{"gene":"HYCC2","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2024,"finding":"FAM126B (HYCC2) functions redundantly with FAM126A to facilitate recruitment of PI4KIIIα to the plasma membrane for PI4P synthesis. Loss-of-function via genetic perturbation and inducible protein degradation demonstrated that FAM126B dependency arises specifically when FAM126A expression is lost.","method":"Genetic perturbation (knockdown/knockout) and inducible protein degradation in colorectal cancer cell lines; DepMap mining; functional PI4P synthesis assays","journal":"iScience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal genetic perturbation and inducible degradation in cell lines with defined biochemical readout (PI4P synthesis/PI4KIIIα membrane recruitment), single lab but two orthogonal methods","pmids":["38638566"],"is_preprint":false},{"year":2021,"finding":"In Drosophila, FAM126B overexpression fully rescues glial enrichment defects, disrupted axonal sheaths, and impaired visual ability caused by Hyccin/FAM126A knockdown in glia, demonstrating functional redundancy between FAM126A and FAM126B in supporting the PI4KIIIα complex at the plasma membrane in glia.","method":"Drosophila genetic rescue experiments: glial-specific knockdown of Hyccin/FAM126A with overexpression of human FAM126B; phenotypic readout of glial enrichment, axonal sheath integrity, and visual function","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo rescue genetics with multiple phenotypic readouts in a single study, but limited to Drosophila model","pmids":["34894559"],"is_preprint":false}],"current_model":"HYCC2 (FAM126B) acts redundantly with its paralog FAM126A as a scaffold/adaptor that recruits PI4KIIIα to the plasma membrane to support PI4P synthesis; when FAM126A is lost (e.g., by promoter hypermethylation in colorectal cancer), cells become selectively dependent on FAM126B for this lipid kinase complex function."},"narrative":{"mechanistic_narrative":"HYCC2 (FAM126B) is a scaffold/adaptor that supports plasma-membrane PI4P synthesis by facilitating recruitment of the lipid kinase PI4KIIIα, functioning redundantly with its paralog FAM126A [PMID:38638566]. Reciprocal genetic perturbation and inducible degradation in colorectal cancer cells established that dependence on FAM126B emerges specifically when FAM126A expression is lost, defining a redundant module for PI4KIIIα membrane recruitment and PI4P production [PMID:38638566]. This redundancy is conserved in vivo: in Drosophila, human FAM126B overexpression fully rescues the glial enrichment defects, disrupted axonal sheaths, and impaired visual function caused by knockdown of Hyccin/FAM126A in glia [PMID:34894559]. Beyond this redundant scaffolding role in PI4KIIIα-dependent PI4P synthesis, no further mechanistic detail has been characterized in the available corpus.","teleology":[{"year":2021,"claim":"Whether FAM126B can functionally substitute for FAM126A in supporting the PI4KIIIα complex was unknown; in vivo rescue showed it can compensate for FAM126A loss at the organismal level.","evidence":"Drosophila glial-specific Hyccin/FAM126A knockdown rescued by human FAM126B overexpression, scored for glial enrichment, axonal sheath integrity, and visual function","pmids":["34894559"],"confidence":"Medium","gaps":["Demonstrated only in a Drosophila glial model, not mammalian tissue","Does not pinpoint the biochemical step (recruitment vs. activation) rescued","No direct measurement of PI4P or PI4KIIIα localization in the rescue setting"]},{"year":2024,"claim":"The molecular basis and conditional nature of FAM126B function were undefined; perturbation and degradation showed it recruits PI4KIIIα to the plasma membrane for PI4P synthesis redundantly with FAM126A, with dependency arising specifically upon FAM126A loss.","evidence":"Genetic knockdown/knockout and inducible protein degradation in colorectal cancer cell lines with PI4P synthesis assays and DepMap mining","pmids":["38638566"],"confidence":"High","gaps":["Single-lab study; structural basis of PI4KIIIα recruitment not resolved","Direct physical interaction interfaces between FAM126B and PI4KIIIα not mapped","Therapeutic exploitation of the synthetic dependency in FAM126A-silenced tumors untested in vivo"]},{"year":null,"claim":"How FAM126B physically engages the PI4KIIIα complex and what distinguishes its scaffolding from FAM126A remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of the FAM126B-PI4KIIIα complex","Mechanism of membrane recruitment not defined at molecular resolution","Non-redundant or paralog-specific roles, if any, uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"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":[0,1]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0]}],"complexes":[],"partners":["PI4KA","FAM126A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IXS8","full_name":"Hyccin 