{"gene":"FOXK2","run_date":"2026-04-28T17:46:04","timeline":{"discoveries":[{"year":1992,"finding":"FOXK2 (originally called ILF) contains a forkhead DNA-binding domain sufficient to mediate DNA binding to purine-rich regulatory sequences in the HIV-1 LTR and IL2 promoter; the forkhead domain alone is sufficient for DNA binding.","method":"Gel retardation (EMSA), expression library screening, domain mapping","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro DNA binding assay with domain mapping, single study","pmids":["1339390"],"is_preprint":false},{"year":2010,"finding":"FOXK2 is phosphorylated by CDK1·cyclin B (and also CDK2·cyclin A) at serines 368 and 423 during mitosis; these phosphorylation events regulate FOXK2 protein stability and its activity as a transcriptional repressor, and expression of a mutant lacking these sites causes apoptosis.","method":"Cell cycle synchronization, CDK kinase assays, site-directed mutagenesis, transcriptional reporter assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro kinase assay with mutagenesis, multiple functional readouts in single study","pmids":["20810654"],"is_preprint":false},{"year":2010,"finding":"The forkhead domain of FOXK2 binds G/T-mismatch DNA with higher affinity than matched consensus DNA; it also recognizes hypoxanthine/T and G/uracil mispairs; EMSA with anti-FOXK2 antibody confirmed FOXK2 is the G/T-mismatch binding activity in HL60 nuclear extracts.","method":"Expression library screening for mismatch DNA binding, EMSA, antibody supershift, recombinant domain binding assays","journal":"Journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro binding assay with recombinant protein and nuclear extract confirmation, single lab","pmids":["20097901"],"is_preprint":false},{"year":2011,"finding":"FOXK2 binds genome-wide regulatory regions that are co-associated with AP-1 binding motifs and is required for efficient recruitment of AP-1 to chromatin and subsequent AP-1-dependent gene expression changes.","method":"ChIP-seq, genome-wide binding analysis, ChIP-qPCR, gene expression analysis after knockdown","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal ChIP, genome-wide binding, functional KD with defined chromatin recruitment phenotype","pmids":["22083952"],"is_preprint":false},{"year":2014,"finding":"FOXK2 binds the SIN3A and PR-DUB (BAP1-containing) complexes; FOXK2 recruits BAP1 to specific genomic loci via its forkhead-associated (FHA) domain, promotes local histone H2A deubiquitination, and thereby alters target gene activity.","method":"Co-immunoprecipitation, ChIP, histone deubiquitination assays, domain mapping","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, ChIP, functional deubiquitination assay, multiple orthogonal methods","pmids":["24748658"],"is_preprint":false},{"year":2014,"finding":"FOXK2 recruits BAP1 to target gene loci through its FHA domain, which recognizes phospho-Thr493 on BAP1; BAP1 in turn recruits HCF-1, forming a ternary FOXK2–BAP1–HCF-1 complex; BAP1 DUB activity (but not HCF-1 interaction) is required to repress FOXK2 target genes; BAP1 depletion causes Ring1B–Bmi1-dependent upregulation of these targets.","method":"Co-immunoprecipitation, pulldown, deubiquitinase activity assays, RNAi knockdown, epistasis with Ring1B-Bmi1","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — biochemical reconstitution of complex, enzymatic activity requirement, genetic epistasis","pmids":["25451922"],"is_preprint":false},{"year":2015,"finding":"FOXK2 interacts with ERα and with BARD1 (of the BRCA1/BARD1 E3 ubiquitin ligase), acting as a scaffold to bring BRCA1/BARD1 and ERα together, thereby enhancing ubiquitin-mediated degradation of ERα and reducing its transcriptional activity; knockdown of both FOXK2 and ERα abolished the proliferative effect of FOXK2 KD.","method":"Co-immunoprecipitation, ubiquitination assays, reporter assays, siRNA knockdown, proliferation assays","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, ubiquitination assay, genetic epistasis by double KD, multiple orthogonal methods","pmids":["25740706"],"is_preprint":false},{"year":2015,"finding":"FoxK2 knockdown in neural/proliferating cells decreases BrdU incorporation and H3 phosphorylation (proliferation markers), increases caspase 3 activity and cell death, upregulates pro-apoptotic Puma and Noxa, and increases p70S6K phosphorylation; rapamycin blocks p70S6K increase and synergizes with FoxK2 KD on proliferation but not apoptosis, indicating mTOR forms a compensatory feedback loop.","method":"siRNA knockdown, BrdU incorporation, caspase activity assay, flow cytometry, qRT-PCR, Western blot, rapamycin epistasis","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 — KD with multiple defined readouts and pharmacological epistasis, single lab","pmids":["25216324"],"is_preprint":false},{"year":2016,"finding":"FOXK2 interacts with transcription corepressor complexes NCoR/SMRT, SIN3A, NuRD, and REST/CoREST to repress a cohort of genes including HIF1β and EZH2, suppressing the hypoxic response; ERα transactivates FOXK2, and HIF1β/EZH2 reciprocally repress FOXK2 expression in a feedback loop.","method":"Co-immunoprecipitation, ChIP, gene expression analysis, luciferase reporter assays, KD/OE functional assays","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 — multiple Co-IPs with distinct complexes, ChIP, functional epistasis, multiple orthogonal methods, highly cited","pmids":["27773593"],"is_preprint":false},{"year":2018,"finding":"FOXK2 is SUMOylated at lysines 527 and 633; SUMOylation-defective mutants (K527/633R) are unable to bind the FOXO3 promoter by ChIP and fail to upregulate FOXO3 transcription, reducing paclitaxel sensitivity, despite similar protein levels and subcellular localization to wild-type FOXK2.","method":"Site-directed mutagenesis of SUMO consensus sites, ChIP, cell viability/clonogenic assays, qRT-PCR, Western blot","journal":"Oncogenesis","confidence":"High","confidence_rationale":"Tier 1-2 — mutagenesis of modification sites with ChIP and functional readout, multiple orthogonal methods","pmids":["29540677"],"is_preprint":false},{"year":2019,"finding":"FOXK1 and FOXK2 induce aerobic glycolysis by transcriptionally upregulating glycolytic enzymes (hexokinase-2, phosphofructokinase, pyruvate kinase, lactate dehydrogenase) and pyruvate dehydrogenase kinases 1 and 4 (PDK1/4), while suppressing pyruvate dehydrogenase phosphatase 1 (PDP1), resulting in increased phosphorylation of pyruvate dehydrogenase E1α subunit and inhibition of mitochondrial pyruvate oxidation.","method":"KO/KD and overexpression in cell lines and primary human cells, metabolic flux assays, gene expression profiling, in vivo mouse experiments","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (KO, KD, OE, metabolomics, in vivo), replicated in multiple cell types and in vivo, highly cited","pmids":["30700909"],"is_preprint":false},{"year":2019,"finding":"FoxK1 and FoxK2 nuclear translocation following insulin stimulation is dependent on the Akt–mTOR pathway, while cytoplasmic retention in basal state depends on GSK3; this translocation is reciprocal to FoxO1 nuclear-to-cytoplasmic translocation. Knockdown reduces lipid metabolism and cell proliferation genes and alters mitochondrial fatty acid metabolism.","method":"Subcellular fractionation, live-cell imaging of translocation, pharmacological inhibitors (Akt, mTOR, GSK3), siRNA knockdown, RNA-seq, metabolic assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — direct localization experiments with functional consequences, pharmacological epistasis, RNA-seq, multiple orthogonal methods","pmids":["30952843"],"is_preprint":false},{"year":2021,"finding":"FOXK2 directly regulates IRE1α (ERN1) expression by binding to an intronic regulatory enhancer element of the ERN1 gene, as shown by ChIP-seq; blocking this binding with dCas9 diminished IRE1α transcription; FOXK2-driven IRE1α upregulation leads to alternative XBP1 splicing and activation of stemness pathways in ovarian cancer stem cells.","method":"ChIP-seq, CRISPR/dCas9 enhancer blocking, RNA-seq, genetic depletion with stem cell functional assays","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP-seq + dCas9 enhancer blocking + functional readout, multiple orthogonal