{"gene":"HYCC1","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2015,"finding":"FAM126A (hyccin/HYCC1) is an intrinsic component of the plasma membrane phosphatidylinositol 4-kinase complex comprising PI4KIIIα, TTC7, and EFR3, and regulates synthesis of phosphatidylinositol 4-phosphate (PtdIns(4)P) at the plasma membrane. HCC patient fibroblasts show reduced PtdIns(4)P levels, and absence of FAM126A destabilizes the PI4KIIIα complex in mouse brain and patient fibroblasts.","method":"Co-immunoprecipitation, phosphoinositide measurements in patient fibroblasts, co-crystal structure of FAM126A-TTC7 heterodimer, mouse brain fractionation","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional validation, patient fibroblast biochemistry, and mouse brain complex studies in a single rigorous study","pmids":["26571211"],"is_preprint":false},{"year":2015,"finding":"Crystal structure of FAM126A-TTC7 reveals an all-α-helical heterodimer with a large protein-protein interface and a conserved surface that mediates binding to PI4KIIIα.","method":"X-ray crystallography (co-crystal structure of FAM126A-TTC7)","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct structural determination with functional surface identified","pmids":["26571211"],"is_preprint":false},{"year":2006,"finding":"Mutations in FAM126A (hyccin) cause deficiency of the hyccin protein, an essential membrane protein, leading to hypomyelination of the central and peripheral nervous system and congenital cataract in an autosomal recessive disorder.","method":"Genetic mapping and mutation identification in five affected families; protein characterization","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — human genetics with multiple families, replicated in multiple affected pedigrees establishing essential role in myelination","pmids":["16951682"],"is_preprint":false},{"year":2012,"finding":"Hyccin (FAM126A/HYCC1) is primarily expressed in neuronal cells (CA1 hippocampal pyramidal neurons, olfactory bulb, cortical pyramidal neurons) and not in oligodendrocytes or astrocytes. In the peripheral nervous system, hyccin is detectable along neurites but absent from Schwann cells. Expression is upregulated during early postnatal myelinogenesis and declines when myelination is complete, suggesting a neuron-to-glia signaling role in initiating or maintaining myelination.","method":"LacZ reporter knock-in mouse, immunofluorescence with cell-type markers, organotypic rat Schwann cell/DRG cultures","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by reporter mouse and immunostaining, single lab, two orthogonal approaches","pmids":["22461884"],"is_preprint":false},{"year":2013,"finding":"The disease-associated missense mutant L53P of FAM126A (hyccin/DRCTNNB1A) aggregates in the endoplasmic reticulum, in contrast to wild-type FAM126A which distributes throughout the cytoplasm. L53P mutant expression promotes activities of kinases involved in the unfolded protein response.","method":"Subcellular localization by immunofluorescence in transfected cells; UPR kinase activity assays","journal":"Journal of clinical neuroscience","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct subcellular localization with functional consequence (UPR activation), single lab, two methods","pmids":["24417797"],"is_preprint":false},{"year":2000,"finding":"DRCTNNB1A (HYCC1/FAM126A) expression is down-regulated in response to activated beta-catenin. Expression was significantly increased in SW480 colon cancer cells upon reduction of intracellular beta-catenin by adenovirus-mediated APC transfer. Reduced expression was documented in 12 of 15 primary colorectal cancers, implicating the gene in the beta-catenin-Tcf/Lef signaling pathway.","method":"Adenovirus-mediated APC transfer with RT-PCR, Northern blot in primary colorectal tumors","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional experiment (adenoviral APC transfer with mRNA readout), validated in primary tumors, single lab","pmids":["10910037"],"is_preprint":false},{"year":2022,"finding":"FAM126A interacts directly with ENO1 (alpha-enolase), as confirmed by co-localization and co-immunoprecipitation, and this interaction activates the PI3K/AKT signaling pathway to promote pancreatic cancer cell proliferation, invasion, and migration. ENO1 knockdown reversed the pro-tumorigenic effects of FAM126A overexpression.","method":"Co-immunoprecipitation, co-localization assay, ENO1 knockdown rescue experiments in vitro and in vivo","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — reciprocal Co-IP and rescue experiments, single lab, multiple orthogonal functional assays","pmids":["35513377"],"is_preprint":false}],"current_model":"HYCC1 (FAM126A/hyccin) functions as an essential subunit of the plasma membrane PI4KIIIα lipid kinase complex (with TTC7 and EFR3), directly stabilizing the complex and enabling synthesis of phosphatidylinositol 4-phosphate (PtdIns(4)P) at the plasma membrane; its loss destabilizes this complex and reduces PtdIns(4)P levels, mechanistically linking FAM126A deficiency to impaired myelination in the leukodystrophy hypomyelination and congenital cataract (HCC disease), and it is also subject to transcriptional repression downstream of beta-catenin signaling."