{"gene":"FOXK2","run_date":"2026-06-09T23:54:44","timeline":{"discoveries":[{"year":1992,"finding":"FOXK2 (then called ILF) was identified as a DNA-binding protein containing a forkhead domain; the forkhead domain is sufficient to mediate DNA binding to purine-rich regulatory sequences in the HIV-1 LTR and IL2 promoter.","method":"Gel retardation assay, cDNA characterization, chromosomal mapping","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vitro DNA binding assay with domain mapping, single lab, foundational characterization paper","pmids":["1339390"],"is_preprint":false},{"year":2010,"finding":"FOXK2 is phosphorylated by CDK1·cyclin B (primarily) and CDK2·cyclin A during mitosis; two phosphorylation sites, Ser368 and Ser423, regulate FOXK2 stability and its activity as a transcriptional repressor. Expression of a CDK phosphorylation-site mutant lacking these sites causes apoptosis.","method":"Cell cycle synchronization, kinase assays, site-directed mutagenesis, phosphorylation site mapping, transcriptional reporter assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay plus mutagenesis of specific sites, with functional phenotype (apoptosis), multiple orthogonal methods","pmids":["20810654"],"is_preprint":false},{"year":2010,"finding":"FOXK2 binds G/T-mismatch DNA through its forkhead domain with higher affinity than matched consensus DNA; it also recognizes hypoxanthine/T and G/uracil mismatches, identifying it as a novel mismatch DNA-binding protein.","method":"Electrophoretic mobility shift assay (EMSA), cDNA library screening, recombinant domain binding assays","journal":"Journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro binding assay with recombinant domain and nuclear extract antibody supershift, single lab","pmids":["20097901"],"is_preprint":false},{"year":2011,"finding":"FOXK2 promotes AP-1-dependent gene expression by facilitating the recruitment of AP-1 to chromatin; FOXK2 binding regions across the genome are frequently co-associated with AP-1 binding motifs.","method":"ChIP-seq, genome-wide binding analysis, gene expression profiling, chromatin recruitment assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal ChIP and genome-wide binding data with functional gene expression readout, multiple orthogonal methods","pmids":["22083952"],"is_preprint":false},{"year":2014,"finding":"FOXK2 binds the SIN3A and PR-DUB (BAP1-containing) complexes; FOXK2 recruits BAP1 to DNA via its forkhead-associated (FHA) domain, promotes local histone H2A deubiquitination, and causes changes in target gene activity.","method":"Co-immunoprecipitation, ChIP, histone modification assays, gene expression analysis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ChIP, and functional histone modification readout, multiple orthogonal methods in single study","pmids":["24748658"],"is_preprint":false},{"year":2014,"finding":"FOXK2 recruits BAP1 to target gene loci through its FHA domain, which interacts with phospho-Thr493 on BAP1; BAP1 in turn recruits HCF-1, forming a ternary complex (FOXK2–BAP1–HCF-1). BAP1 represses FOXK2 target genes in a manner requiring its deubiquitinase (DUB) activity but not HCF-1 interaction. BAP1 antagonizes the Ring1B-Bmi1 E3 ubiquitin ligase (H2A ubiquitination) at these loci.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, siRNA knockdown, DUB activity mutant analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with domain mapping (phospho-Thr493), functional DUB mutant, and epistasis with Ring1B-Bmi1, multiple orthogonal methods","pmids":["25451922"],"is_preprint":false},{"year":2015,"finding":"FOXK2 interacts with ERα and BARD1 (part of the BRCA1/BARD1 E3 ubiquitin ligase), acting as a scaffold to promote ubiquitin-mediated degradation of ERα, thereby reducing ERα transcriptional activity and inhibiting proliferation of ERα-positive breast cancer cells.","method":"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, transcriptional reporter assays, cell proliferation assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional ubiquitination assay, single lab, two orthogonal methods","pmids":["25740706"],"is_preprint":false},{"year":2015,"finding":"Knockdown of FoxK2 in proliferating cells reduces BrdU incorporation and H3 phosphorylation (proliferation arrest), and in the absence of growth factors causes caspase-3 activation and cell death. FoxK2 loss upregulates pro-apoptotic Bcl-2 family members Puma and Noxa. mTOR/p70S6K provides a compensatory feedback loop, as rapamycin synergizes with FoxK2 knockdown to further reduce H3 phosphorylation.","method":"siRNA knockdown, BrdU incorporation, flow cytometry, caspase-3 activity assay, qRT-PCR, rapamycin treatment","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with multiple cellular phenotype 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 target genes including HIF1β and EZH2. FOXK2 is transcriptionally activated by ERα, and repressed in a feedback loop by HIF1β/EZH2.","method":"Co-immunoprecipitation, ChIP, gene expression profiling, luciferase reporter assays, functional cell assays","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple Co-IPs identifying distinct corepressor complexes, ChIP, and functional gene repression readouts across multiple orthogonal methods","pmids":["27773593"],"is_preprint":false},{"year":2016,"finding":"SOX9 transcriptionally activates FOXK2 by directly binding to its promoter in colorectal cancer cells.","method":"ChIP, luciferase reporter assay, siRNA knockdown, qRT-PCR","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ChIP at FOXK2 promoter plus reporter assay, single lab","pmids":["28007600"],"is_preprint":false},{"year":2017,"finding":"FOXK2 directly suppresses N-cadherin and Snail expression (repressing EMT) and suppresses cyclin D1 and CDK4 expression (inhibiting proliferation) in NSCLC cells, as determined by ChIP-seq and luciferase reporter assays.","method":"ChIP-seq, qChIP, luciferase reporter assays, lentiviral overexpression/knockdown, cell invasion and proliferation assays","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq with functional reporter validation, single lab, multiple target readouts","pmids":["28260088"],"is_preprint":false},{"year":2018,"finding":"SUMOylation of FOXK2 at Lys527 and Lys633 is required for its transcriptional activity and ability to bind the FOXO3 promoter; SUMOylation-defective mutants (K527/633R or E529/635A) lose the ability to mediate paclitaxel cytotoxicity and fail to occupy the FOXO3 promoter despite normal protein levels and subcellular localization.","method":"Site-directed mutagenesis, ChIP, cell viability assays, clonogenic assays, subcellular fractionation","journal":"Oncogenesis","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis of specific SUMOylation sites with ChIP validation of promoter binding, plus functional cytotoxicity readout; single lab