methods","pmids":["35349489"],"is_preprint":false},{"year":2021,"finding":"FOXK2 is acetylated at K223 by the acetyltransferase CBP (CREB-binding protein) and deacetylated by SIRT1; cisplatin attenuates FOXK2–SIRT1 interaction; FOXK2 K223 acetylation reduces its nuclear localization and promotes mitotic catastrophe, enhancing chemosensitivity to cisplatin.","method":"Co-immunoprecipitation, site-directed mutagenesis (K223), Western blot for acetylation, subcellular fractionation, SIRT1 inhibitor experiments, in vitro and in vivo functional assays","journal":"Journal of cellular and molecular medicine","confidence":"High","confidence_rationale":"Tier 1-2 — identification of writer (CBP) and eraser (SIRT1) with mutagenesis and functional consequences, multiple methods","pmids":["34866322"],"is_preprint":false},{"year":2021,"finding":"FOXK2 transcriptionally activates VEGFA by binding directly to its promoter, promoting angiogenesis; VEGFA produced by FOXK2-expressing cells binds VEGFR1 as a compensatory mechanism when VEGFR2 is blocked, activating ERK, PI3K/AKT, and P38/MAPK; a positive feedback loop exists in which VEGFA/VEGFR1 signaling further promotes FOXK2-mediated VEGFA transcription.","method":"RNA-seq, ChIP-seq, ChIP, dual-luciferase reporter assay, functional angiogenesis assays, pharmacological VEGFR inhibition","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — ChIP-seq and ChIP confirming direct promoter binding, luciferase validation, multiple functional assays","pmids":["34489549"],"is_preprint":false},{"year":2021,"finding":"FOXK2 promotes AP-1-mediated transcription by being required for efficient recruitment of AP-1 to chromatin; FOXK2 binding regions genome-wide are co-associated with AP-1 binding motifs.","method":"ChIP-seq, ChIP-qPCR, gene expression analysis, functional assays with AP-1 pathway activation","journal":"Nucleic acids research (2021 paper on ESC premarking)","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP-seq plus functional differentiation assays, single lab","pmids":["33434264"],"is_preprint":false},{"year":2022,"finding":"FOXK2 is SUMOylated by PIAS4, which promotes FOXK2 nuclear translocation; nuclear FOXK2 then binds promoters of nucleotide de novo synthesis genes and activates their transcription; DNA damage suppresses FOXK2 SUMOylation; elevated FOXK2 SUMOylation promotes nucleotide synthesis and causes resistance to 5-FU.","method":"ChIP-seq, RNA-seq, luciferase promoter assay, SUMO modification assays, subcellular fractionation, in vitro and in vivo functional assays","journal":"Drug resistance updates","confidence":"High","confidence_rationale":"Tier 2 — identification of SUMO E3 ligase (PIAS4), ChIP-seq for binding, functional and localization readouts, multiple methods","pmids":["36682222"],"is_preprint":false},{"year":2023,"finding":"FOXK2 is SUMOylated by PIAS4 leading to nuclear translocation and transcriptional activation of nucleotide synthetic genes; DNA damage represses this SUMOylation and reduces resistance to chemotherapy.","method":"ChIP-seq, RNA-seq, SUMO modification assays, subcellular fractionation","journal":"Drug resistance updates","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods linking PTM to localization and function","pmids":["36682222"],"is_preprint":false},{"year":2024,"finding":"FOXK2 is polyubiquitylated by the SCF E3 ligase subunit FBXO24 via the FOXK2 carboxyl terminus (aa 428–478), leading to nuclear proteasomal degradation of FOXK2; FOXK2 is also detected within mitochondria and its depletion or expression of mutants lacking key C-terminal domains impairs mitochondrial function; Fbxo24 heterozygous mice show preserved mitochondrial function and FOXK2 levels during bacterial pneumonia.","method":"Co-immunoprecipitation, domain mapping, ubiquitination assays, subcellular fractionation (mitochondrial), in vivo mouse genetic model","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — Co-IP, domain mapping, ubiquitination assay, in vivo genetic model, multiple orthogonal methods","pmids":["38735474"],"is_preprint":false},{"year":2024,"finding":"PDK2 directly binds the forkhead-associated (FHA) domain of FOXK2 and phosphorylates FOXK2 at Thr13 and Ser30, enhancing its transcriptional activity; FOXK2 transcriptionally regulates PDK2 expression, forming a positive feedback loop sustaining glycolysis in ovarian cancer cells.","method":"Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis, ChIP, luciferase reporter assay, in vitro and in vivo functional assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 — kinase assay, domain mapping, mutagenesis, ChIP, feedback loop demonstrated with multiple methods","pmids":["38734828"],"is_preprint":false},{"year":2024,"finding":"FOXK1 and FOXK2 are ORF45-binding proteins; ORF45 (KSHV immediate early tegument protein) interacts with the FHA domains of FOXK1 and FOXK2 through a conserved short linear serine/threonine-rich motif (a single threonine point mutation abolishes interaction); ORF45 augments FOXK1/2 occupancy on late viral gene promoters and their transcriptional activity to promote late KSHV lytic replication.","method":"Co-immunoprecipitation, pulldown, ChIP, site-directed mutagenesis of ORF45 interaction motif, viral gene expression assays, siRNA knockdown","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, mutagenesis of interaction motif, ChIP for chromatin binding, functional viral assays, multiple orthogonal methods","pmids":["39494902","39287387"],"is_preprint":false},{"year":2025,"finding":"Foxk1 and Foxk2 directly activate CCNB1 (cyclin B1) and CDK1 expression in cardiomyocytes; the resulting CCNB1/CDK1 complex facilitates G2/M transition; Foxk1/2 also upregulate HIF1α to enhance glycolysis and the pentose phosphate pathway, promoting cardiomyocyte proliferation; cardiomyocyte-specific knockout impairs neonatal heart regeneration after MI.","method":"Cardiomyocyte-specific KO, AAV9 overexpression, ChIP, cell cycle analysis, metabolic assays, myocardial infarction model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — tissue-specific KO with defined phenotype, ChIP showing direct gene activation, multiple mechanisms validated in vivo","pmids":["40128196"],"is_preprint":false},{"year":2025,"finding":"FOXK2 mutations cause congenital myopathy with ptosis; FOXK2 deficiency impairs myogenic differentiation and disrupts mitochondrial homeostasis in muscle stem cells and C2C12 cells; FOXK2 directly regulates expression of mitochondrial function-related genes by modulating chromatin accessibility at its binding sites; Coenzyme Q10 treatment rescued mitochondrial function and skeletal muscle defects in Foxk2-deficient mice.","method":"Whole exome sequencing, zebrafish foxk2 KO, mouse muscle stem cell-specific KO, ATAC-seq, gene expression analysis, mitochondrial functional assays, rescue experiments","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 2 — multiple model organisms (zebrafish, mouse KO), ATAC-seq for chromatin regulation, functional rescue, multiple orthogonal methods","pmids":["40410591"],"is_preprint":false},{"year":2025,"finding":"Foxk2 nuclear translocation during adipogenic differentiation is driven by PI3-kinase and mTOR signaling; once nuclear, Foxk2 binds the promoters of Pparγ1 and Pparγ2 to enhance their transcription; PPARγ1 and PPARγ2 reciprocally augment Foxk2 promoter transcriptional activity, forming a Foxk2–PPARγ positive feedback loop driving adipogenesis.","method":"Overexpression/knockdown, subcellular fractionation/nuclear translocation assays, PI3K and mTOR inhibitors, ChIP on Pparγ promoters, luciferase reporter assays, adipogenic differentiation assays","journal":"Journal of cellular and molecular medicine","confidence":"High","confidence_rationale":"Tier 2 — ChIP for direct promoter binding, pharmacological epistasis for localization, functional reporter assays, multiple orthogonal methods","pmids":["39789420"],"is_preprint":false},{"year":2024,"finding":"FOXK2 interacts with both mTOR and DRP1 (detected by co-immunoprecipitation); FOXK2 promotes phosphorylation of mTOR and upregulates CPT1A (fatty acid oxidation) while downregulating ACC1 and FASN (lipogenesis), thereby regulating lipid metabolic reprogramming in cervical cancer via the mTOR/DRP1 signaling axis.","method":"Co-immunoprecipitation, Western