},"narrative":{"mechanistic_narrative":"HYCC1 (FAM126A/hyccin) is an essential subunit of the plasma membrane phosphatidylinositol 4-kinase machinery that controls PtdIns(4)P synthesis required for nervous system myelination [PMID:26571211, PMID:16951682]. It is an intrinsic component of the PI4KIIIα complex together with TTC7 and EFR3, where it forms an all-α-helical heterodimer with TTC7 through a large protein-protein interface whose conserved surface mediates binding to PI4KIIIα [PMID:26571211]. By directly stabilizing this assembly, HYCC1 sustains plasma membrane PtdIns(4)P levels; its loss destabilizes the complex and reduces PtdIns(4)P in patient fibroblasts and mouse brain [PMID:26571211]. Biallelic loss-of-function mutations in HYCC1 cause an autosomal recessive leukodystrophy characterized by hypomyelination of the central and peripheral nervous system with congenital cataract [PMID:16951682], consistent with neuronal expression that peaks during early postnatal myelinogenesis [PMID:22461884]. The disease-associated L53P missense variant misfolds and aggregates in the endoplasmic reticulum, activating unfolded protein response kinases [PMID:24417797]. Beyond its myelination role, HYCC1 (DRCTNNB1A) is transcriptionally repressed downstream of beta-catenin signaling [PMID:10910037], and an interaction with ENO1 that activates PI3K/AKT signaling has been documented in pancreatic cancer cells [PMID:35513377].","teleology":[{"year":2000,"claim":"Established the gene as a transcriptional target downstream of oncogenic signaling, the first functional context before any mechanistic role was known.","evidence":"Adenoviral APC transfer with RT-PCR/Northern blot readout in colon cancer cells and primary colorectal tumors","pmids":["10910037"],"confidence":"Medium","gaps":["Does not identify the gene's molecular function","Direct vs. indirect transcriptional regulation by beta-catenin/Tcf-Lef not resolved"]},{"year":2006,"claim":"Linked the gene to human disease, defining hyccin as an essential protein whose loss causes hypomyelination with congenital cataract.","evidence":"Genetic mapping and mutation identification across five affected families with protein characterization","pmids":["16951682"],"confidence":"High","gaps":["Molecular mechanism connecting loss to hypomyelination not established","Cellular function of the protein unknown at this stage"]},{"year":2012,"claim":"Resolved which cells express hyccin during myelination, pointing to a neuronal rather than glial site of action.","evidence":"LacZ reporter knock-in mouse, cell-type-marker immunofluorescence, and organotypic Schwann cell/DRG cultures","pmids":["22461884"],"confidence":"Medium","gaps":["Proposed neuron-to-glia signaling role not mechanistically demonstrated","Single lab"]},{"year":2013,"claim":"Defined how a specific disease allele acts at the protein level, showing L53P causes ER aggregation and UPR activation.","evidence":"Subcellular localization by immunofluorescence in transfected cells and UPR kinase activity assays","pmids":["24417797"],"confidence":"Medium","gaps":["Whether UPR activation drives myelination defects in vivo unknown","Effect on PI4KIIIα complex not tested in this study"]},{"year":2015,"claim":"Defined the core molecular function: hyccin is an intrinsic subunit of the plasma membrane PI4KIIIα lipid kinase complex that stabilizes it and is required for PtdIns(4)P synthesis, mechanistically explaining disease.","evidence":"Co-IP, phosphoinositide measurements in patient fibroblasts, mouse brain fractionation, and a co-crystal structure of the FAM126A-TTC7 heterodimer with PI4KIIIα-binding surface mapped","pmids":["26571211"],"confidence":"High","gaps":["How reduced PtdIns(4)P specifically impairs myelination not delineated","Structure of the full PI4KIIIα-TTC7-EFR3 holocomplex not resolved here"]},{"year":2022,"claim":"Identified a non-myelination function in cancer, with a direct ENO1 interaction activating PI3K/AKT to drive tumor cell behavior.","evidence":"Reciprocal Co-IP, co-localization, and ENO1 knockdown