but 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 suppressing pyruvate oxidation in mitochondria by increasing pyruvate dehydrogenase kinases 1 and 4 and suppressing pyruvate dehydrogenase phosphatase 1, leading to increased phosphorylation of the E1α subunit of pyruvate dehydrogenase complex and diversion of pyruvate to lactate.","method":"Knockdown/overexpression in cell lines and in vivo models, metabolic flux assays, gene expression profiling, primary human cell studies","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — replicated in multiple cell types and in vivo, in vitro and in vivo experiments, multiple orthogonal metabolic readouts","pmids":["30700909"],"is_preprint":false},{"year":2019,"finding":"FoxK2 (and FoxK1) translocate from cytoplasm to nucleus following insulin stimulation; this nuclear translocation is dependent on the Akt-mTOR pathway, while cytoplasmic localization in the basal state is dependent on GSK3. This is reciprocal to FoxO1 nuclear-to-cytoplasmic translocation after insulin. Knockdown of FoxK1/FoxK2 in liver cells downregulates cell cycle/lipid metabolism genes and upregulates apoptosis genes, resulting in decreased proliferation and altered mitochondrial fatty acid metabolism.","method":"Subcellular fractionation, immunofluorescence, pathway inhibitor studies (Akt, mTOR, GSK3), siRNA knockdown, gene expression profiling, metabolic assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization experiments with pharmacological pathway dissection (Akt-mTOR vs. GSK3), replicated functional readouts, multiple orthogonal methods","pmids":["30952843"],"is_preprint":false},{"year":2021,"finding":"FOXK2 directly regulates IRE1α (ERN1) expression by binding to an intronic regulatory enhancer of ERN1; FOXK2-driven IRE1α upregulation leads to alternative XBP1 splicing and activation of stemness pathways in ovarian cancer stem cells. Blocking FOXK2 binding to this enhancer with dCas9 diminishes IRE1α transcription.","method":"ChIP-seq, CRISPR dCas9 enhancer blocking, RNA-seq, gene expression validation, tumor initiation assays","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1 / Strong — ChIP-seq with CRISPR/dCas9 functional validation of specific enhancer binding, multiple orthogonal methods in a single rigorous study","pmids":["35349489"],"is_preprint":false},{"year":2021,"finding":"FOXK2 is acetylated at Lys223 by the acetyltransferase CBP (cAMP response element binding protein); SIRT1 deacetylates FOXK2 at K223. Acetylation of K223 reduces nuclear localization of FOXK2 and promotes mitotic catastrophe, enhancing chemosensitivity to cisplatin. Cisplatin attenuates the FOXK2-SIRT1 interaction, leading to increased FOXK2 acetylation.","method":"Co-immunoprecipitation, site-directed mutagenesis (K223), subcellular fractionation, SIRT1 inhibitor treatment, in vitro and in vivo drug sensitivity assays","journal":"Journal of cellular and molecular medicine","confidence":"High","confidence_rationale":"Tier 1 / Moderate — identification of writer (CBP) and eraser (SIRT1) with K223 mutagenesis, localization change, and functional drug-sensitivity phenotype in vitro and in vivo","pmids":["34866322"],"is_preprint":false},{"year":2021,"finding":"FOXK2 transcriptionally activates VEGFA by directly binding the VEGFA promoter, promoting angiogenesis. FOXK2-induced VEGFA binds VEGFR1 as a compensatory mechanism when VEGFR2 is blocked, activating ERK, PI3K/AKT, and P38/MAPK signaling, thereby conferring resistance to VEGFR2 inhibitor (apatinib). This constitutes a positive feedback loop: VEGFA/VEGFR1 signaling further promotes FOXK2-mediated VEGFA transcription.","method":"ChIP-seq, RNA-seq, ChIP, dual-luciferase reporter, VEGFR1 inhibition, in vitro angiogenesis assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-seq and ChIP confirming direct VEGFA promoter binding, luciferase validation, pharmacological epistasis defining feedback loop, multiple orthogonal methods","pmids":["34489549"],"is_preprint":false},{"year":2021,"finding":"FOXK2 premarks lineage-specific regulatory regions in human embryonic stem cells (ESCs) before differentiation; its binding at thousands of regulatory regions is associated with active histone marks and predicts regions activated during neural precursor cell (NPC) differentiation. FOXK transcription factors have a role in gene activation during NPC differentiation.","method":"Genome-wide ChIP-seq in ESCs and differentiated cell types, histone mark analysis, FOXK2 knockdown during NPC differentiation","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide ChIP-seq with functional knockdown during differentiation, single lab","pmids":["33434264"],"is_preprint":false},{"year":2022,"finding":"FOXK2 is SUMOylated by PIAS4, which drives FOXK2 nuclear translocation, enabling it to bind promoters of nucleotide de novo synthesis genes and activate their transcription. DNA damage represses FOXK2 SUMOylation, and elevated FOXK2 SUMOylation promotes resistance to 5-FU in hepatocellular carcinoma.","method":"ChIP-seq, RNA-seq, luciferase promoter assay, SUMOylation assays, nuclear fractionation, DNA damage treatment, in vitro and in vivo drug resistance assays","journal":"Drug resistance updates","confidence":"High","confidence_rationale":"Tier 1 / Strong — identification of SUMOylation writer (PIAS4) with ChIP-seq validation of promoter binding, nuclear translocation, and functional drug resistance readout in vitro and in vivo","pmids":["36682222"],"is_preprint":false},{"year":2024,"finding":"FOXK2 is targeted for ubiquitin-mediated proteasomal degradation in the nucleus by the SCF E3 ligase subunit FBXO24, which binds FOXK2's carboxyl terminus (aa 428–478) and mediates multisite polyubiquitylation. FOXK2 is also detected within mitochondria, and its depletion or expression of carboxy-terminal mutants impairs mitochondrial function.","method":"Co-immunoprecipitation, ubiquitination assays, domain-deletion mutants, subcellular fractionation/mitochondrial localization, Fbxo24 heterozygous mouse model, bacterial pneumonia model","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — Co-IP with domain mapping, in vitro ubiquitination, in vivo mouse model validation, 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 FOXK2 transcriptional activity. FOXK2 in turn transcriptionally regulates PDK2 expression, forming a positive feedback loop that sustains glycolysis in ovarian cancer cells.","method":"Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis (Thr13, Ser30), ChIP, luciferase reporter assay, cell proliferation and migration assays, in vivo xenograft","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct binding (Co-IP with FHA domain), in vitro phosphorylation at defined sites, ChIP confirming FOXK2 binds PDK2 promoter, multiple orthogonal methods","pmids":["38734828"],"is_preprint":false},{"year":2024,"finding":"FOXK2 