blot, OCR measurement, in vivo xenograft","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP for interaction, metabolic assays, single lab, limited mechanistic depth for mTOR phosphorylation","pmids":["40641601"],"is_preprint":false}],"current_model":"FOXK2 is a ubiquitously expressed forkhead transcription factor that functions as both a transcriptional repressor and activator depending on context: it recruits corepressor complexes (SIN3A, NCoR/SMRT, NuRD, REST/CoREST) and the BAP1-containing PR-DUB deubiquitinase complex to repress target genes (via its FHA domain interacting with phospho-Thr493 of BAP1), while also promoting AP-1-dependent gene activation and directly activating glycolytic enzyme genes, IRE1α, CCNB1/CDK1, and PPARγ; its activity and localization are regulated by CDK1/2-mediated phosphorylation (S368/S423) during mitosis, insulin/Akt-mTOR and GSK3 pathways controlling nuclear-cytoplasmic shuttling, PIAS4-mediated SUMOylation (K527/K633) promoting nuclear translocation and transcriptional activity, CBP-mediated acetylation (K223) and SIRT1-mediated deacetylation controlling nuclear localization and drug sensitivity, and FBXO24-mediated polyubiquitylation leading to proteasomal degradation; PDK2 also phosphorylates FOXK2 at T13/S30 to enhance its transcriptional output in a positive feedback loop sustaining glycolysis."},"narrative":{"teleology":[{"year":1992,"claim":"Identification of FOXK2 as a forkhead-domain transcription factor established that it uses this domain for sequence-specific DNA binding to purine-rich regulatory elements, providing the first molecular handle on the gene.","evidence":"EMSA and expression library screening with HIV-1 LTR and IL-2 promoter probes","pmids":["1339390"],"confidence":"Medium","gaps":["Endogenous genomic targets unknown","No functional consequence of DNA binding demonstrated","In vitro binding only, no chromatin context"]},{"year":2010,"claim":"Demonstration that CDK1/cyclin B and CDK2/cyclin A phosphorylate FOXK2 at S368 and S423 during mitosis revealed the first regulatory post-translational modification controlling its stability and repressor activity, and showed that disrupting this regulation triggers apoptosis.","evidence":"In vitro kinase assays, site-directed mutagenesis, cell cycle synchronization, transcriptional reporters","pmids":["20810654"],"confidence":"High","gaps":["Phosphatase(s) reversing these modifications unidentified","Downstream apoptotic pathway not fully dissected","In vivo relevance not tested"]},{"year":2010,"claim":"Discovery that FOXK2's forkhead domain binds G/T-mismatch DNA with higher affinity than matched consensus raised the possibility of a non-canonical role in DNA damage recognition, though functional consequences remain unclear.","evidence":"EMSA with recombinant forkhead domain and antibody supershift in HL60 nuclear extracts","pmids":["20097901"],"confidence":"Medium","gaps":["No demonstration of mismatch repair activity","Physiological relevance of mismatch binding untested","Single-lab finding without in vivo validation"]},{"year":2011,"claim":"Genome-wide ChIP-seq showed FOXK2 binding sites are enriched for AP-1 motifs and that FOXK2 is required for efficient AP-1 chromatin recruitment, establishing FOXK2 as a pioneer or cooperative factor for AP-1-dependent transcription.","evidence":"ChIP-seq, ChIP-qPCR, knockdown with gene expression analysis","pmids":["22083952"],"confidence":"High","gaps":["Mechanism of cooperative binding (direct interaction vs. chromatin remodeling) not resolved","AP-1 subunit specificity not defined"]},{"year":2014,"claim":"Biochemical dissection of the FOXK2–BAP1 axis showed that the FHA domain of FOXK2 recognizes phospho-Thr493 on BAP1 to recruit the PR-DUB complex to chromatin, where BAP1's deubiquitinase activity on H2AK119ub is required for target gene repression — establishing FOXK2 as a sequence-specific recruiter of an epigenetic eraser.","evidence":"Co-IP, pulldown, domain mapping, histone deubiquitination assays, ChIP, RNAi epistasis with Ring1B–Bmi1","pmids":["24748658","25451922"],"confidence":"High","gaps":["Kinase phosphorylating BAP1 T493 to enable FOXK2 interaction not identified in these studies","Structural basis of FHA–pThr recognition not resolved","Genome-wide extent of FOXK2-dependent H2A deubiquitination not mapped"]},{"year":2015,"claim":"FOXK2 was shown to scaffold the BRCA1/BARD1 E3 ligase onto ERα, promoting ERα ubiquitylation and degradation, revealing a non-transcriptional adaptor function in protein turnover that links FOXK2 to estrogen signaling and breast cancer cell proliferation.","evidence":"Co-IP, ubiquitination assays, reporter assays, double knockdown epistasis","pmids":["25740706"],"confidence":"High","gaps":["Whether FOXK2 scaffolding of BRCA1/BARD1 extends to other substrates unknown","Structural basis of tripartite complex not resolved"]},{"year":2016,"claim":"Identification of FOXK2 interactions with four distinct corepressor complexes (NCoR/SMRT, SIN3A, NuRD, REST/CoREST) and its repression of HIF1β and EZH2 positioned FOXK2 as a multi-complex transcriptional repressor that suppresses the hypoxic response.","evidence":"Co-IP with multiple complexes, ChIP, knockdown/overexpression, luciferase reporters","pmids":["27773593"],"confidence":"High","gaps":["How FOXK2 selects among different corepressor complexes at specific loci unknown","Stoichiometry of complex engagement at individual promoters not determined"]},{"year":2018,"claim":"Mapping SUMOylation at K527 and K633 and showing that these modifications are required for FOXK2 binding to the FOXO3 promoter and for paclitaxel sensitivity established SUMOylation as a critical activating switch for FOXK2's transcriptional function.","evidence":"SUMO-site mutagenesis, ChIP, clonogenic and viability assays","pmids":["29540677"],"confidence":"High","gaps":["SUMO E3 ligase responsible not identified in this study (later found to be PIAS4)","Mechanism by which SUMO modification enables DNA binding unclear"]},{"year":2019,"claim":"Two landmark studies established FOXK2 (with FOXK1) as a master metabolic switch: it transcriptionally upregulates glycolytic enzymes and PDK1/4 while suppressing PDP1 to drive aerobic glycolysis, and its nuclear translocation is controlled by the insulin–Akt–mTOR axis opposed by GSK3 cytoplasmic retention — linking growth factor signaling to metabolic gene programs.","evidence":"KO/KD/OE in multiple cell types and in vivo mice, metabolic flux assays, subcellular fractionation, pharmacological inhibitors, RNA-seq","pmids":["30700909","30952843"],"confidence":"High","gaps":["Direct phosphorylation sites mediating Akt/mTOR-dependent nuclear import not mapped","Relative contributions of FOXK1 vs FOXK2 to glycolytic regulation not fully separated"]},{"year":2021,"claim":"Multiple 2021 studies expanded FOXK2's transcriptional target repertoire to include IRE1α (via intronic enhancer binding driving UPR/stemness), VEGFA (driving angiogenesis with a VEGFR1-mediated feedback loop), and identified CBP-mediated K223 acetylation counteracted by SIRT1 as a regulatory switch controlling nuclear localization and chemosensitivity.","evidence":"ChIP-seq, dCas9 enhancer blocking, luciferase reporters, site-directed mutagenesis of K223, subcellular fractionation, in vivo assays","pmids":["35349489","34489549","34866322"],"confidence":"High","gaps":["Interplay between acetylation and SUMOylation on the same FOXK2 molecule not explored","Tissue specificity of enhancer-level regulation (e.g., IRE1α) not defined"]},{"year":2022,"claim":"Identification of PIAS4 as the SUMO E3 ligase for FOXK2 completed the SUMOylation pathway: PIAS4-mediated SUMOylation drives nuclear translocation and activates nucleotide de novo synthesis genes, while DNA damage suppresses this modification, explaining 5-FU chemoresistance.","evidence":"ChIP-seq, RNA-seq, SUMO modification assays, subcellular fractionation, in vivo functional assays","pmids":["36682222"],"confidence":"High","gaps":["De-SUMOylation enzyme (SENP) for FOXK2 not identified","Whether DNA damage signals directly to PIAS4 or to FOXK2 to suppress SUMOylation unknown"]},{"year":2024,"claim":"Discovery that FBXO24 polyubiquitylates FOXK2 via its C-terminus for proteasomal degradation, and that PDK2 