde trafficking of the copper ATPase ATP7A to the cell periphery, thereby regulating cellular copper homeostasis; its subcellular localization is governed cooperatively by its WW, PH, and C-terminal domains; and in cancer contexts it positively modulates Wnt/β-catenin signaling, while oncogenic fusions of PLEKHA6 with NTRK3 or NTRK1 activate the MAPK pathway."},"narrative":{"mechanistic_narrative":"PLEKHA6 is a PH- and WW-domain-containing scaffold protein that organizes membrane trafficking and cell-junction signaling in epithelial cells [PMID:34613798, PMID:34568338]. Through its WW domains it binds the N-terminus of PDZD11, and this PLEKHA6–PDZD11 complex is required for efficient anterograde delivery of the Menkes copper ATPase ATP7A to the cell periphery under elevated copper, thereby promoting copper extrusion and maintaining cellular copper homeostasis [PMID:34613798]. Its subcellular positioning is set cooperatively by distinct regions: the C-terminal region directs localization to adherens junctions, while the WW-mediated PDZD11 interaction supports cytoplasmic microtubule association [PMID:34568338]. In cancer contexts PLEKHA6 acts as a positive regulator of Wnt/β-catenin signaling, with its loss suppressing β-catenin and VE-cadherin expression and impairing proliferation, migration, and survival of lung adenocarcinoma cells [PMID:40814363]. Oncogenic chromosomal rearrangements fusing PLEKHA6 to NTRK3 generate a chimeric protein that activates the RAS-RAF-MEK-ERK pathway and drives cell growth [PMID:30098202].","teleology":[{"year":2000,"claim":"The first question was whether PLEKHA6 (PEPP3) could engage membrane phosphoinositides through its PH domain, which would define it as a lipid-binding module.","evidence":"In vitro phosphoinositide-binding assay of expressed PH domains and EST-based motif search, with PEPP3 binding inferred from homology to PEPP1/PEPP2","pmids":["11001876"],"confidence":"Low","gaps":["PtdIns3P binding was inferred from homology, not directly demonstrated for PEPP3/PLEKHA6","no cellular function attached to the lipid-binding activity","no structural characterization of the PH domain"]},{"year":2018,"claim":"A clinical genomics finding addressed whether PLEKHA6 rearrangements have oncogenic potential, establishing that a PLEKHA6-NTRK3 fusion drives mitogenic signaling.","evidence":"Whole-genome sequencing to identify the fusion plus overexpression of the PLEKHA6-NTRK3 construct in NIH 3T3 cells with MAPK activation and growth assays","pmids":["30098202"],"confidence":"Medium","gaps":["tested only by overexpression in NIH 3T3, not in patient-derived contexts","contribution of the PLEKHA6 portion versus NTRK3 kinase to transformation not dissected","does not address endogenous PLEKHA6 function"]},{"year":2021,"claim":"The core mechanistic question of what PLEKHA6 does was answered by showing its WW domains bind PDZD11 to promote anterograde trafficking of ATP7A and control copper homeostasis.","evidence":"Reciprocal pull-downs, CRISPR-KO of PLEKHA5/6/7 in kidney epithelial cells, immunofluorescence of ATP7A, and copper/metallothionein/viability readouts","pmids":["34613798"],"confidence":"High","gaps":["redundancy among PLEKHA5/6/7 not fully resolved","molecular mechanism linking the complex to the trafficking machinery not defined","in vivo relevance to organismal copper handling untested"]},{"year":2021,"claim":"A parallel study addressed how PLEKHA6 is targeted within cells, showing its localization is partitioned between adherens junctions and microtubules by separable domains.","evidence":"Domain-deletion and chimeric WW-PLEKHA constructs expressed in cultured cells with immunofluorescence","pmids":["34568338"],"confidence":"Medium","gaps":["based on ectopic constructs rather than endogenous protein","junctional and microtubule pools not linked to specific functional outputs","single-lab imaging readout"]},{"year":2025,"claim":"Whether PLEKHA6 influences a defined signaling pathway in cancer was tested, placing it as a positive regulator of Wnt/β-catenin signaling in lung adenocarcinoma.","evidence":"siRNA/shRNA knockdown in A549 cells with Western blot for β-catenin/VE-cadherin and proliferation, migration, colony, apoptosis, and cell-cycle assays","pmids":["40814363"],"confidence":"Medium","gaps":["mechanism linking PLEKHA6 to β-catenin stability or transcription not defined","single