binds to the KSHV immediate-early tegument protein ORF45 via its forkhead-associated (FHA) domain, which recognizes a conserved serine/threonine-rich short linear motif in ORF45. ORF45 augments FOXK2 occupancy at late viral gene promoters and enhances FOXK2 transcriptional activity, promoting late KSHV lytic gene expression and virion production.","method":"Co-immunoprecipitation, point mutagenesis of ORF45 threonine motif, ChIP at viral promoters, siRNA knockdown of FOXK1/K2, lytic reactivation assays","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with FHA domain requirement, point mutation abolishing interaction, ChIP at viral promoters, functional lytic replication readout","pmids":["39494902","39287387"],"is_preprint":false},{"year":2024,"finding":"FOXK2 promotes adipogenic differentiation of bone marrow stromal cells by directly binding to the promoters of PPARγ1 and PPARγ2 and enhancing their transcriptional activation. Nuclear translocation of Foxk2 during adipogenic stimulation is dependent on PI3-kinase and mTOR signaling. A Foxk2–PPARγ positive feedback loop drives adipogenesis.","method":"ChIP, luciferase reporter assays, overexpression/knockdown, nuclear fractionation, pathway inhibitor studies","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirming promoter binding, reporter validation, pharmacological localization control, single lab","pmids":["39789420"],"is_preprint":false},{"year":2024,"finding":"FOXK2 interacts with SIRT2, and SIRT2 overexpression rescues the inhibition of EMT and glycolysis caused by FOXK2 knockdown in TGF-β1-treated bronchial epithelial cells, establishing that FOXK2 regulates EMT and glycolysis in a SIRT2-dependent manner.","method":"Co-immunoprecipitation, siRNA knockdown, SIRT2 overexpression rescue, EMT marker and glycolysis enzyme expression assays","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP validating FOXK2-SIRT2 binding plus epistasis rescue experiment, single lab","pmids":["38949649"],"is_preprint":false},{"year":2025,"finding":"Foxk1 and Foxk2 directly activate CCNB1 and CDK1 transcription, forming the CCNB1/CDK1 complex that facilitates G2/M transition and cardiomyocyte cell cycle progression. They also upregulate HIF1α expression to enhance glycolysis and the pentose phosphate pathway, further supporting cardiomyocyte proliferation. Cardiomyocyte-specific knockout of Foxk2 impairs neonatal heart regeneration after myocardial infarction.","method":"Cardiomyocyte-specific knockout, AAV9-mediated overexpression, ChIP (direct CCNB1/CDK1 promoter binding), in vivo myocardial infarction model, cell cycle analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct ChIP evidence for target gene activation, cardiac-specific KO and AAV rescue in vivo, multiple orthogonal methods","pmids":["40128196"],"is_preprint":false},{"year":2025,"finding":"FOXK2 deficiency in skeletal muscle stem cells impairs myogenic differentiation and disrupts mitochondrial homeostasis. FOXK2 directly regulates the expression of mitochondrial function-related genes by modulating chromatin accessibility at its binding sites.","method":"Muscle stem cell (MuSC)-specific Foxk2 knockout in mice, zebrafish foxk2 morpholino knockdown, ATAC-seq/omics analysis of chromatin accessibility, C2C12 differentiation assays, coenzyme Q10 rescue","journal":"EMBO molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse and zebrafish models with ATAC-seq chromatin accessibility data, functional rescue; omics analysis is correlative, single lab","pmids":["40410591"],"is_preprint":false},{"year":2025,"finding":"FOXK2 interacts with mTOR and DRP1 (co-immunoprecipitation), and promotes phosphorylation of mTOR. Via the mTOR/DRP1 signaling axis, FOXK2 upregulates CPT1A (fatty acid oxidation) while downregulating ACC1 and FASN (lipogenesis), driving lipid metabolic reprogramming in cervical cancer cells.","method":"Co-immunoprecipitation, Western blot for phospho-mTOR, overexpression/knockdown, xenograft in vivo model","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP confirming FOXK2-mTOR and mTOR-DRP1 interactions, functional lipid metabolism readouts, in vivo validation, single lab","pmids":["40641601"],"is_preprint":false}],"current_model":"FOXK2 is a ubiquitously expressed forkhead transcription factor that directly binds DNA (via its forkhead domain) and acts as both a transcriptional activator and repressor depending on context; it recruits distinct corepressor complexes (SIN3A, NCoR/SMRT, NuRD, REST/CoREST) and the BAP1 PR-DUB deubiquitinase complex (via its FHA domain interacting with phospho-Thr493 on BAP1) to target loci, promotes AP-1-dependent gene activation, and drives aerobic glycolysis by upregulating glycolytic enzymes while suppressing mitochondrial pyruvate oxidation. Its activity and localization are tightly regulated by post-translational modifications: CDK1·cyclin B phosphorylates Ser368/Ser423 to control stability and repressor activity during mitosis; GSK3 retains FOXK2 in the cytoplasm under basal conditions while insulin-Akt-mTOR signaling drives nuclear translocation reciprocal to FoxO1; PIAS4-mediated SUMOylation at Lys527/633 promotes nuclear translocation and promoter binding; CBP acetylates Lys223 while SIRT1 deacetylates it to control nuclear distribution and chemosensitivity; and FBXO24-SCF E3 ligase mediates polyubiquitylation and nuclear proteasomal degradation of FOXK2."},"narrative":{"mechanistic_narrative":"FOXK2 is a ubiquitously expressed forkhead transcription factor that binds DNA through its forkhead domain and acts as both an activator and repressor to coordinate cell proliferation, metabolic reprogramming, and lineage-specific gene programs [PMID:1339390, PMID:22083952, PMID:27773593]. At chromatin it nucleates corepressor activity by recruiting the SIN3A, NCoR/SMRT, NuRD, and REST/CoREST complexes to repress targets such as HIF1β and EZH2, and it uses its forkhead-associated (FHA) domain to recruit the BAP1 PR-DUB deubiquitinase—engaging phospho-Thr493 of BAP1 and a downstream BAP1–HCF-1 ternary complex—to deubiquitinate histone H2A and antagonize Ring1B-Bmi1 at target loci [PMID:24748658, PMID:25451922, PMID:27773593]. FOXK2 also activates gene expression, facilitating AP-1 recruitment to chromatin, and premarking lineage regulatory regions in embryonic stem cells ahead of differentiation [PMID:22083952, PMID:33434264]. A central output is metabolic control: FOXK2 (with FOXK1) drives aerobic glycolysis by upregulating glycolytic enzymes and the pyruvate dehydrogenase kinases that suppress mitochondrial pyruvate oxidation, while also governing mitochondrial gene programs in differentiating muscle and lipid metabolic reprogramming [PMID:30700909, PMID:40410591, PMID:40641601]. FOXK2 activity and localization are tightly tuned by post-translational modification: CDK1·cyclin B phosphorylation at Ser368/Ser423 