phosphorylates FOXK2 at T13/S30 via the FHA domain to enhance transcriptional activity in a positive feedback loop with glycolysis, revealed two new regulatory circuits controlling FOXK2 protein levels and metabolic output.","evidence":"Co-IP, domain mapping, in vitro kinase assay, ubiquitination assay, ChIP, luciferase reporters, Fbxo24 heterozygous mouse model","pmids":["38735474","38734828"],"confidence":"High","gaps":["Signals triggering FBXO24-mediated degradation not identified","Whether PDK2 phosphorylation affects FOXK2 interaction with BAP1 or corepressors unknown","Mitochondrial function of FOXK2 detected by fractionation but mechanism undefined"]},{"year":2024,"claim":"KSHV ORF45 hijacks FOXK2's FHA domain through a phospho-Thr-containing linear motif to augment FOXK2 occupancy on late viral promoters, establishing FOXK2 as a host factor co-opted for herpesviral lytic gene expression.","evidence":"Co-IP, pulldown, mutagenesis of ORF45 interaction motif, ChIP, siRNA, viral gene expression assays","pmids":["39494902","39287387"],"confidence":"High","gaps":["Whether other viruses exploit FOXK2's FHA domain unknown","Cellular consequences of ORF45 competition with BAP1 for FHA domain not tested"]},{"year":2025,"claim":"FOXK2 was shown to directly activate CCNB1/CDK1 and PPARγ to drive cardiomyocyte proliferation and adipogenesis, respectively, with PI3K/mTOR-dependent nuclear entry and positive feedback loops, broadening its role as a metabolic-proliferative transcription factor across differentiation contexts.","evidence":"Cardiomyocyte-specific KO, AAV9 OE, ChIP, MI model, adipogenic differentiation assays, pharmacological inhibitors","pmids":["40128196","39789420"],"confidence":"High","gaps":["Tissue-specific cofactors determining target gene selection undefined","Whether FOXK1 and FOXK2 are functionally redundant in these contexts not fully resolved"]},{"year":2025,"claim":"Identification of FOXK2 mutations as causative for congenital myopathy with ptosis, with KO models showing impaired myogenic differentiation, disrupted mitochondrial homeostasis, and rescue by Coenzyme Q10, established the first Mendelian disease caused by FOXK2 deficiency.","evidence":"Whole exome sequencing in patients, zebrafish and mouse muscle-specific KO, ATAC-seq, mitochondrial assays, CoQ10 rescue","pmids":["40410591"],"confidence":"High","gaps":["Specific FOXK2 target genes mediating CoQ10-responsive mitochondrial defect not fully enumerated","Genotype-phenotype correlation across different FOXK2 mutations not established","Whether congenital myopathy involves loss of metabolic or corepressor functions (or both) not dissected"]},{"year":null,"claim":"Key unresolved questions include: how FOXK2 selects among its multiple corepressor and coactivator complexes at individual loci; the direct Akt/mTOR phosphorylation sites controlling nuclear import; the structural basis of FHA domain interactions with BAP1, PDK2, and ORF45; and whether the mitochondrial pool of FOXK2 has a transcription-independent function.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of FOXK2 FHA domain with any partner","Direct phosphorylation sites for Akt-mediated nuclear import not mapped","Mitochondrial function of FOXK2 detected but mechanism undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,2,3,4,9,12,14]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,3,8,10,12,14,21,23]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[6]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,9,11,13,16,23]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[11]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[18]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3,8,10,12,14,21,23]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[4,5,22]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[10,11,19,21]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1,21]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[11,14,24]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[6,9,13,16,18]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[22,23]}],"complexes":["PR-DUB (BAP1–ASXL)","SIN3A corepressor complex","NCoR/SMRT corepressor complex","NuRD complex"],"partners":["BAP1","PIAS4","FBXO24","BARD1","SIRT1","CBP","HCF1","PDK2"],"other_free_text":[]},"mechanistic_narrative":"FOXK2 is a forkhead-box transcription factor that integrates signal-dependent nuclear-cytoplasmic shuttling with chromatin remodeling to control cell proliferation, metabolic reprogramming, and differentiation. Its FHA domain recruits the BAP1 deubiquitinase complex (via phospho-Thr493 on BAP1) and multiple corepressor complexes (SIN3A, NCoR/SMRT, NuRD, REST/CoREST) to repress target genes including HIF1β and EZH2, while it also functions as a transcriptional activator of glycolytic enzymes, CCNB1/CDK1, PPARγ, IRE1α, and VEGFA through direct promoter or enhancer binding [PMID:25451922, PMID:27773593, PMID:30700909, PMID:35349489, PMID:40128196, PMID:39789420]. Nuclear entry and transcriptional output are controlled by insulin/Akt–mTOR signaling (promoting nuclear translocation opposed by GSK3-mediated cytoplasmic retention), PIAS4-mediated SUMOylation at K527/K633, CBP acetylation at K223 counteracted by SIRT1 deacetylation, CDK1/2 phosphorylation at S368/S423 during mitosis, PDK2 phosphorylation at T13/S30, and FBXO24-mediated polyubiquitylation leading to proteasomal degradation [PMID:30952843, PMID:36682222, PMID:34866322, PMID:20810654, PMID:38734828, PMID:38735474]. Loss-of-function mutations in FOXK2 cause congenital myopathy with ptosis, linked to impaired myogenic differentiation and disrupted mitochondrial homeostasis in muscle stem cells [PMID:40410591]."},"prefetch_data":{"uniprot":{"accession":"Q01167","full_name":"Forkhead box protein K2","aliases":["G/T-mismatch specific binding protein","nGTBP","Interleukin enhancer-binding factor 1"],"length_aa":660,"mass_kda":69.1,"function":"Transcriptional regulator involved in different processes such as glucose metabolism, aerobic glycolysis and autophagy (PubMed:38735474). Recognizes and binds the forkhead DNA sequence motif (5'-GTAAACA-3') and can both act as a transcription activator or repressor, depending on the context (PubMed:22083952, PubMed:25451922). Together with FOXK1, acts as a key regulator of metabolic reprogramming towards aerobic glycolysis, a process in which glucose is converted to lactate in the presence of oxygen (By similarity). Acts by promoting expression of enzymes for glycolysis (such as hexokinase-2 (HK2), phosphofructokinase, pyruvate kinase (PKLR) and lactate dehydrogenase), while suppressing further oxidation of pyruvate in the mitochondria by up-regulating pyruvate dehydrogenase kinases PDK1 and PDK4 (By similarity). Probably plays a role in gluconeogenesis during overnight fasting, when lactate from white adipose tissue and muscle is the main substrate (By similarity). Together with FOXK1, acts as a negative regulator of autophagy in skeletal muscle: in response to starvation, enters the nucleus, binds the promoters of autophagy genes and represses their expression, preventing proteolysis of skeletal muscle proteins (By similarity). In addition to the 5'-GTAAACA-3' DNA motif, also binds the 5'-TGANTCA-3' palindromic DNA motif, and co-associates with JUN/AP-1 to activate transcription (PubMed:22083952). Also able to bind to a minimal DNA heteroduplex containing a G/T-mismatch with 5'-TRT[G/T]NB-3' sequence (PubMed:20097901). Binds to NFAT-like motifs (purine-rich) in the IL2 promoter (PubMed:1339390). Positively regulates WNT/beta-catenin signaling by translocating DVL proteins into the nucleus (PubMed:25805136). Also binds to HIV-1 long terminal repeat. May be involved in both positive and negative regulation of important viral and cellular promoter elements (PubMed:1909027). Accessory component of the polycomb repressive deubiquitinase (PR-DUB) complex; recruits the PR-DUB complex to specific FOXK2-bound genes (PubMed:24634419, PubMed:30664650)","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q01167/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FOXK2","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PPM1G","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/FOXK2","total_profiled":1310},"omim":[{"mim_id":"619458","title":"METHYL-CpG-BINDING DOMAIN PROTEIN 6; MBD6","url":"https://www.omim.org/entry/619458"},{"mim_id":"616302","title":"FORKHEAD BOX K1; FOXK1","url":"https://www.omim.org/entry/616302"},{"mim_id":"147685","title":"FORKHEAD BOX K2; FOXK2","url":"https://www.omim.org/entry/147685"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"},{"location":"Mitochondria","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/FOXK2"},"hgnc":{"alias_symbol":[],"prev_symbol":["ILF","ILF1"]},"alphafold":{"accession":"Q01167","domains":[{"cath_id":"2.60.200.20","chopping":"39-86_108-157","consensus_level":"high","plddt":90.5026,"start":39,"end":157},{"cath_id":"1.10.10.10","chopping":"264-348","consensus_level":"high","plddt":94.0076,"start":264,"end":348}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q01167","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q01167-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q01167-F1-predicted_aligned_error_v6.png","plddt_mean":56.