cell line, single lab","relationship between this signaling role and its ATP7A/PDZD11 trafficking function unknown"]},{"year":null,"claim":"It remains unknown how PLEKHA6's scaffolding/trafficking activity mechanistically connects to its reported roles in Wnt/β-catenin signaling and how these are integrated within polarized epithelia.","evidence":"","pmids":[],"confidence":"Low","gaps":["no unifying mechanism linking copper-ATPase trafficking, junctional localization, and β-catenin regulation","no in vivo or structural data on the full-length protein","endogenous regulation and upstream signals unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,2]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[2]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2]}],"pathway":[],"complexes":[],"partners":["PDZD11","ATP7A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y2H5","full_name":"Pleckstrin homology domain-containing family A member 6","aliases":["Phosphoinositol 3-phosphate-binding protein 3","PEPP-3"],"length_aa":1048,"mass_kda":117.1,"function":"","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q9Y2H5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PLEKHA6","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PLEKHA6","total_profiled":1310},"omim":[{"mim_id":"607771","title":"PLECKSTRIN HOMOLOGY DOMAIN-CONTAINING PROTEIN, FAMILY A, MEMBER 6; PLEKHA6","url":"https://www.omim.org/entry/607771"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cell Junctions","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PLEKHA6"},"hgnc":{"alias_symbol":["PEPP3","KIAA0969"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y2H5","domains":[{"cath_id":"2.30.29.30","chopping":"61-158","consensus_level":"high","plddt":91.9201,"start":61,"end":158},{"cath_id":"-","chopping":"528-666","consensus_level":"high","plddt":90.2574,"start":528,"end":666}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y2H5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y2H5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y2H5-F1-predicted_aligned_error_v6.png","plddt_mean":56.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PLEKHA6","jax_strain_url":"https://www.jax.org/strain/search?query=PLEKHA6"},"sequence":{"accession":"Q9Y2H5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y2H5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y2H5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y2H5"}},"corpus_meta":[{"pmid":"11001876","id":"PMC_11001876","title":"Identification of pleckstrin-homology-domain-containing proteins with novel phosphoinositide-binding specificities.","date":"2000","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/11001876","citation_count":480,"is_preprint":false},{"pmid":"12640683","id":"PMC_12640683","title":"Refined mapping of 1q32 amplicons in malignant gliomas confirms MDM4 as the main amplification target.","date":"2003","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/12640683","citation_count":83,"is_preprint":false},{"pmid":"22430805","id":"PMC_22430805","title":"Peripheral blood DNA methylation profiles are indicative of head and neck squamous cell carcinoma: an epigenome-wide association study.","date":"2012","source":"Epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/22430805","citation_count":71,"is_preprint":false},{"pmid":"34613798","id":"PMC_34613798","title":"PLEKHA5, PLEKHA6, and PLEKHA7 bind to PDZD11 to target the Menkes ATPase ATP7A to the cell periphery and regulate copper homeostasis.","date":"2021","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/34613798","citation_count":36,"is_preprint":false},{"pmid":"31593922","id":"PMC_31593922","title":"Tumor expression of environmental chemical-responsive genes and breast cancer mortality.","date":"2019","source":"Endocrine-related cancer","url":"https://pubmed.ncbi.nlm.nih.gov/31593922","citation_count":19,"is_preprint":false},{"pmid":"34568338","id":"PMC_34568338","title":"WW, PH and C-Terminal Domains Cooperate to Direct the Subcellular Localizations of PLEKHA5, PLEKHA6 and PLEKHA7.","date":"2021","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/34568338","citation_count":18,"is_preprint":false},{"pmid":"34413927","id":"PMC_34413927","title":"Dynamic Patterns of N6-Methyladenosine Profiles of Messenger RNA Correlated with the Cardiomyocyte Regenerability during the Early Heart Development in