controls its stability and repressor activity during mitosis [PMID:20810654]; insulin–Akt–mTOR signaling drives nuclear translocation that is held in check by GSK3 in the basal state, reciprocal to FoxO1 [PMID:30952843]; PIAS4-mediated SUMOylation at Lys527/Lys633 promotes nuclear entry and promoter binding [PMID:29540677, PMID:36682222]; CBP acetylation versus SIRT1 deacetylation at Lys223 reciprocally controls nuclear distribution and chemosensitivity [PMID:34866322]; and the FBXO24-SCF E3 ligase mediates nuclear polyubiquitylation and degradation [PMID:38735474]. Through these activities FOXK2 supports proliferation and survival—its loss triggers caspase-dependent apoptosis and upregulation of Puma/Noxa—and contributes to cardiomyocyte cell-cycle re-entry and neonatal heart regeneration [PMID:25216324, PMID:40128196].","teleology":[{"year":1992,"claim":"Established that FOXK2 is a sequence-specific DNA-binding protein, defining its forkhead domain as the DNA-binding module on purine-rich regulatory elements.","evidence":"Gel retardation and cDNA characterization with domain mapping on HIV-1 LTR and IL2 promoter sequences","pmids":["1339390"],"confidence":"Medium","gaps":["No genome-wide binding map at this stage","Cellular function and target genes undefined","No regulation or partner data"]},{"year":2010,"claim":"Defined FOXK2 as a cell-cycle-regulated factor whose mitotic CDK phosphorylation controls its stability and repressor activity, and whose disruption triggers apoptosis.","evidence":"Cell-cycle synchronization, in vitro kinase assays, Ser368/Ser423 mutagenesis, and reporter assays; separate EMSA work identified G/T-mismatch DNA binding","pmids":["20810654","20097901"],"confidence":"High","gaps":["Downstream apoptotic effectors of phospho-mutant not mapped","Biological role of mismatch DNA binding unresolved","Target genes during mitosis not enumerated"]},{"year":2011,"claim":"Placed FOXK2 in a genome-wide regulatory context, showing it co-localizes with AP-1 motifs and facilitates AP-1 chromatin recruitment to activate gene expression.","evidence":"ChIP-seq, genome-wide binding analysis, and gene expression profiling","pmids":["22083952"],"confidence":"High","gaps":["Mechanism of AP-1 cooperativity not structurally defined","Distinction of activator vs repressor target sets incomplete"]},{"year":2014,"claim":"Revealed FOXK2 as a chromatin-modifying hub that recruits corepressor and deubiquitinase complexes, explaining how it represses target loci.","evidence":"Co-IP, ChIP, DUB activity mutants, and histone modification assays defining FHA–phospho-Thr493 recruitment of BAP1 and the BAP1–HCF-1 complex antagonizing Ring1B-Bmi1","pmids":["24748658","25451922"],"confidence":"High","gaps":["Determinants of complex choice at a given locus unclear","Structural basis of FHA–phospho-Thr493 not solved"]},{"year":2015,"claim":"Connected FOXK2 to E3-ligase scaffolding and growth control, showing it promotes ERα degradation and that its loss arrests proliferation and triggers apoptosis with Puma/Noxa induction.","evidence":"Co-IP, ubiquitination assays, siRNA knockdown with BrdU/caspase-3 readouts and rapamycin epistasis","pmids":["25740706","25216324"],"confidence":"Medium","gaps":["Scaffold mechanism for BRCA1/BARD1-mediated ERα ubiquitylation not detailed","mTOR/p70S6K compensatory loop mechanism partially defined"]},{"year":2016,"claim":"Defined the full corepressor repertoire of FOXK2 and embedded it in transcriptional feedback circuits with ERα, HIF1β, and EZH2.","evidence":"Multiple Co-IPs identifying NCoR/SMRT, SIN3A, NuRD, REST/CoREST; ChIP and reporter assays; promoter ChIP showing SOX9 activates FOXK2","pmids":["27773593","28007600"],"confidence":"High","gaps":["Context selectivity of corepressor recruitment unresolved","Upstream activator hierarchy across tissues unclear"]},{"year":2017,"claim":"Showed FOXK2 directly represses EMT and proliferation programs (N-cadherin, Snail, cyclin D1, CDK4), framing a tumor-suppressive transcriptional output in some contexts.","evidence":"ChIP-seq, qChIP, luciferase reporters, and invasion/proliferation assays in NSCLC cells","pmids":["28260088"],"confidence":"Medium","gaps":["Cofactors mediating repression at these promoters not identified","Context-dependence vs oncogenic roles elsewhere unreconciled"]},{"year":2019,"claim":"Established FOXK2 as a master driver of aerobic glycolysis downstream of insulin signaling, with localization gated by Akt-mTOR versus GSK3 reciprocal to FoxO1.","evidence":"Knockdown/overexpression in cells and in vivo, metabolic flux assays, and pathway-inhibitor subcellular fractionation/immunofluorescence","pmids":["30700909","30952843"],"confidence":"High","gaps":["Direct nuclear import machinery downstream of mTOR not defined","Tissue-specific metabolic target sets only partially mapped"]},{"year":2021,"claim":"Demonstrated multilayer PTM control of FOXK2 nuclear function and chemosensitivity, and expanded its activator targets to enhancers and angiogenic/stem programs.","evidence":"SUMOylation-site mutants with ChIP (Lys527/633); CBP/SIRT1 K223 acetylation with localization and cisplatin assays; dCas9 enhancer blocking at ERN1; VEGFA promoter ChIP-seq; ESC ChIP-seq premarking","pmids":["29540677","34866322","35349489","34489549","33434264"],"confidence":"High","gaps":["How distinct PTMs are integrated on a single FOXK2 molecule unknown","Relationship between enhancer premarking and later activation mechanistically incomplete"]},{"year":2022,"claim":"Identified PIAS4 as the SUMO ligase that drives FOXK2 nuclear translocation to activate nucleotide synthesis genes, linking FOXK2 SUMOylation to chemoresistance.","evidence":"ChIP-seq, RNA-seq, SUMOylation and luciferase assays with DNA-damage modulation and in vivo 5-FU resistance","pmids":["36682222"],"confidence":"High","gaps":["DNA-damage signal that represses SUMOylation not pinpointed","SUMO-dependent import receptor unidentified"]},{"year":2024,"claim":"Mapped FOXK2 degradation and an FHA-domain interaction repertoire (kinase, viral, and mitochondrial), broadening its regulatory and effector landscape.","evidence":"FBXO24-SCF Co-IP/ubiquitination with mitochondrial localization (mouse model); PDK2 FHA binding/Thr13-Ser30 phosphorylation feedback; KSHV ORF45 FHA-motif binding at viral promoters; SIRT2 rescue of EMT/glycolysis; PPARγ adipogenic activation","pmids":["38735474","38734828","39494902","39287387","38949649","39789420"],"confidence":"High","gaps":["Functional role of mitochondrial FOXK2 pool only partly defined","How FHA domain discriminates among diverse phospho-partners unclear"]},{"year":2025,"claim":"Extended FOXK2 to organ regeneration and stem-cell differentiation, showing it drives cardiomyocyte cell-cycle re-entry and controls mitochondrial gene programs via chromatin accessibility.","evidence":"Cardiomyocyte- and