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FOXK2","jax_strain_url":"https://www.jax.org/strain/search?query=FOXK2"},"sequence":{"accession":"Q01167","fasta_url":"https://rest.uniprot.org/uniprotkb/Q01167.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q01167/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q01167"}},"corpus_meta":[{"pmid":"30700909","id":"PMC_30700909","title":"FOXK1 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\"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro DNA binding assay with domain mapping, single study\",\n      \"pmids\": [\"1339390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"FOXK2 is phosphorylated by CDK1·cyclin B (and also CDK2·cyclin A) at serines 368 and 423 during mitosis; these phosphorylation events regulate FOXK2 protein stability and its activity as a transcriptional repressor, and expression of a mutant lacking these sites causes apoptosis.\",\n      \"method\": \"Cell cycle synchronization, CDK kinase assays, site-directed mutagenesis, transcriptional reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro kinase assay with mutagenesis, multiple functional readouts in single study\",\n      \"pmids\": [\"20810654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The forkhead domain of FOXK2 binds G/T-mismatch DNA with higher affinity than matched consensus DNA; it also recognizes hypoxanthine/T and G/uracil mispairs; EMSA with anti-FOXK2 antibody confirmed FOXK2 is the G/T-mismatch binding activity in HL60 nuclear extracts.\",\n      \"method\": \"Expression library screening for mismatch DNA binding, EMSA, antibody supershift, recombinant domain binding assays\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro binding assay with recombinant protein and nuclear extract confirmation, single lab\",\n      \"pmids\": [\"20097901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"FOXK2 binds genome-wide regulatory regions that are co-associated with AP-1 binding motifs and is required for efficient recruitment of AP-1 to chromatin and subsequent AP-1-dependent gene expression changes.\",\n      \"method\": \"ChIP-seq, genome-wide binding analysis, ChIP-qPCR, gene expression analysis after knockdown\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal ChIP, genome-wide binding, functional KD with defined chromatin recruitment phenotype\",\n      \"pmids\": [\"22083952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FOXK2 binds the SIN3A and PR-DUB (BAP1-containing) complexes; FOXK2 recruits BAP1 to specific genomic loci via its forkhead-associated (FHA) domain, promotes local histone H2A deubiquitination, and thereby alters target gene activity.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, histone deubiquitination assays, domain mapping\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, ChIP, functional deubiquitination assay, multiple orthogonal methods\",\n      \"pmids\": [\"24748658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FOXK2 recruits BAP1 to target gene loci through its FHA domain, which recognizes phospho-Thr493 on BAP1; BAP1 in turn recruits HCF-1, forming a ternary FOXK2–BAP1–HCF-1 complex; BAP1 DUB activity (but not HCF-1 interaction) is required to repress FOXK2 target genes; BAP1 depletion causes Ring1B–Bmi1-dependent upregulation of these targets.\",\n      \"method\": \"Co-immunoprecipitation, pulldown, deubiquitinase activity assays, RNAi knockdown, epistasis with Ring1B-Bmi1\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biochemical reconstitution of complex, enzymatic activity requirement, genetic epistasis\",\n      \"pmids\": [\"25451922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FOXK2 interacts with ERα and with BARD1 (of the BRCA1/BARD1 E3 ubiquitin ligase), acting as a scaffold to bring BRCA1/BARD1 and ERα together, thereby enhancing ubiquitin-mediated degradation of ERα and reducing its transcriptional activity; knockdown of both FOXK2 and ERα abolished the proliferative effect of FOXK2 KD.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, reporter assays, siRNA knockdown, proliferation assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, ubiquitination assay, genetic epistasis by double KD, multiple orthogonal methods\",\n      \"pmids\": [\"25740706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FoxK2 knockdown in neural/proliferating cells decreases BrdU incorporation and H3 phosphorylation (proliferation markers), increases caspase 3 activity and cell death, upregulates pro-apoptotic Puma and Noxa, and increases p70S6K phosphorylation; rapamycin blocks p70S6K increase and synergizes with FoxK2 KD on proliferation but not apoptosis, indicating mTOR forms a compensatory feedback loop.\",\n      \"method\": \"siRNA knockdown, BrdU incorporation, caspase activity assay, flow cytometry, qRT-PCR, Western blot, rapamycin epistasis\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD with multiple defined readouts and pharmacological epistasis, single lab\",\n      \"pmids\": [\"25216324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FOXK2 interacts with transcription corepressor complexes NCoR/SMRT, SIN3A, NuRD, and REST/CoREST to repress a cohort of genes including HIF1β and EZH2, suppressing the hypoxic response; ERα transactivates FOXK2, and HIF1β/EZH2 reciprocally repress FOXK2 expression in a feedback loop.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, gene expression analysis, luciferase reporter assays, KD/OE functional assays\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple Co-IPs with distinct complexes, ChIP, functional epistasis, multiple orthogonal methods, highly cited\",\n      \"pmids\": [\"27773593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FOXK2 is SUMOylated at lysines 527 and 633; SUMOylation-defective mutants (K527/633R) are unable to bind the FOXO3 promoter by ChIP and fail to upregulate FOXO3 transcription, reducing paclitaxel sensitivity, despite similar protein levels and subcellular localization to wild-type FOXK2.\",\n      \"method\": \"Site-directed mutagenesis of SUMO consensus sites, ChIP, cell viability/clonogenic assays, qRT-PCR, Western blot\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis of modification sites with ChIP and functional readout, multiple orthogonal methods\",\n      \"pmids\": [\"29540677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FOXK1 and FOXK2 induce aerobic glycolysis by transcriptionally upregulating glycolytic enzymes (hexokinase-2, phosphofructokinase, pyruvate kinase, lactate dehydrogenase) and pyruvate dehydrogenase kinases 1 and 4 (PDK1/4), while suppressing pyruvate dehydrogenase phosphatase 1 (PDP1), resulting in increased phosphorylation of pyruvate dehydrogenase E1α subunit and inhibition of mitochondrial pyruvate oxidation.\",\n      \"method\": \"KO/KD and overexpression in cell lines and primary human cells, metabolic flux assays, gene expression profiling, in vivo mouse experiments\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (KO, KD, OE, metabolomics, in vivo), replicated in multiple cell types and in vivo, highly cited\",\n      \"pmids\": [\"30700909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FoxK1 and FoxK2 nuclear translocation following insulin stimulation is dependent on the Akt–mTOR pathway, while cytoplasmic retention in basal state depends on GSK3; this translocation is reciprocal to FoxO1 nuclear-to-cytoplasmic translocation. Knockdown reduces lipid metabolism and cell proliferation genes and alters mitochondrial fatty acid metabolism.