Mice.","date":"2021","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/34413927","citation_count":17,"is_preprint":false},{"pmid":"30098202","id":"PMC_30098202","title":"A novel fusion gene PLEKHA6-NTRK3 in langerhans cell histiocytosis.","date":"2018","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/30098202","citation_count":16,"is_preprint":false},{"pmid":"35237889","id":"PMC_35237889","title":"Gene fusions and oncogenic mutations in MLH1 deficient and BRAFV600E wild-type colorectal cancers.","date":"2022","source":"Virchows Archiv : an international journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/35237889","citation_count":15,"is_preprint":false},{"pmid":"14709678","id":"PMC_14709678","title":"Differential expression of the closely linked KISS1, REN, and FLJ10761 genes in transgenic mice.","date":"2004","source":"Physiological genomics","url":"https://pubmed.ncbi.nlm.nih.gov/14709678","citation_count":10,"is_preprint":false},{"pmid":"40814363","id":"PMC_40814363","title":"Multi-omics profiling reveals PLEKHA6 as a modulator of β-catenin signaling and therapeutic vulnerability in lung adenocarcinoma.","date":"2025","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/40814363","citation_count":9,"is_preprint":false},{"pmid":"24576533","id":"PMC_24576533","title":"Pleckstrin homology domain containing 6 protein (PLEKHA6) polymorphisms are associated with psychopathology and response to treatment in schizophrenic patients.","date":"2014","source":"Progress in neuro-psychopharmacology & biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/24576533","citation_count":8,"is_preprint":false},{"pmid":"35977594","id":"PMC_35977594","title":"Pan-tropomyosin receptor kinase immunohistochemistry is a feasible routine screening strategy for NTRK fusions in mismatch repair-deficient colorectal carcinomas.","date":"2022","source":"Human pathology","url":"https://pubmed.ncbi.nlm.nih.gov/35977594","citation_count":8,"is_preprint":false},{"pmid":"35399503","id":"PMC_35399503","title":"Origin and Evolution of the Multifaceted Adherens Junction Component Plekha7.","date":"2022","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/35399503","citation_count":6,"is_preprint":false},{"pmid":"31520345","id":"PMC_31520345","title":"In silico analysis of human renin gene-gene interactions and neighborhood topologically associated domains suggests breakdown of insulators contribute to ageing-associated diseases.","date":"2019","source":"Biogerontology","url":"https://pubmed.ncbi.nlm.nih.gov/31520345","citation_count":6,"is_preprint":false},{"pmid":"14970691","id":"PMC_14970691","title":"Improving the comparative map of porcine chromosome 9 with respect to human chromosomes 1, 7 and 11.","date":"2003","source":"Cytogenetic and genome research","url":"https://pubmed.ncbi.nlm.nih.gov/14970691","citation_count":4,"is_preprint":false},{"pmid":"35810566","id":"PMC_35810566","title":"The genomic profile of double primary secretory breast carcinoma in one patient provides evidence for the treatment of such carcinoma: A case report.","date":"2022","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/35810566","citation_count":4,"is_preprint":false},{"pmid":"41229824","id":"PMC_41229824","title":"Research on the correlation between lung adenocarcinoma and necrosis by sodium overload.","date":"2025","source":"Journal of thoracic disease","url":"https://pubmed.ncbi.nlm.nih.gov/41229824","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12093,"output_tokens":1412,"usd":0.02873,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8087,"output_tokens":2275,"usd":0.048655,"stage2_stop_reason":"end_turn"},"total_usd":0.077385,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"The PH domain of PLEKHA6 (referred to as PEPP3) was identified as a novel phosphoinositide-binding module that may interact with PtdIns3P in vitro, based on its sequence similarity to PEPP1 and PEPP2 which were shown to bind PtdIns3P.\",\n      \"method\": \"In vitro phosphoinositide-binding assay using expressed PH domains; sequence-based PPBM motif search in EST databases\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — binding for PEPP3 specifically was inferred from homology to PEPP1/PEPP2; the paper states PEPP3 'may also interact with PtdIns3P' without direct experimental confirmation for PEPP3 itself\",\n      \"pmids\": [\"11001876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PLEKHA6 interacts with PDZD11 through its WW domains (binding to the PDZD11 N-terminus), and this WW-PLEKHA6–PDZD11 complex is required for efficient anterograde targeting of the Menkes copper ATPase ATP7A to the cell periphery under elevated copper conditions, thereby promoting copper extrusion.