muscle-stem-cell-specific knockouts with ChIP/ATAC-seq, AAV9 rescue, infarction and differentiation models, plus mTOR/DRP1 lipid-metabolism axis in cancer","pmids":["40128196","40410591","40641601"],"confidence":"High","gaps":["Direct vs indirect control of mitochondrial gene chromatin not fully separated","Regenerative role tissue-restricted; human translation untested"]},{"year":null,"claim":"How FOXK2 selects between activating and repressive outputs at a given locus, and how its many PTMs and FHA-mediated interactions are integrated into context-specific programs, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model integrating PTM state with cofactor choice","Rules governing activator vs corepressor recruitment undefined","Physiological role of mitochondrial FOXK2 unclear"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[3,8,12,16,24]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,2,4,14]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,5,6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,6]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[13,18,11,15]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[13]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[19,25]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3,8,16,24]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[12,26]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[4,5,25]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[13,16]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1,24]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[7]}],"complexes":["FOXK2–BAP1–HCF-1 (PR-DUB) complex"],"partners":["BAP1","SIN3A","BARD1","ERΑ","PDK2","SIRT1","PIAS4","FBXO24"],"other_free_text":[]}},"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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Disease","date":"2025-05-21","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.19.25327915","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":30501,"output_tokens":7011,"usd":0.098334,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16265,"output_tokens":4835,"usd":0.1011,"stage2_stop_reason":"end_turn"},"total_usd":0.199434,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1992,\n      \"finding\": \"FOXK2 (then called ILF) was identified as a DNA-binding protein containing a forkhead domain; the forkhead domain is sufficient to mediate DNA binding to purine-rich regulatory sequences in the HIV-1 LTR and IL2 promoter.\",\n      \"method\": \"Gel retardation assay, cDNA characterization, chromosomal mapping\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vitro DNA binding assay with domain mapping, single lab, foundational characterization paper\",\n      \"pmids\": [\"1339390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"FOXK2 is phosphorylated by CDK1·cyclin B (primarily) and CDK2·cyclin A during mitosis; two phosphorylation sites, Ser368 and Ser423, regulate FOXK2 stability and its activity as a transcriptional repressor. Expression of a CDK phosphorylation-site mutant lacking these sites causes apoptosis.\",\n      \"method\": \"Cell cycle synchronization, kinase assays, site-directed mutagenesis, phosphorylation site mapping, transcriptional reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay plus mutagenesis of specific sites, with functional phenotype (apoptosis), multiple orthogonal methods\",\n      \"pmids\": [\"20810654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"FOXK2 binds G/T-mismatch DNA through its forkhead domain with higher affinity than matched consensus DNA; it also recognizes hypoxanthine/T and G/uracil mismatches, identifying it as a novel mismatch DNA-binding protein.\",\n      \"method\": \"Electrophoretic mobility shift assay (EMSA), cDNA library screening, recombinant domain binding assays\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro binding assay with recombinant domain and nuclear extract antibody supershift, single lab\",\n      \"pmids\": [\"20097901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"FOXK2 promotes AP-1-dependent gene expression by facilitating the recruitment of AP-1 to chromatin; FOXK2 binding regions across the genome are frequently co-associated with AP-1 binding motifs.\",\n      \"method\": \"ChIP-seq, genome-wide binding analysis, gene expression profiling, chromatin recruitment assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal ChIP and genome-wide binding data with functional gene expression readout, multiple orthogonal methods\",\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 DNA via its forkhead-associated (FHA) domain, promotes local histone H2A deubiquitination, and causes changes in target gene activity.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, histone modification assays, gene expression analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ChIP, and functional histone modification readout, multiple orthogonal methods in single study\",\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 interacts with phospho-Thr493 on BAP1; BAP1 in turn recruits HCF-1, forming a ternary complex (FOXK2–BAP1–HCF-1). BAP1 represses FOXK2 target genes in a manner requiring its deubiquitinase (DUB) activity but not HCF-1 interaction. BAP1 antagonizes the Ring1B-Bmi1 E3 ubiquitin ligase (H2A ubiquitination) at these loci.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, siRNA knockdown, DUB activity mutant analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with domain mapping (phospho-Thr493), functional DUB mutant, and epistasis with Ring1B-Bmi1, multiple orthogonal methods\",\n      \"pmids\": [\"25451922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FOXK2 interacts with ERα and BARD1 (part of the BRCA1/BARD1 E3 ubiquitin ligase), acting as a scaffold to promote ubiquitin-mediated degradation of ERα, thereby reducing ERα transcriptional activity and inhibiting proliferation of ERα-positive breast cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, transcriptional reporter assays, cell proliferation assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional ubiquitination assay, single lab, two orthogonal methods\",\n      \"pmids\": [\"25740706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Knockdown of FoxK2 in proliferating cells reduces BrdU incorporation and H3 phosphorylation (proliferation arrest), and in the absence of growth factors causes caspase-3 activation and cell death. FoxK2 loss upregulates pro-apoptotic Bcl-2 family members Puma and Noxa. mTOR/p70S6K provides a compensatory feedback loop, as rapamycin synergizes with FoxK2 knockdown to further reduce H3 phosphorylation.\",\n      \"method\": \"siRNA knockdown, BrdU incorporation, flow cytometry, caspase-3 activity assay, qRT-PCR, rapamycin treatment\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with multiple cellular phenotype 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 target genes including HIF1β and EZH2. FOXK2 is transcriptionally activated by ERα, and repressed in a feedback loop by HIF1β/EZH2.