\",\n      \"method\": \"Subcellular fractionation, live-cell imaging of translocation, pharmacological inhibitors (Akt, mTOR, GSK3), siRNA knockdown, RNA-seq, metabolic assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiments with functional consequences, pharmacological epistasis, RNA-seq, multiple orthogonal methods\",\n      \"pmids\": [\"30952843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FOXK2 directly regulates IRE1α (ERN1) expression by binding to an intronic regulatory enhancer element of the ERN1 gene, as shown by ChIP-seq; blocking this binding with dCas9 diminished IRE1α transcription; FOXK2-driven IRE1α upregulation leads to alternative XBP1 splicing and activation of stemness pathways in ovarian cancer stem cells.\",\n      \"method\": \"ChIP-seq, CRISPR/dCas9 enhancer blocking, RNA-seq, genetic depletion with stem cell functional assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP-seq + dCas9 enhancer blocking + functional readout, multiple orthogonal methods\",\n      \"pmids\": [\"35349489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FOXK2 is acetylated at K223 by the acetyltransferase CBP (CREB-binding protein) and deacetylated by SIRT1; cisplatin attenuates FOXK2–SIRT1 interaction; FOXK2 K223 acetylation reduces its nuclear localization and promotes mitotic catastrophe, enhancing chemosensitivity to cisplatin.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis (K223), Western blot for acetylation, subcellular fractionation, SIRT1 inhibitor experiments, in vitro and in vivo functional assays\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — identification of writer (CBP) and eraser (SIRT1) with mutagenesis and functional consequences, multiple methods\",\n      \"pmids\": [\"34866322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FOXK2 transcriptionally activates VEGFA by binding directly to its promoter, promoting angiogenesis; VEGFA produced by FOXK2-expressing cells binds VEGFR1 as a compensatory mechanism when VEGFR2 is blocked, activating ERK, PI3K/AKT, and P38/MAPK; a positive feedback loop exists in which VEGFA/VEGFR1 signaling further promotes FOXK2-mediated VEGFA transcription.\",\n      \"method\": \"RNA-seq, ChIP-seq, ChIP, dual-luciferase reporter assay, functional angiogenesis assays, pharmacological VEGFR inhibition\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP-seq and ChIP confirming direct promoter binding, luciferase validation, multiple functional assays\",\n      \"pmids\": [\"34489549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FOXK2 promotes AP-1-mediated transcription by being required for efficient recruitment of AP-1 to chromatin; FOXK2 binding regions genome-wide are co-associated with AP-1 binding motifs.\",\n      \"method\": \"ChIP-seq, ChIP-qPCR, gene expression analysis, functional assays with AP-1 pathway activation\",\n      \"journal\": \"Nucleic acids research (2021 paper on ESC premarking)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP-seq plus functional differentiation assays, single lab\",\n      \"pmids\": [\"33434264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FOXK2 is SUMOylated by PIAS4, which promotes FOXK2 nuclear translocation; nuclear FOXK2 then binds promoters of nucleotide de novo synthesis genes and activates their transcription; DNA damage suppresses FOXK2 SUMOylation; elevated FOXK2 SUMOylation promotes nucleotide synthesis and causes resistance to 5-FU.\",\n      \"method\": \"ChIP-seq, RNA-seq, luciferase promoter assay, SUMO modification assays, subcellular fractionation, in vitro and in vivo functional assays\",\n      \"journal\": \"Drug resistance updates\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — identification of SUMO E3 ligase (PIAS4), ChIP-seq for binding, functional and localization readouts, multiple methods\",\n      \"pmids\": [\"36682222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FOXK2 is SUMOylated by PIAS4 leading to nuclear translocation and transcriptional activation of nucleotide synthetic genes; DNA damage represses this SUMOylation and reduces resistance to chemotherapy.\",\n      \"method\": \"ChIP-seq, RNA-seq, SUMO modification assays, subcellular fractionation\",\n      \"journal\": \"Drug resistance updates\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods linking PTM to localization and function\",\n      \"pmids\": [\"36682222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FOXK2 is polyubiquitylated by the SCF E3 ligase subunit FBXO24 via the FOXK2 carboxyl terminus (aa 428–478), leading to nuclear proteasomal degradation of FOXK2; FOXK2 is also detected within mitochondria and its depletion or expression of mutants lacking key C-terminal domains impairs mitochondrial function; Fbxo24 heterozygous mice show preserved mitochondrial function and FOXK2 levels during bacterial pneumonia.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, ubiquitination assays, subcellular fractionation (mitochondrial), in vivo mouse genetic model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — Co-IP, domain mapping, ubiquitination assay, in vivo genetic model, multiple orthogonal methods\",\n      \"pmids\": [\"38735474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PDK2 directly binds the forkhead-associated (FHA) domain of FOXK2 and phosphorylates FOXK2 at Thr13 and Ser30, enhancing its transcriptional activity; FOXK2 transcriptionally regulates PDK2 expression, forming a positive feedback loop sustaining glycolysis in ovarian cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis, ChIP, luciferase reporter assay, in vitro and in vivo functional assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — kinase assay, domain mapping, mutagenesis, ChIP, feedback loop demonstrated with multiple methods\",\n      \"pmids\": [\"38734828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FOXK1 and FOXK2 are ORF45-binding proteins; ORF45 (KSHV immediate early tegument protein) interacts with the FHA domains of FOXK1 and FOXK2 through a conserved short linear serine/threonine-rich motif (a single threonine point mutation abolishes interaction); ORF45 augments FOXK1/2 occupancy on late viral gene promoters and their transcriptional activity to promote late KSHV lytic replication.\",\n      \"method\": \"Co-immunoprecipitation, pulldown, ChIP, site-directed mutagenesis of ORF45 interaction motif, viral gene expression assays, siRNA knockdown\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, mutagenesis of interaction motif, ChIP for chromatin binding, functional viral assays, multiple orthogonal methods\",\n      \"pmids\": [\"39494902\", \"39287387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Foxk1 and Foxk2 directly activate CCNB1 (cyclin B1) and CDK1 expression in cardiomyocytes; the resulting CCNB1/CDK1 complex facilitates G2/M transition; Foxk1/2 also upregulate HIF1α to enhance glycolysis and the pentose phosphate pathway, promoting cardiomyocyte proliferation; cardiomyocyte-specific knockout impairs neonatal heart regeneration after MI.\",\n      \"method\": \"Cardiomyocyte-specific KO, AAV9 overexpression, ChIP, cell cycle analysis, metabolic assays, myocardial infarction model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — tissue-specific KO with defined phenotype, ChIP showing direct gene activation, multiple mechanisms validated in vivo\",\n      \"pmids\": [\"40128196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FOXK2 mutations cause congenital myopathy with ptosis; FOXK2 deficiency impairs myogenic differentiation and disrupts mitochondrial homeostasis in muscle stem cells and C2C12 cells; FOXK2 directly regulates expression of mitochondrial function-related genes by modulating chromatin accessibility at its binding sites; Coenzyme Q10 treatment rescued mitochondrial function and skeletal muscle defects in Foxk2-deficient mice.