2","aliases":[],"length_aa":530,"mass_kda":58.6,"function":"Component of a complex required to localize phosphatidylinositol 4-kinase (PI4K) to the plasma membrane","subcellular_location":"Cytoplasm, cytosol; Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q8IXS8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HYCC2","classification":"Not Classified","n_dependent_lines":30,"n_total_lines":1208,"dependency_fraction":0.024834437086092714},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PI4KA","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/search/HYCC2","total_profiled":1310},"omim":[{"mim_id":"620060","title":"TETRATRICOPEPTIDE REPEAT DOMAIN-CONTAINING PROTEIN 7B; TTC7B","url":"https://www.omim.org/entry/620060"},{"mim_id":"616797","title":"EFR3 HOMOLOG B; EFR3B","url":"https://www.omim.org/entry/616797"},{"mim_id":"611798","title":"EFR3 HOMOLOG A; EFR3A","url":"https://www.omim.org/entry/611798"},{"mim_id":"610531","title":"HYCCIN, PI4KA LIPID KINASE COMPLEX, SUBUNIT 1; HYCC1","url":"https://www.omim.org/entry/610531"},{"mim_id":"600286","title":"PHOSPHATIDYLINOSITOL 4-KINASE, ALPHA; PI4KA","url":"https://www.omim.org/entry/600286"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cell Junctions","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/HYCC2"},"hgnc":{"alias_symbol":["MGC39518"],"prev_symbol":["FAM126B"]},"alphafold":{"accession":"Q8IXS8","domains":[{"cath_id":"-","chopping":"123-163","consensus_level":"medium","plddt":79.3056,"start":123,"end":163},{"cath_id":"-","chopping":"196-284","consensus_level":"high","plddt":95.8563,"start":196,"end":284},{"cath_id":"1.20.1050","chopping":"1-121","consensus_level":"medium","plddt":91.3898,"start":1,"end":121}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IXS8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IXS8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IXS8-F1-predicted_aligned_error_v6.png","plddt_mean":68.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HYCC2","jax_strain_url":"https://www.jax.org/strain/search?query=HYCC2"},"sequence":{"accession":"Q8IXS8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IXS8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IXS8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IXS8"}},"corpus_meta":[{"pmid":"32319195","id":"PMC_32319195","title":"LncRNA-mediated ceRNA network was identified as a crucial determinant of differential effects in periodontitis and periimplantitis by high-throughput sequencing.","date":"2020","source":"Clinical implant dentistry and related research","url":"https://pubmed.ncbi.nlm.nih.gov/32319195","citation_count":34,"is_preprint":false},{"pmid":"32497068","id":"PMC_32497068","title":"Peripheral blood transcriptome identifies high-risk benign and malignant breast lesions.","date":"2020","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/32497068","citation_count":16,"is_preprint":false},{"pmid":"29566008","id":"PMC_29566008","title":"Genomic and transcriptomic comparison of allergen and silver nanoparticle-induced mast cell degranulation reveals novel non-immunoglobulin E mediated mechanisms.","date":"2018","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/29566008","citation_count":11,"is_preprint":false},{"pmid":"38638566","id":"PMC_38638566","title":"Frequent loss of FAM126A expression in colorectal cancer results in selective FAM126B dependency.","date":"2024","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/38638566","citation_count":5,"is_preprint":false},{"pmid":"34894559","id":"PMC_34894559","title":"Hyccin/FAM126A deficiency reduces glial enrichment and axonal sheath, which are rescued by overexpression of a plasma membrane-targeting PI4KIIIα in Drosophila.","date":"2021","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/34894559","citation_count":4,"is_preprint":false},{"pmid":"41429611","id":"PMC_41429611","title":"[Acupuncture alleviates chronic airway inflammation in obese asthmatic mice by downregulating Vnn1 and FAM126B].","date":"2025","source":"Nan fang yi ke da xue xue bao = Journal of Southern Medical University","url":"https://pubmed.ncbi.nlm.nih.gov/41429611","citation_count":0,"is_preprint":false},{"pmid":"41971655","id":"PMC_41971655","title":"The computational analysis of tumor cell sensitivity to supertarget deletion.","date":"2026","source":"Vavilovskii zhurnal genetiki i selektsii","url":"https://pubmed.ncbi.nlm.nih.gov/41971655","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":5956,"output_tokens":626,"usd":0.013629,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6997,"output_tokens":1373,"usd":0.034655,"stage2_stop_reason":"end_turn"},"total_usd":0.048284,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2024,\n      \"finding\": \"FAM126B (HYCC2) functions redundantly with FAM126A to facilitate recruitment of PI4KIIIα to the plasma membrane for PI4P synthesis. Loss-of-function via genetic perturbation and inducible protein degradation demonstrated that FAM126B dependency arises specifically when FAM126A expression is lost.