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, gene expression profiling, luciferase reporter assays, functional cell assays\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple Co-IPs identifying distinct corepressor complexes, ChIP, and functional gene repression readouts across multiple orthogonal methods\",\n      \"pmids\": [\"27773593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SOX9 transcriptionally activates FOXK2 by directly binding to its promoter in colorectal cancer cells.\",\n      \"method\": \"ChIP, luciferase reporter assay, siRNA knockdown, qRT-PCR\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ChIP at FOXK2 promoter plus reporter assay, single lab\",\n      \"pmids\": [\"28007600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FOXK2 directly suppresses N-cadherin and Snail expression (repressing EMT) and suppresses cyclin D1 and CDK4 expression (inhibiting proliferation) in NSCLC cells, as determined by ChIP-seq and luciferase reporter assays.\",\n      \"method\": \"ChIP-seq, qChIP, luciferase reporter assays, lentiviral overexpression/knockdown, cell invasion and proliferation assays\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq with functional reporter validation, single lab, multiple target readouts\",\n      \"pmids\": [\"28260088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SUMOylation of FOXK2 at Lys527 and Lys633 is required for its transcriptional activity and ability to bind the FOXO3 promoter; SUMOylation-defective mutants (K527/633R or E529/635A) lose the ability to mediate paclitaxel cytotoxicity and fail to occupy the FOXO3 promoter despite normal protein levels and subcellular localization.\",\n      \"method\": \"Site-directed mutagenesis, ChIP, cell viability assays, clonogenic assays, subcellular fractionation\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis of specific SUMOylation sites with ChIP validation of promoter binding, plus functional cytotoxicity readout; single lab but 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 suppressing pyruvate oxidation in mitochondria by increasing pyruvate dehydrogenase kinases 1 and 4 and suppressing pyruvate dehydrogenase phosphatase 1, leading to increased phosphorylation of the E1α subunit of pyruvate dehydrogenase complex and diversion of pyruvate to lactate.\",\n      \"method\": \"Knockdown/overexpression in cell lines and in vivo models, metabolic flux assays, gene expression profiling, primary human cell studies\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — replicated in multiple cell types and in vivo, in vitro and in vivo experiments, multiple orthogonal metabolic readouts\",\n      \"pmids\": [\"30700909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FoxK2 (and FoxK1) translocate from cytoplasm to nucleus following insulin stimulation; this nuclear translocation is dependent on the Akt-mTOR pathway, while cytoplasmic localization in the basal state is dependent on GSK3. This is reciprocal to FoxO1 nuclear-to-cytoplasmic translocation after insulin. Knockdown of FoxK1/FoxK2 in liver cells downregulates cell cycle/lipid metabolism genes and upregulates apoptosis genes, resulting in decreased proliferation and altered mitochondrial fatty acid metabolism.\",\n      \"method\": \"Subcellular fractionation, immunofluorescence, pathway inhibitor studies (Akt, mTOR, GSK3), siRNA knockdown, gene expression profiling, metabolic assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization experiments with pharmacological pathway dissection (Akt-mTOR vs. GSK3), replicated functional readouts, 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 of ERN1; FOXK2-driven IRE1α upregulation leads to alternative XBP1 splicing and activation of stemness pathways in ovarian cancer stem cells. Blocking FOXK2 binding to this enhancer with dCas9 diminishes IRE1α transcription.\",\n      \"method\": \"ChIP-seq, CRISPR dCas9 enhancer blocking, RNA-seq, gene expression validation, tumor initiation assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — ChIP-seq with CRISPR/dCas9 functional validation of specific enhancer binding, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"35349489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FOXK2 is acetylated at Lys223 by the acetyltransferase CBP (cAMP response element binding protein); SIRT1 deacetylates FOXK2 at K223. Acetylation of K223 reduces nuclear localization of FOXK2 and promotes mitotic catastrophe, enhancing chemosensitivity to cisplatin. Cisplatin attenuates the FOXK2-SIRT1 interaction, leading to increased FOXK2 acetylation.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis (K223), subcellular fractionation, SIRT1 inhibitor treatment, in vitro and in vivo drug sensitivity assays\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — identification of writer (CBP) and eraser (SIRT1) with K223 mutagenesis, localization change, and functional drug-sensitivity phenotype in vitro and in vivo\",\n      \"pmids\": [\"34866322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FOXK2 transcriptionally activates VEGFA by directly binding the VEGFA promoter, promoting angiogenesis. FOXK2-induced VEGFA binds VEGFR1 as a compensatory mechanism when VEGFR2 is blocked, activating ERK, PI3K/AKT, and P38/MAPK signaling, thereby conferring resistance to VEGFR2 inhibitor (apatinib). This constitutes a positive feedback loop: VEGFA/VEGFR1 signaling further promotes FOXK2-mediated VEGFA transcription.\",\n      \"method\": \"ChIP-seq, RNA-seq, ChIP, dual-luciferase reporter, VEGFR1 inhibition, in vitro angiogenesis assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-seq and ChIP confirming direct VEGFA promoter binding, luciferase validation, pharmacological epistasis defining feedback loop, multiple orthogonal methods\",\n      \"pmids\": [\"34489549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FOXK2 premarks lineage-specific regulatory regions in human embryonic stem cells (ESCs) before differentiation; its binding at thousands of regulatory regions is associated with active histone marks and predicts regions activated during neural precursor cell (NPC) differentiation. FOXK transcription factors have a role in gene activation during NPC differentiation.\",\n      \"method\": \"Genome-wide ChIP-seq in ESCs and differentiated cell types, histone mark analysis, FOXK2 knockdown during NPC differentiation\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide ChIP-seq with functional knockdown during differentiation, single lab\",\n      \"pmids\": [\"33434264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FOXK2 is SUMOylated by PIAS4, which drives FOXK2 nuclear translocation, enabling it to bind promoters of nucleotide de novo synthesis genes and activate their transcription. DNA damage represses FOXK2 SUMOylation, and elevated FOXK2 SUMOylation promotes resistance to 5-FU in hepatocellular carcinoma.