\",\n      \"method\": \"Whole exome sequencing, zebrafish foxk2 KO, mouse muscle stem cell-specific KO, ATAC-seq, gene expression analysis, mitochondrial functional assays, rescue experiments\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple model organisms (zebrafish, mouse KO), ATAC-seq for chromatin regulation, functional rescue, multiple orthogonal methods\",\n      \"pmids\": [\"40410591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Foxk2 nuclear translocation during adipogenic differentiation is driven by PI3-kinase and mTOR signaling; once nuclear, Foxk2 binds the promoters of Pparγ1 and Pparγ2 to enhance their transcription; PPARγ1 and PPARγ2 reciprocally augment Foxk2 promoter transcriptional activity, forming a Foxk2–PPARγ positive feedback loop driving adipogenesis.\",\n      \"method\": \"Overexpression/knockdown, subcellular fractionation/nuclear translocation assays, PI3K and mTOR inhibitors, ChIP on Pparγ promoters, luciferase reporter assays, adipogenic differentiation assays\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP for direct promoter binding, pharmacological epistasis for localization, functional reporter assays, multiple orthogonal methods\",\n      \"pmids\": [\"39789420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FOXK2 interacts with both mTOR and DRP1 (detected by co-immunoprecipitation); FOXK2 promotes phosphorylation of mTOR and upregulates CPT1A (fatty acid oxidation) while downregulating ACC1 and FASN (lipogenesis), thereby regulating lipid metabolic reprogramming in cervical cancer via the mTOR/DRP1 signaling axis.\",\n      \"method\": \"Co-immunoprecipitation, Western blot, OCR measurement, in vivo xenograft\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP for interaction, metabolic assays, single lab, limited mechanistic depth for mTOR phosphorylation\",\n      \"pmids\": [\"40641601\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FOXK2 is a ubiquitously expressed forkhead transcription factor that functions as both a transcriptional repressor and activator depending on context: it recruits corepressor complexes (SIN3A, NCoR/SMRT, NuRD, REST/CoREST) and the BAP1-containing PR-DUB deubiquitinase complex to repress target genes (via its FHA domain interacting with phospho-Thr493 of BAP1), while also promoting AP-1-dependent gene activation and directly activating glycolytic enzyme genes, IRE1α, CCNB1/CDK1, and PPARγ; its activity and localization are regulated by CDK1/2-mediated phosphorylation (S368/S423) during mitosis, insulin/Akt-mTOR and GSK3 pathways controlling nuclear-cytoplasmic shuttling, PIAS4-mediated SUMOylation (K527/K633) promoting nuclear translocation and transcriptional activity, CBP-mediated acetylation (K223) and SIRT1-mediated deacetylation controlling nuclear localization and drug sensitivity, and FBXO24-mediated polyubiquitylation leading to proteasomal degradation; PDK2 also phosphorylates FOXK2 at T13/S30 to enhance its transcriptional output in a positive feedback loop sustaining glycolysis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"FOXK2 is a forkhead-box transcription factor that integrates signal-dependent nuclear-cytoplasmic shuttling with chromatin remodeling to control cell proliferation, metabolic reprogramming, and differentiation. Its FHA domain recruits the BAP1 deubiquitinase complex (via phospho-Thr493 on BAP1) and multiple corepressor complexes (SIN3A, NCoR/SMRT, NuRD, REST/CoREST) to repress target genes including HIF1β and EZH2, while it also functions as a transcriptional activator of glycolytic enzymes, CCNB1/CDK1, PPARγ, IRE1α, and VEGFA through direct promoter or enhancer binding [PMID:25451922, PMID:27773593, PMID:30700909, PMID:35349489, PMID:40128196, PMID:39789420]. Nuclear entry and transcriptional output are controlled by insulin/Akt–mTOR signaling (promoting nuclear translocation opposed by GSK3-mediated cytoplasmic retention), PIAS4-mediated SUMOylation at K527/K633, CBP acetylation at K223 counteracted by SIRT1 deacetylation, CDK1/2 phosphorylation at S368/S423 during mitosis, PDK2 phosphorylation at T13/S30, and FBXO24-mediated polyubiquitylation leading to proteasomal degradation [PMID:30952843, PMID:36682222, PMID:34866322, PMID:20810654, PMID:38734828, PMID:38735474]. Loss-of-function mutations in FOXK2 cause congenital myopathy with ptosis, linked to impaired myogenic differentiation and disrupted mitochondrial homeostasis in muscle stem cells [PMID:40410591].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Identification of FOXK2 as a forkhead-domain transcription factor established that it uses this domain for sequence-specific DNA binding to purine-rich regulatory elements, providing the first molecular handle on the gene.\",\n      \"evidence\": \"EMSA and expression library screening with HIV-1 LTR and IL-2 promoter probes\",\n      \"pmids\": [\"1339390\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous genomic targets unknown\", \"No functional consequence of DNA binding demonstrated\", \"In vitro binding only, no chromatin context\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstration that CDK1/cyclin B and CDK2/cyclin A phosphorylate FOXK2 at S368 and S423 during mitosis revealed the first regulatory post-translational modification controlling its stability and repressor activity, and showed that disrupting this regulation triggers apoptosis.\",\n      \"evidence\": \"In vitro kinase assays, site-directed mutagenesis, cell cycle synchronization, transcriptional reporters\",\n      \"pmids\": [\"20810654\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphatase(s) reversing these modifications unidentified\", \"Downstream apoptotic pathway not fully dissected\", \"In vivo relevance not tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Discovery that FOXK2's forkhead domain binds G/T-mismatch DNA with higher affinity than matched consensus raised the possibility of a non-canonical role in DNA damage recognition, though functional consequences remain unclear.\",\n      \"evidence\": \"EMSA with recombinant forkhead domain and antibody supershift in HL60 nuclear extracts\",\n      \"pmids\": [\"20097901\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No demonstration of mismatch repair activity\", \"Physiological relevance of mismatch binding untested\", \"Single-lab finding without in vivo validation\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Genome-wide ChIP-seq showed FOXK2 binding sites are enriched for AP-1 motifs and that FOXK2 is required for efficient AP-1 chromatin recruitment, establishing FOXK2 as a pioneer or cooperative factor for AP-1-dependent transcription.\",\n      \"evidence\": \"ChIP-seq, ChIP-qPCR, knockdown with gene expression analysis\",\n      \"pmids\": [\"22083952\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of cooperative binding (direct interaction vs. chromatin remodeling) not resolved\", \"AP-1 subunit specificity not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Biochemical dissection of the FOXK2–BAP1 axis showed that the FHA domain of FOXK2 recognizes phospho-Thr493 on BAP1 to recruit the PR-DUB complex to chromatin, where BAP1's deubiquitinase activity on H2AK119ub is required for target gene repression — establishing FOXK2 as a sequence-specific recruiter of an epigenetic eraser.\",\n      \"evidence\": \"Co-IP, pulldown, domain mapping, histone deubiquitination assays, ChIP, RNAi epistasis with Ring1B–Bmi1\",\n      \"pmids\": [\"24748658\", \"25451922\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase phosphorylating BAP1 T493 to enable FOXK2 interaction not identified in these studies\", \"Structural basis of FHA–pThr recognition not resolved\", \"Genome-wide extent of FOXK2-dependent H2A deubiquitination not mapped\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"FOXK2 was shown to scaffold the BRCA1/BARD1 E3 ligase onto ERα, promoting ERα ubiquitylation and degradation, revealing a non-transcriptional adaptor function in protein turnover that links FOXK2 to estrogen signaling and breast cancer cell proliferation.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, reporter assays, double knockdown epistasis\",\n      \"pmids\": [\"25740706\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether FOXK2 scaffolding of BRCA1/BARD1 extends to other substrates unknown\", \"Structural basis of tripartite complex not resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identification of FOXK2 interactions with four distinct corepressor complexes (NCoR/SMRT, SIN3A, NuRD, REST/CoREST) and its repression of HIF1β and EZH2 positioned FOXK2 as a multi-complex transcriptional repressor that suppresses the hypoxic response.