{"gene":"ASB14","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2024,"finding":"ASB14 functions as an E3 ubiquitin ligase that promotes ubiquitination and degradation of MAPRE2 (microtubule-associated protein RP/EB family member 2); loss of ASB14 decreases MAPRE2 protein degradation, which in turn promotes cardiomyocyte nuclear proliferation and enhances cardiac repair after myocardial infarction.","method":"Microarray analysis of cardiac tissue, ASB14 silencing in vitro and in vivo, assessment of cardiomyocyte nuclear proliferation, cardiac function assays in ASB14-deficient mice following ischemic injury, mechanistic investigation of MAPRE2 protein degradation","journal":"Cell biochemistry and biophysics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function in vitro and in vivo with defined phenotypic readout and mechanistic substrate identification, single lab, abstract does not describe direct biochemical reconstitution of ubiquitination","pmids":["38319584"],"is_preprint":false},{"year":2025,"finding":"ASB14 overexpression in AC16 cardiomyocytes promotes apoptosis, inhibits cell proliferation, and inhibits mitochondrial function; proteomics and metabolomics identified downstream effectors including suppression of PIP4K2A, ferritin light chain, AMPK alpha-1, GLB1, ABCC9, and NME7, and upregulation of RRAGC, with enrichment in linoleic acid and purine metabolism pathways.","method":"ASB14 overexpression via pCDH-ASB14 transfection in AC16 cells, CCK8 proliferation assay, flow cytometry apoptosis assay, ATP level measurement, TMT-iTRAQ proteomics, LC-MS/MS metabolomics, Western blotting validation of key proteins","journal":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (proteomics, metabolomics, functional assays, Western blot) in a single study, single lab, in vitro only","pmids":["40417864"],"is_preprint":false}],"current_model":"ASB14 (Ankyrin Repeat and SOCS Box Containing 14) is an E3 ubiquitin ligase that promotes ubiquitination and proteasomal degradation of MAPRE2, thereby inhibiting cardiomyocyte proliferation; ASB14 overexpression also suppresses mitochondrial function and promotes apoptosis in cardiomyocytes through pathways involving AMPK signaling and lipid/purine metabolism, while its loss preserves cardiac function after ischemic injury by enabling cardiomyocyte nuclear proliferation."},"narrative":{"mechanistic_narrative":"ASB14 (Ankyrin Repeat and SOCS Box Containing 14) is an E3 ubiquitin ligase that restrains cardiomyocyte proliferation and cardiac repair by targeting the microtubule-associated protein MAPRE2 for ubiquitination and proteasomal degradation [PMID:38319584]. Loss of ASB14 stabilizes MAPRE2, driving cardiomyocyte nuclear proliferation and enhancing recovery of cardiac function after myocardial infarction [PMID:38319584]. Conversely, ASB14 overexpression in cardiomyocytes promotes apoptosis, suppresses proliferation, and impairs mitochondrial function, acting through downstream effectors including PIP4K2A, AMPK alpha-1, and RRAGC with metabolic reprogramming in linoleic acid and purine pathways [PMID:40417864]. Beyond these cardiomyocyte phenotypes, no further mechanistic detail has been characterized in the available corpus.","teleology":[{"year":2024,"claim":"Established ASB14 as an E3 ubiquitin ligase with a defined substrate, answering what molecular activity it carries and how it controls cardiac regeneration after injury.","evidence":"ASB14 silencing in vitro and in vivo, cardiomyocyte nuclear proliferation and cardiac function assays in ASB14-deficient mice after ischemic injury, with MAPRE2 degradation as readout","pmids":["38319584"],"confidence":"Medium","gaps":["Ubiquitination of MAPRE2 was not reconstituted biochemically (no direct in vitro ligase assay)","Single lab; mechanism of MAPRE2 recognition by the ASB14 SOCS box / ankyrin repeats not defined","Whether MAPRE2 stabilization alone is sufficient for the proliferation phenotype is unresolved"]},{"year":2025,"claim":"Defined the downstream consequences of elevated ASB14, showing it drives apoptosis and mitochondrial dysfunction and reprograms cardiomyocyte metabolism.","evidence":"ASB14 overexpression in AC16 cardiomyocytes with CCK8 proliferation, flow cytometry apoptosis, ATP measurement, TMT-iTRAQ proteomics, LC-MS/MS metabolomics, and Western validation","pmids":["40417864"],"confidence":"Medium","gaps":["In vitro overexpression only; no in vivo confirmation of the metabolic/apoptotic axis","The listed effectors (PIP4K2A, AMPK alpha-1, RRAGC, etc.) are correlative proteomic/metabolomic hits, not validated direct targets","Relationship between the MAPRE2 axis and the mitochondrial/metabolic phenotype is not established"]},{"year":null,"claim":"How ASB14 physically recognizes its substrates and