\",\n      \"method\": \"Genetic perturbation (knockdown/knockout) and inducible protein degradation in colorectal cancer cell lines; DepMap mining; functional PI4P synthesis assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal genetic perturbation and inducible degradation in cell lines with defined biochemical readout (PI4P synthesis/PI4KIIIα membrane recruitment), single lab but two orthogonal methods\",\n      \"pmids\": [\"38638566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In Drosophila, FAM126B overexpression fully rescues glial enrichment defects, disrupted axonal sheaths, and impaired visual ability caused by Hyccin/FAM126A knockdown in glia, demonstrating functional redundancy between FAM126A and FAM126B in supporting the PI4KIIIα complex at the plasma membrane in glia.\",\n      \"method\": \"Drosophila genetic rescue experiments: glial-specific knockdown of Hyccin/FAM126A with overexpression of human FAM126B; phenotypic readout of glial enrichment, axonal sheath integrity, and visual function\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo rescue genetics with multiple phenotypic readouts in a single study, but limited to Drosophila model\",\n      \"pmids\": [\"34894559\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HYCC2 (FAM126B) acts redundantly with its paralog FAM126A as a scaffold/adaptor that recruits PI4KIIIα to the plasma membrane to support PI4P synthesis; when FAM126A is lost (e.g., by promoter hypermethylation in colorectal cancer), cells become selectively dependent on FAM126B for this lipid kinase complex function.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HYCC2 (FAM126B) is a scaffold/adaptor that supports plasma-membrane PI4P synthesis by facilitating recruitment of the lipid kinase PI4KIIIα, functioning redundantly with its paralog FAM126A [#0]. Reciprocal genetic perturbation and inducible degradation in colorectal cancer cells established that dependence on FAM126B emerges specifically when FAM126A expression is lost, defining a redundant module for PI4KIIIα membrane recruitment and PI4P production [#0]. This redundancy is conserved in vivo: in Drosophila, human FAM126B overexpression fully rescues the glial enrichment defects, disrupted axonal sheaths, and impaired visual function caused by knockdown of Hyccin/FAM126A in glia [#1]. Beyond this redundant scaffolding role in PI4KIIIα-dependent PI4P synthesis, no further mechanistic detail has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2021,\n      \"claim\": \"Whether FAM126B can functionally substitute for FAM126A in supporting the PI4KIIIα complex was unknown; in vivo rescue showed it can compensate for FAM126A loss at the organismal level.\",\n      \"evidence\": \"Drosophila glial-specific Hyccin/FAM126A knockdown rescued by human FAM126B overexpression, scored for glial enrichment, axonal sheath integrity, and visual function\",\n      \"pmids\": [\"34894559\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Demonstrated only in a Drosophila glial model, not mammalian tissue\",\n        \"Does not pinpoint the biochemical step (recruitment vs. activation) rescued\",\n        \"No direct measurement of PI4P or PI4KIIIα localization in the rescue setting\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The molecular basis and conditional nature of FAM126B function were undefined; perturbation and degradation showed it recruits PI4KIIIα to the plasma membrane for PI4P synthesis redundantly with FAM126A, with dependency arising specifically upon FAM126A loss.\",\n      \"evidence\": \"Genetic knockdown/knockout and inducible protein degradation in colorectal cancer cell lines with PI4P synthesis assays and DepMap mining\",\n      \"pmids\": [\"38638566\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Single-lab study; structural basis of PI4KIIIα recruitment not resolved\",\n        \"Direct physical interaction interfaces between FAM126B and PI4KIIIα not mapped\",\n        \"Therapeutic exploitation of the synthetic dependency in FAM126A-silenced tumors untested in vivo\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How FAM126B physically engages the PI4KIIIα complex and what distinguishes its scaffolding from FAM126A remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural model of the FAM126B-PI4KIIIα complex\",\n        \"Mechanism of membrane recruitment not defined at molecular resolution\",\n        \"Non-redundant or paralog-specific roles, if any, uncharacterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PI4KA\", \"FAM126A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":3,"faith_pct":100.0}}