\",\n      \"evidence\": \"Co-IP with multiple complexes, ChIP, knockdown/overexpression, luciferase reporters\",\n      \"pmids\": [\"27773593\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How FOXK2 selects among different corepressor complexes at specific loci unknown\", \"Stoichiometry of complex engagement at individual promoters not determined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Mapping SUMOylation at K527 and K633 and showing that these modifications are required for FOXK2 binding to the FOXO3 promoter and for paclitaxel sensitivity established SUMOylation as a critical activating switch for FOXK2's transcriptional function.\",\n      \"evidence\": \"SUMO-site mutagenesis, ChIP, clonogenic and viability assays\",\n      \"pmids\": [\"29540677\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SUMO E3 ligase responsible not identified in this study (later found to be PIAS4)\", \"Mechanism by which SUMO modification enables DNA binding unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Two landmark studies established FOXK2 (with FOXK1) as a master metabolic switch: it transcriptionally upregulates glycolytic enzymes and PDK1/4 while suppressing PDP1 to drive aerobic glycolysis, and its nuclear translocation is controlled by the insulin–Akt–mTOR axis opposed by GSK3 cytoplasmic retention — linking growth factor signaling to metabolic gene programs.\",\n      \"evidence\": \"KO/KD/OE in multiple cell types and in vivo mice, metabolic flux assays, subcellular fractionation, pharmacological inhibitors, RNA-seq\",\n      \"pmids\": [\"30700909\", \"30952843\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct phosphorylation sites mediating Akt/mTOR-dependent nuclear import not mapped\", \"Relative contributions of FOXK1 vs FOXK2 to glycolytic regulation not fully separated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Multiple 2021 studies expanded FOXK2's transcriptional target repertoire to include IRE1α (via intronic enhancer binding driving UPR/stemness), VEGFA (driving angiogenesis with a VEGFR1-mediated feedback loop), and identified CBP-mediated K223 acetylation counteracted by SIRT1 as a regulatory switch controlling nuclear localization and chemosensitivity.\",\n      \"evidence\": \"ChIP-seq, dCas9 enhancer blocking, luciferase reporters, site-directed mutagenesis of K223, subcellular fractionation, in vivo assays\",\n      \"pmids\": [\"35349489\", \"34489549\", \"34866322\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay between acetylation and SUMOylation on the same FOXK2 molecule not explored\", \"Tissue specificity of enhancer-level regulation (e.g., IRE1α) not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identification of PIAS4 as the SUMO E3 ligase for FOXK2 completed the SUMOylation pathway: PIAS4-mediated SUMOylation drives nuclear translocation and activates nucleotide de novo synthesis genes, while DNA damage suppresses this modification, explaining 5-FU chemoresistance.\",\n      \"evidence\": \"ChIP-seq, RNA-seq, SUMO modification assays, subcellular fractionation, in vivo functional assays\",\n      \"pmids\": [\"36682222\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"De-SUMOylation enzyme (SENP) for FOXK2 not identified\", \"Whether DNA damage signals directly to PIAS4 or to FOXK2 to suppress SUMOylation unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Discovery that FBXO24 polyubiquitylates FOXK2 via its C-terminus for proteasomal degradation, and that PDK2 phosphorylates FOXK2 at T13/S30 via the FHA domain to enhance transcriptional activity in a positive feedback loop with glycolysis, revealed two new regulatory circuits controlling FOXK2 protein levels and metabolic output.\",\n      \"evidence\": \"Co-IP, domain mapping, in vitro kinase assay, ubiquitination assay, ChIP, luciferase reporters, Fbxo24 heterozygous mouse model\",\n      \"pmids\": [\"38735474\", \"38734828\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals triggering FBXO24-mediated degradation not identified\", \"Whether PDK2 phosphorylation affects FOXK2 interaction with BAP1 or corepressors unknown\", \"Mitochondrial function of FOXK2 detected by fractionation but mechanism undefined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"KSHV ORF45 hijacks FOXK2's FHA domain through a phospho-Thr-containing linear motif to augment FOXK2 occupancy on late viral promoters, establishing FOXK2 as a host factor co-opted for herpesviral lytic gene expression.\",\n      \"evidence\": \"Co-IP, pulldown, mutagenesis of ORF45 interaction motif, ChIP, siRNA, viral gene expression assays\",\n      \"pmids\": [\"39494902\", \"39287387\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other viruses exploit FOXK2's FHA domain unknown\", \"Cellular consequences of ORF45 competition with BAP1 for FHA domain not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"FOXK2 was shown to directly activate CCNB1/CDK1 and PPARγ to drive cardiomyocyte proliferation and adipogenesis, respectively, with PI3K/mTOR-dependent nuclear entry and positive feedback loops, broadening its role as a metabolic-proliferative transcription factor across differentiation contexts.\",\n      \"evidence\": \"Cardiomyocyte-specific KO, AAV9 OE, ChIP, MI model, adipogenic differentiation assays, pharmacological inhibitors\",\n      \"pmids\": [\"40128196\", \"39789420\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific cofactors determining target gene selection undefined\", \"Whether FOXK1 and FOXK2 are functionally redundant in these contexts not fully resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identification of FOXK2 mutations as causative for congenital myopathy with ptosis, with KO models showing impaired myogenic differentiation, disrupted mitochondrial homeostasis, and rescue by Coenzyme Q10, established the first Mendelian disease caused by FOXK2 deficiency.\",\n      \"evidence\": \"Whole exome sequencing in patients, zebrafish and mouse muscle-specific KO, ATAC-seq, mitochondrial assays, CoQ10 rescue\",\n      \"pmids\": [\"40410591\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific FOXK2 target genes mediating CoQ10-responsive mitochondrial defect not fully enumerated\", \"Genotype-phenotype correlation across different FOXK2 mutations not established\", \"Whether congenital myopathy involves loss of metabolic or corepressor functions (or both) not dissected\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: how FOXK2 selects among its multiple corepressor and coactivator complexes at individual loci; the direct Akt/mTOR phosphorylation sites controlling nuclear import; the structural basis of FHA domain interactions with BAP1, PDK2, and ORF45; and whether the mitochondrial pool of FOXK2 has a transcription-independent function.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of FOXK2 FHA domain with any partner\", \"Direct phosphorylation sites for Akt-mediated nuclear import not mapped\", \"Mitochondrial function of FOXK2 detected but mechanism undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 2, 3, 4, 9, 12, 14]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 3, 8, 10, 12, 14, 21, 23]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 9, 11, 13, 16, 23]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 8, 10, 12, 14, 21, 23]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [4, 5, 22]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [10, 11, 19, 21]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 21]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [11, 14, 24]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [6, 9, 13, 16, 18]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [22, 23]}\n    ],\n    \"complexes\": [\n      \"PR-DUB (BAP1–ASXL)\",\n      \"SIN3A corepressor complex\",\n      \"NCoR/SMRT corepressor complex\",\n      \"NuRD complex\"\n    ],\n    \"partners\": [\n      \"BAP1\",\n      \"PIAS4\",\n      \"FBXO24\",\n      \"BARD1\",\n      \"SIRT1\",\n      \"CBP\",\n      \"HCF1\",\n      \"PDK2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}