\",\n      \"method\": \"Pull-down experiments; CRISPR-KO of PLEKHA5/6/7 in kidney epithelial cells; immunofluorescence microscopy; measurement of bioavailable and total cellular copper; metallothionein-1 expression assay; cell viability assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal pull-down, CRISPR-KO with defined cellular phenotype (ATP7A mislocalization, elevated copper), multiple orthogonal functional readouts in a single rigorous study\",\n      \"pmids\": [\"34613798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The subcellular localization of PLEKHA6 is cooperatively determined by its WW domains, PH domain, and C-terminal region: the C-terminal region of PLEKHA6 promotes its localization at adherens junctions in epithelial cells, while WW-mediated interaction with PDZD11 is required for cytoplasmic microtubule association.\",\n      \"method\": \"Expression of mutant and chimeric WW-PLEKHA proteins in cultured cells; immunofluorescence microscopy\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — domain-deletion and chimeric constructs in live cells with imaging readout, single lab, multiple constructs tested\",\n      \"pmids\": [\"34568338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A chromosomal translocation creating a PLEKHA6-NTRK3 fusion gene results in a chimeric protein that activates the RAS-RAF-MEK-ERK (MAPK) signaling pathway and promotes cell growth when overexpressed in NIH 3T3 cells.\",\n      \"method\": \"Whole genome sequencing to identify the fusion; overexpression of PLEKHA6-NTRK3 fusion construct in NIH 3T3 cells with MAPK pathway activation assay and cell growth assay\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional cell-based assay with defined pathway readout (MAPK activation, proliferation), single lab, single method per readout\",\n      \"pmids\": [\"30098202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Knockdown of PLEKHA6 in A549 lung adenocarcinoma cells suppresses β-catenin and VE-cadherin expression, impairs proliferation, migration, and colony formation, and enhances apoptosis and cell cycle arrest, placing PLEKHA6 as a positive regulator of Wnt/β-catenin signaling in LUAD cells.\",\n      \"method\": \"siRNA/shRNA knockdown in A549 cells; Western blot for β-catenin and VE-cadherin; proliferation, migration, colony formation, apoptosis, and cell cycle assays\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — loss-of-function with multiple cellular phenotype readouts and molecular target identification (β-catenin), single lab\",\n      \"pmids\": [\"40814363\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PLEKHA6 is a PH- and WW-domain-containing scaffold protein that interacts with PDZD11 via its WW domains to promote anterograde trafficking of the copper ATPase ATP7A to the cell periphery, thereby regulating cellular copper homeostasis; its subcellular localization is governed cooperatively by its WW, PH, and C-terminal domains; and in cancer contexts it positively modulates Wnt/β-catenin signaling, while oncogenic fusions of PLEKHA6 with NTRK3 or NTRK1 activate the MAPK pathway.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PLEKHA6 is a PH- and WW-domain-containing scaffold protein that organizes membrane trafficking and cell-junction signaling in epithelial cells [#1, #2]. Through its WW domains it binds the N-terminus of PDZD11, and this PLEKHA6–PDZD11 complex is required for efficient anterograde delivery of the Menkes copper ATPase ATP7A to the cell periphery under elevated copper, thereby promoting copper extrusion and maintaining cellular copper homeostasis [#1]. Its subcellular positioning is set cooperatively by distinct regions: the C-terminal region directs localization to adherens junctions, while the WW-mediated PDZD11 interaction supports cytoplasmic microtubule association [#2]. In cancer contexts PLEKHA6 acts as a positive regulator of Wnt/β-catenin signaling, with its loss suppressing β-catenin and VE-cadherin expression and impairing proliferation, migration, and survival of lung adenocarcinoma cells [#4]. Oncogenic chromosomal rearrangements fusing PLEKHA6 to NTRK3 generate a chimeric protein that activates the RAS-RAF-MEK-ERK pathway and drives cell growth [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"The first question was whether PLEKHA6 (PEPP3) could engage membrane phosphoinositides through its PH domain, which would define it as a lipid-binding module.