rescue in vitro and in vivo","pmids":["35513377"],"confidence":"Medium","gaps":["Relationship between ENO1 binding and the PI4KIIIα complex role unclear","Single lab; mechanism of PI3K/AKT activation downstream of the interaction not detailed"]},{"year":null,"claim":"How loss of plasma membrane PtdIns(4)P is translated into the specific failure of CNS/PNS myelination, and how this reconciles with hyccin's neuronal expression and signaling-context functions, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No mechanistic link from PtdIns(4)P deficit to myelin biogenesis","Cell-type-specific requirement for the PI4KIIIα complex in myelination untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[4]}],"pathway":[],"complexes":["PI4KIIIα plasma membrane complex (PI4KA-TTC7-EFR3)"],"partners":["TTC7","PI4KA","EFR3","ENO1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BYI3","full_name":"Hyccin","aliases":["Down-regulated by CTNNB1 protein A"],"length_aa":521,"mass_kda":57.6,"function":"Component of a complex required to localize phosphatidylinositol 4-kinase (PI4K) to the plasma membrane (PubMed:26571211). The complex acts as a regulator of phosphatidylinositol 4-phosphate (PtdIns(4)P) synthesis (PubMed:26571211). HYCC1 plays a key role in oligodendrocytes formation, a cell type with expanded plasma membrane that requires generation of PtdIns(4)P (PubMed:26571211). Its role in oligodendrocytes formation probably explains its importance in myelination of the central and peripheral nervous system (PubMed:16951682, PubMed:26571211). May also have a role in the beta-catenin/Lef signaling pathway (Probable)","subcellular_location":"Cytoplasm, cytosol; Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9BYI3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HYCC1","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":[{"gene":"PI4KA","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/search/HYCC1","total_profiled":1310},"omim":[{"mim_id":"620060","title":"TETRATRICOPEPTIDE REPEAT DOMAIN-CONTAINING PROTEIN 7B; TTC7B","url":"https://www.omim.org/entry/620060"},{"mim_id":"610532","title":"LEUKODYSTROPHY, HYPOMYELINATING, 5; HLD5","url":"https://www.omim.org/entry/610532"},{"mim_id":"610531","title":"HYCCIN, PI4KA LIPID KINASE COMPLEX, SUBUNIT 1; HYCC1","url":"https://www.omim.org/entry/610531"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/HYCC1"},"hgnc":{"alias_symbol":["DRCTNNB1A","HCC","hyccin"],"prev_symbol":["FAM126A"]},"alphafold":{"accession":"Q9BYI3","domains":[{"cath_id":"-","chopping":"123-163","consensus_level":"medium","plddt":80.4702,"start":123,"end":163},{"cath_id":"1.20.1050","chopping":"1-118","consensus_level":"medium","plddt":88.6411,"start":1,"end":118},{"cath_id":"1.20.1050","chopping":"196-290","consensus_level":"medium","plddt":95.9403,"start":196,"end":290}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BYI3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BYI3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BYI3-F1-predicted_aligned_error_v6.png","plddt_mean":67.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HYCC1","jax_strain_url":"https://www.jax.org/strain/search?query=HYCC1"},"sequence":{"accession":"Q9BYI3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BYI3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BYI3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BYI3"}},"corpus_meta":[{"pmid":"33579421","id":"PMC_33579421","title":"Hepatocellular 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HCC patient fibroblasts show reduced PtdIns(4)P levels, and absence of FAM126A destabilizes the PI4KIIIα complex in mouse brain and patient fibroblasts.\",\n      \"method\": \"Co-immunoprecipitation, phosphoinositide measurements in patient fibroblasts, co-crystal structure of FAM126A-TTC7 heterodimer, mouse brain fractionation\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional validation, patient fibroblast biochemistry, and mouse brain complex studies in a single rigorous study\",\n      \"pmids\": [\"26571211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structure of FAM126A-TTC7 reveals an all-α-helical heterodimer with a large protein-protein interface and a conserved surface that mediates binding to PI4KIIIα.\",\n      \"method\": \"X-ray crystallography (co-crystal structure of FAM126A-TTC7)\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct structural determination with functional surface identified\",\n      \"pmids\": [\"26571211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Mutations in FAM126A (hyccin) cause deficiency of the hyccin protein, an essential membrane protein, leading to hypomyelination of the central and peripheral nervous system and congenital cataract in an autosomal recessive disorder.