\",\n      \"method\": \"ChIP-seq, RNA-seq, luciferase promoter assay, SUMOylation assays, nuclear fractionation, DNA damage treatment, in vitro and in vivo drug resistance assays\",\n      \"journal\": \"Drug resistance updates\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — identification of SUMOylation writer (PIAS4) with ChIP-seq validation of promoter binding, nuclear translocation, and functional drug resistance readout in vitro and in vivo\",\n      \"pmids\": [\"36682222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FOXK2 is targeted for ubiquitin-mediated proteasomal degradation in the nucleus by the SCF E3 ligase subunit FBXO24, which binds FOXK2's carboxyl terminus (aa 428–478) and mediates multisite polyubiquitylation. FOXK2 is also detected within mitochondria, and its depletion or expression of carboxy-terminal mutants impairs mitochondrial function.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, domain-deletion mutants, subcellular fractionation/mitochondrial localization, Fbxo24 heterozygous mouse model, bacterial pneumonia model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — Co-IP with domain mapping, in vitro ubiquitination, in vivo mouse model validation, 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 FOXK2 transcriptional activity. FOXK2 in turn transcriptionally regulates PDK2 expression, forming a positive feedback loop that sustains glycolysis in ovarian cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis (Thr13, Ser30), ChIP, luciferase reporter assay, cell proliferation and migration assays, in vivo xenograft\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct binding (Co-IP with FHA domain), in vitro phosphorylation at defined sites, ChIP confirming FOXK2 binds PDK2 promoter, multiple orthogonal methods\",\n      \"pmids\": [\"38734828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FOXK2 binds to the KSHV immediate-early tegument protein ORF45 via its forkhead-associated (FHA) domain, which recognizes a conserved serine/threonine-rich short linear motif in ORF45. ORF45 augments FOXK2 occupancy at late viral gene promoters and enhances FOXK2 transcriptional activity, promoting late KSHV lytic gene expression and virion production.\",\n      \"method\": \"Co-immunoprecipitation, point mutagenesis of ORF45 threonine motif, ChIP at viral promoters, siRNA knockdown of FOXK1/K2, lytic reactivation assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with FHA domain requirement, point mutation abolishing interaction, ChIP at viral promoters, functional lytic replication readout\",\n      \"pmids\": [\"39494902\", \"39287387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FOXK2 promotes adipogenic differentiation of bone marrow stromal cells by directly binding to the promoters of PPARγ1 and PPARγ2 and enhancing their transcriptional activation. Nuclear translocation of Foxk2 during adipogenic stimulation is dependent on PI3-kinase and mTOR signaling. A Foxk2–PPARγ positive feedback loop drives adipogenesis.\",\n      \"method\": \"ChIP, luciferase reporter assays, overexpression/knockdown, nuclear fractionation, pathway inhibitor studies\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirming promoter binding, reporter validation, pharmacological localization control, single lab\",\n      \"pmids\": [\"39789420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FOXK2 interacts with SIRT2, and SIRT2 overexpression rescues the inhibition of EMT and glycolysis caused by FOXK2 knockdown in TGF-β1-treated bronchial epithelial cells, establishing that FOXK2 regulates EMT and glycolysis in a SIRT2-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, SIRT2 overexpression rescue, EMT marker and glycolysis enzyme expression assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP validating FOXK2-SIRT2 binding plus epistasis rescue experiment, single lab\",\n      \"pmids\": [\"38949649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Foxk1 and Foxk2 directly activate CCNB1 and CDK1 transcription, forming the CCNB1/CDK1 complex that facilitates G2/M transition and cardiomyocyte cell cycle progression. They also upregulate HIF1α expression to enhance glycolysis and the pentose phosphate pathway, further supporting cardiomyocyte proliferation. Cardiomyocyte-specific knockout of Foxk2 impairs neonatal heart regeneration after myocardial infarction.\",\n      \"method\": \"Cardiomyocyte-specific knockout, AAV9-mediated overexpression, ChIP (direct CCNB1/CDK1 promoter binding), in vivo myocardial infarction model, cell cycle analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct ChIP evidence for target gene activation, cardiac-specific KO and AAV rescue in vivo, multiple orthogonal methods\",\n      \"pmids\": [\"40128196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FOXK2 deficiency in skeletal muscle stem cells impairs myogenic differentiation and disrupts mitochondrial homeostasis. FOXK2 directly regulates the expression of mitochondrial function-related genes by modulating chromatin accessibility at its binding sites.\",\n      \"method\": \"Muscle stem cell (MuSC)-specific Foxk2 knockout in mice, zebrafish foxk2 morpholino knockdown, ATAC-seq/omics analysis of chromatin accessibility, C2C12 differentiation assays, coenzyme Q10 rescue\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse and zebrafish models with ATAC-seq chromatin accessibility data, functional rescue; omics analysis is correlative, single lab\",\n      \"pmids\": [\"40410591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FOXK2 interacts with mTOR and DRP1 (co-immunoprecipitation), and promotes phosphorylation of mTOR. Via the mTOR/DRP1 signaling axis, FOXK2 upregulates CPT1A (fatty acid oxidation) while downregulating ACC1 and FASN (lipogenesis), driving lipid metabolic reprogramming in cervical cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, Western blot for phospho-mTOR, overexpression/knockdown, xenograft in vivo model\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP confirming FOXK2-mTOR and mTOR-DRP1 interactions, functional lipid metabolism readouts, in vivo validation, single lab\",\n      \"pmids\": [\"40641601\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FOXK2 is a ubiquitously expressed forkhead transcription factor that directly binds DNA (via its forkhead domain) and acts as both a transcriptional activator and repressor depending on context; it recruits distinct corepressor complexes (SIN3A, NCoR/SMRT, NuRD, REST/CoREST) and the BAP1 PR-DUB deubiquitinase complex (via its FHA domain interacting with phospho-Thr493 on BAP1) to target loci, promotes AP-1-dependent gene activation, and drives aerobic glycolysis by upregulating glycolytic enzymes while suppressing mitochondrial pyruvate oxidation. Its activity and localization are tightly regulated by post-translational modifications: CDK1·cyclin B phosphorylates Ser368/Ser423 to control stability and repressor activity during mitosis; GSK3 retains FOXK2 in the cytoplasm under basal conditions while insulin-Akt-mTOR signaling drives nuclear translocation reciprocal to FoxO1; PIAS4-mediated SUMOylation at Lys527/633 promotes nuclear translocation and promoter binding; CBP acetylates Lys223 while SIRT1 deacetylates it to control nuclear distribution and chemosensitivity; and FBXO24-SCF E3 ligase mediates polyubiquitylation and nuclear proteasomal degradation of FOXK2.