\",\n      \"evidence\": \"In vitro phosphoinositide-binding assay of expressed PH domains and EST-based motif search, with PEPP3 binding inferred from homology to PEPP1/PEPP2\",\n      \"pmids\": [\"11001876\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"PtdIns3P binding was inferred from homology, not directly demonstrated for PEPP3/PLEKHA6\",\n        \"no cellular function attached to the lipid-binding activity\",\n        \"no structural characterization of the PH domain\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"A clinical genomics finding addressed whether PLEKHA6 rearrangements have oncogenic potential, establishing that a PLEKHA6-NTRK3 fusion drives mitogenic signaling.\",\n      \"evidence\": \"Whole-genome sequencing to identify the fusion plus overexpression of the PLEKHA6-NTRK3 construct in NIH 3T3 cells with MAPK activation and growth assays\",\n      \"pmids\": [\"30098202\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"tested only by overexpression in NIH 3T3, not in patient-derived contexts\",\n        \"contribution of the PLEKHA6 portion versus NTRK3 kinase to transformation not dissected\",\n        \"does not address endogenous PLEKHA6 function\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The core mechanistic question of what PLEKHA6 does was answered by showing its WW domains bind PDZD11 to promote anterograde trafficking of ATP7A and control copper homeostasis.\",\n      \"evidence\": \"Reciprocal pull-downs, CRISPR-KO of PLEKHA5/6/7 in kidney epithelial cells, immunofluorescence of ATP7A, and copper/metallothionein/viability readouts\",\n      \"pmids\": [\"34613798\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"redundancy among PLEKHA5/6/7 not fully resolved\",\n        \"molecular mechanism linking the complex to the trafficking machinery not defined\",\n        \"in vivo relevance to organismal copper handling untested\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"A parallel study addressed how PLEKHA6 is targeted within cells, showing its localization is partitioned between adherens junctions and microtubules by separable domains.\",\n      \"evidence\": \"Domain-deletion and chimeric WW-PLEKHA constructs expressed in cultured cells with immunofluorescence\",\n      \"pmids\": [\"34568338\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"based on ectopic constructs rather than endogenous protein\",\n        \"junctional and microtubule pools not linked to specific functional outputs\",\n        \"single-lab imaging readout\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Whether PLEKHA6 influences a defined signaling pathway in cancer was tested, placing it as a positive regulator of Wnt/β-catenin signaling in lung adenocarcinoma.\",\n      \"evidence\": \"siRNA/shRNA knockdown in A549 cells with Western blot for β-catenin/VE-cadherin and proliferation, migration, colony, apoptosis, and cell-cycle assays\",\n      \"pmids\": [\"40814363\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"mechanism linking PLEKHA6 to β-catenin stability or transcription not defined\",\n        \"single cell line, single lab\",\n        \"relationship between this signaling role and its ATP7A/PDZD11 trafficking function unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how PLEKHA6's scaffolding/trafficking activity mechanistically connects to its reported roles in Wnt/β-catenin signaling and how these are integrated within polarized epithelia.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"no unifying mechanism linking copper-ATPase trafficking, junctional localization, and β-catenin regulation\",\n        \"no in vivo or structural data on the full-length protein\",\n        \"endogenous regulation and upstream signals unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": []}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PDZD11\", \"ATP7A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":4,"faith_total":5,"faith_pct":80.0}}