assembles into an E3 ligase complex, and whether its functions extend beyond cardiomyocytes, remain unknown.","evidence":"No structural or biochemical reconstitution data in the available corpus","pmids":[],"confidence":"Medium","gaps":["No structural model or domain-level substrate-binding mechanism","No identification of associated E3 complex components (e.g. Cullin/Elongin partners)","Function in non-cardiac tissues uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0]}],"localization":[],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[1]}],"complexes":[],"partners":["MAPRE2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"A6NK59","full_name":"Ankyrin repeat and SOCS box protein 14","aliases":[],"length_aa":587,"mass_kda":65.3,"function":"May be a substrate-recognition component of a SCF-like ECS (Elongin-Cullin-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Plays a role in the inhibition of cardiomyocyte nuclear proliferation by mediating the ubiquitination and degradation of MAPRE2","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/A6NK59/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ASB14","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/ASB14","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"skeletal 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Loss of ASB14 stabilizes MAPRE2, driving cardiomyocyte nuclear proliferation and enhancing recovery of cardiac function after myocardial infarction [#0]. Conversely, ASB14 overexpression in cardiomyocytes promotes apoptosis, suppresses proliferation, and impairs mitochondrial function, acting through downstream effectors including PIP4K2A, AMPK alpha-1, and RRAGC with metabolic reprogramming in linoleic acid and purine pathways [#1]. Beyond these cardiomyocyte phenotypes, no further mechanistic detail has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2024,\n      \"claim\": \"Established ASB14 as an E3 ubiquitin ligase with a defined substrate, answering what molecular activity it carries and how it controls cardiac regeneration after injury.\",\n      \"evidence\": \"ASB14 silencing in vitro and in vivo, cardiomyocyte nuclear proliferation and cardiac function assays in ASB14-deficient mice after ischemic injury, with MAPRE2 degradation as readout\",\n      \"pmids\": [\n        \"38319584\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Ubiquitination of MAPRE2 was not reconstituted biochemically (no direct in vitro ligase assay)\",\n        \"Single lab; mechanism of MAPRE2 recognition by the ASB14 SOCS box / ankyrin repeats not defined\",\n        \"Whether MAPRE2 stabilization alone is sufficient for the proliferation phenotype is unresolved\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined the downstream consequences of elevated ASB14, showing it drives apoptosis and mitochondrial dysfunction and reprograms cardiomyocyte metabolism.\",\n      \"evidence\": \"ASB14 overexpression in AC16 cardiomyocytes with CCK8 proliferation, flow cytometry apoptosis, ATP measurement, TMT-iTRAQ proteomics, LC-MS/MS metabolomics, and Western validation\",\n      \"pmids\": [\n        \"40417864\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"In vitro overexpression only; no in vivo confirmation of the metabolic/apoptotic axis\",\n        \"The listed effectors (PIP4K2A, AMPK alpha-1, RRAGC, etc.) are correlative proteomic/metabolomic hits, not validated direct targets\",\n        \"Relationship between the MAPRE2 axis and the mitochondrial/metabolic phenotype is not established\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ASB14 physically recognizes its substrates and assembles into an E3 ligase complex, and whether its functions extend beyond cardiomyocytes, remain unknown.\",\n      \"evidence\": \"No structural or biochemical reconstitution data in the available corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural model or domain-level substrate-binding mechanism\",\n        \"No identification of associated E3 complex components (e.g. Cullin/Elongin partners)\",\n        \"Function in non-cardiac tissues uncharacterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0140096\",\n        \"supporting_discovery_ids\": [\n          0\n        ]\n      },\n      {\n        \"term_id\": \"GO:0016874\",\n        \"supporting_discovery_ids\": [\n          0\n        ]\n      }\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\n        \"term_id\": \"R-HSA-392499\",\n        \"supporting_discovery_ids\": [\n          0\n        ]\n      },\n      {\n        \"term_id\": \"R-HSA-5357801\",\n        \"supporting_discovery_ids\": [\n          1\n        ]\n      }\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"MAPRE2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":3,"faith_pct":100.0}}