\",\n      \"method\": \"Genetic mapping and mutation identification in five affected families; protein characterization\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human genetics with multiple families, replicated in multiple affected pedigrees establishing essential role in myelination\",\n      \"pmids\": [\"16951682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Hyccin (FAM126A/HYCC1) is primarily expressed in neuronal cells (CA1 hippocampal pyramidal neurons, olfactory bulb, cortical pyramidal neurons) and not in oligodendrocytes or astrocytes. In the peripheral nervous system, hyccin is detectable along neurites but absent from Schwann cells. Expression is upregulated during early postnatal myelinogenesis and declines when myelination is complete, suggesting a neuron-to-glia signaling role in initiating or maintaining myelination.\",\n      \"method\": \"LacZ reporter knock-in mouse, immunofluorescence with cell-type markers, organotypic rat Schwann cell/DRG cultures\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by reporter mouse and immunostaining, single lab, two orthogonal approaches\",\n      \"pmids\": [\"22461884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The disease-associated missense mutant L53P of FAM126A (hyccin/DRCTNNB1A) aggregates in the endoplasmic reticulum, in contrast to wild-type FAM126A which distributes throughout the cytoplasm. L53P mutant expression promotes activities of kinases involved in the unfolded protein response.\",\n      \"method\": \"Subcellular localization by immunofluorescence in transfected cells; UPR kinase activity assays\",\n      \"journal\": \"Journal of clinical neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct subcellular localization with functional consequence (UPR activation), single lab, two methods\",\n      \"pmids\": [\"24417797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"DRCTNNB1A (HYCC1/FAM126A) expression is down-regulated in response to activated beta-catenin. Expression was significantly increased in SW480 colon cancer cells upon reduction of intracellular beta-catenin by adenovirus-mediated APC transfer. Reduced expression was documented in 12 of 15 primary colorectal cancers, implicating the gene in the beta-catenin-Tcf/Lef signaling pathway.\",\n      \"method\": \"Adenovirus-mediated APC transfer with RT-PCR, Northern blot in primary colorectal tumors\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional experiment (adenoviral APC transfer with mRNA readout), validated in primary tumors, single lab\",\n      \"pmids\": [\"10910037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FAM126A interacts directly with ENO1 (alpha-enolase), as confirmed by co-localization and co-immunoprecipitation, and this interaction activates the PI3K/AKT signaling pathway to promote pancreatic cancer cell proliferation, invasion, and migration. ENO1 knockdown reversed the pro-tumorigenic effects of FAM126A overexpression.\",\n      \"method\": \"Co-immunoprecipitation, co-localization assay, ENO1 knockdown rescue experiments in vitro and in vivo\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — reciprocal Co-IP and rescue experiments, single lab, multiple orthogonal functional assays\",\n      \"pmids\": [\"35513377\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HYCC1 (FAM126A/hyccin) functions as an essential subunit of the plasma membrane PI4KIIIα lipid kinase complex (with TTC7 and EFR3), directly stabilizing the complex and enabling synthesis of phosphatidylinositol 4-phosphate (PtdIns(4)P) at the plasma membrane; its loss destabilizes this complex and reduces PtdIns(4)P levels, mechanistically linking FAM126A deficiency to impaired myelination in the leukodystrophy hypomyelination and congenital cataract (HCC disease), and it is also subject to transcriptional repression downstream of beta-catenin signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HYCC1 (FAM126A/hyccin) is an essential subunit of the plasma membrane phosphatidylinositol 4-kinase machinery that controls PtdIns(4)P synthesis required for nervous system myelination [#0, #2]. It is an intrinsic component of the PI4KIIIα complex together with TTC7 and EFR3, where it forms an all-α-helical heterodimer with TTC7 through a large protein-protein interface whose conserved surface mediates binding to PI4KIIIα [#0, #1]. By directly stabilizing this assembly, HYCC1 sustains plasma membrane PtdIns(4)P levels; its loss destabilizes the complex and reduces PtdIns(4)P in patient fibroblasts and mouse brain [#0]. Biallelic loss-of-function mutations in HYCC1 cause an autosomal recessive leukodystrophy characterized by hypomyelination of the central and peripheral nervous system with congenital cataract [#2], consistent with neuronal expression that peaks during early postnatal myelinogenesis [#3]. The disease-associated L53P missense variant misfolds and aggregates in the endoplasmic reticulum, activating unfolded protein response kinases [#4]. Beyond its myelination role, HYCC1 (DRCTNNB1A) is transcriptionally repressed downstream of beta-catenin signaling [#5], and an interaction with ENO1 that activates PI3K/AKT signaling has been documented in pancreatic cancer cells [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established the gene as a transcriptional target downstream of oncogenic signaling, the first functional context before any mechanistic role was known.\",\n      \"evidence\": \"Adenoviral APC transfer with RT-PCR/Northern blot readout in colon cancer cells and primary colorectal tumors\",\n      \"pmids\": [\"10910037\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not identify the gene's molecular function\", \"Direct vs. indirect transcriptional regulation by beta-catenin/Tcf-Lef not resolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Linked the gene to human disease, defining hyccin as an essential protein whose loss causes hypomyelination with congenital cataract.\",\n      \"evidence\": \"Genetic mapping and mutation identification across five affected families with protein characterization\",\n      \"pmids\": [\"16951682\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism connecting loss to hypomyelination not established\", \"Cellular function of the protein unknown at this stage\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Resolved which cells express hyccin during myelination, pointing to a neuronal rather than glial site of action.\",\n      \"evidence\": \"LacZ reporter knock-in mouse, cell-type-marker immunofluorescence, and organotypic Schwann cell/DRG cultures\",\n      \"pmids\": [\"22461884\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Proposed neuron-to-glia signaling role not mechanistically demonstrated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined how a specific disease allele acts at the protein level, showing L53P causes ER aggregation and UPR activation.\",\n      \"evidence\": \"Subcellular localization by immunofluorescence in transfected cells and UPR kinase activity assays\",\n      \"pmids\": [\"24417797\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether UPR activation drives myelination defects in vivo unknown\", \"Effect on PI4KIIIα complex not tested in this study\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined the core molecular function: hyccin is an intrinsic subunit of the plasma membrane PI4KIIIα lipid kinase complex that stabilizes it and is required for PtdIns(4)P synthesis, mechanistically explaining disease.\",\n      \"evidence\": \"Co-IP, phosphoinositide measurements in patient fibroblasts, mouse brain fractionation, and a co-crystal structure of the FAM126A-TTC7 heterodimer with PI4KIIIα-binding surface mapped\",\n      \"pmids\": [\"26571211\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How reduced PtdIns(4)P specifically impairs myelination not delineated\", \"Structure of the full PI4KIIIα-TTC7-EFR3 holocomplex not resolved here\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified a non-myelination function in cancer, with a direct ENO1 interaction activating PI3K/AKT to drive tumor cell behavior.\",\n      \"evidence\": \"Reciprocal Co-IP, co-localization, and ENO1 knockdown rescue in vitro and in vivo\",\n      \"pmids\": [\"35513377\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relationship between ENO1 binding and the PI4KIIIα complex role unclear\", \"Single lab; mechanism of PI3K/AKT activation downstream of the interaction not detailed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How loss of plasma membrane PtdIns(4)P is translated into the specific failure of CNS/PNS myelination, and how this reconciles with hyccin's neuronal expression and signaling-context functions, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mechanistic link from PtdIns(4)P deficit to myelin biogenesis\", \"Cell-type-specific requirement for the PI4KIIIα complex in myelination untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0046488\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\"PI4KIIIα plasma membrane complex (PI4KA-TTC7-EFR3)\"],\n    \"partners\": [\"TTC7\", \"PI4KA\", \"EFR3\", \"ENO1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}