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FOXK2 is a ubiquitously expressed forkhead transcription factor that binds DNA through its forkhead domain and acts as both an activator and repressor to coordinate cell proliferation, metabolic reprogramming, and lineage-specific gene programs [#0, #3, #8]. At chromatin it nucleates corepressor activity by recruiting the SIN3A, NCoR/SMRT, NuRD, and REST/CoREST complexes to repress targets such as HIF1\\u03b2 and EZH2, and it uses its forkhead-associated (FHA) domain to recruit the BAP1 PR-DUB deubiquitinase\\u2014engaging phospho-Thr493 of BAP1 and a downstream BAP1\\u2013HCF-1 ternary complex\\u2014to deubiquitinate histone H2A and antagonize Ring1B-Bmi1 at target loci [#4, #5, #8]. FOXK2 also activates gene expression, facilitating AP-1 recruitment to chromatin, and premarking lineage regulatory regions in embryonic stem cells ahead of differentiation [#3, #17]. A central output is metabolic control: FOXK2 (with FOXK1) drives aerobic glycolysis by upregulating glycolytic enzymes and the pyruvate dehydrogenase kinases that suppress mitochondrial pyruvate oxidation, while also governing mitochondrial gene programs in differentiating muscle and lipid metabolic reprogramming [#12, #25, #26]. FOXK2 activity and localization are tightly tuned by post-translational modification: CDK1\\u00b7cyclin B phosphorylation at Ser368/Ser423 controls its stability and repressor activity during mitosis [#1]; insulin\\u2013Akt\\u2013mTOR signaling drives nuclear translocation that is held in check by GSK3 in the basal state, reciprocal to FoxO1 [#13]; PIAS4-mediated SUMOylation at Lys527/Lys633 promotes nuclear entry and promoter binding [#11, #18]; CBP acetylation versus SIRT1 deacetylation at Lys223 reciprocally controls nuclear distribution and chemosensitivity [#15]; and the FBXO24-SCF E3 ligase mediates nuclear polyubiquitylation and degradation [#19]. Through these activities FOXK2 supports proliferation and survival\\u2014its loss triggers caspase-dependent apoptosis and upregulation of Puma/Noxa\\u2014and contributes to cardiomyocyte cell-cycle re-entry and neonatal heart regeneration [#7, #24].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Established that FOXK2 is a sequence-specific DNA-binding protein, defining its forkhead domain as the DNA-binding module on purine-rich regulatory elements.\",\n      \"evidence\": \"Gel retardation and cDNA characterization with domain mapping on HIV-1 LTR and IL2 promoter sequences\",\n      \"pmids\": [\"1339390\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No genome-wide binding map at this stage\", \"Cellular function and target genes undefined\", \"No regulation or partner data\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined FOXK2 as a cell-cycle-regulated factor whose mitotic CDK phosphorylation controls its stability and repressor activity, and whose disruption triggers apoptosis.\",\n      \"evidence\": \"Cell-cycle synchronization, in vitro kinase assays, Ser368/Ser423 mutagenesis, and reporter assays; separate EMSA work identified G/T-mismatch DNA binding\",\n      \"pmids\": [\"20810654\", \"20097901\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream apoptotic effectors of phospho-mutant not mapped\", \"Biological role of mismatch DNA binding unresolved\", \"Target genes during mitosis not enumerated\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Placed FOXK2 in a genome-wide regulatory context, showing it co-localizes with AP-1 motifs and facilitates AP-1 chromatin recruitment to activate gene expression.\",\n      \"evidence\": \"ChIP-seq, genome-wide binding analysis, and gene expression profiling\",\n      \"pmids\": [\"22083952\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of AP-1 cooperativity not structurally defined\", \"Distinction of activator vs repressor target sets incomplete\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealed FOXK2 as a chromatin-modifying hub that recruits corepressor and deubiquitinase complexes, explaining how it represses target loci.\",\n      \"evidence\": \"Co-IP, ChIP, DUB activity mutants, and histone modification assays defining FHA\\u2013phospho-Thr493 recruitment of BAP1 and the BAP1\\u2013HCF-1 complex antagonizing Ring1B-Bmi1\",\n      \"pmids\": [\"24748658\", \"25451922\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of complex choice at a given locus unclear\", \"Structural basis of FHA\\u2013phospho-Thr493 not solved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connected FOXK2 to E3-ligase scaffolding and growth control, showing it promotes ER\\u03b1 degradation and that its loss arrests proliferation and triggers apoptosis with Puma/Noxa induction.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, siRNA knockdown with BrdU/caspase-3 readouts and rapamycin epistasis\",\n      \"pmids\": [\"25740706\", \"25216324\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Scaffold mechanism for BRCA1/BARD1-mediated ER\\u03b1 ubiquitylation not detailed\", \"mTOR/p70S6K compensatory loop mechanism partially defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined the full corepressor repertoire of FOXK2 and embedded it in transcriptional feedback circuits with ER\\u03b1, HIF1\\u03b2, and EZH2.\",\n      \"evidence\": \"Multiple Co-IPs identifying NCoR/SMRT, SIN3A, NuRD, REST/CoREST; ChIP and reporter assays; promoter ChIP showing SOX9 activates FOXK2\",\n      \"pmids\": [\"27773593\", \"28007600\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Context selectivity of corepressor recruitment unresolved\", \"Upstream activator hierarchy across tissues unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed FOXK2 directly represses EMT and proliferation programs (N-cadherin, Snail, cyclin D1, CDK4), framing a tumor-suppressive transcriptional output in some contexts.\",\n      \"evidence\": \"ChIP-seq, qChIP, luciferase reporters, and invasion/proliferation assays in NSCLC cells\",\n      \"pmids\": [\"28260088\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cofactors mediating repression at these promoters not identified\", \"Context-dependence vs oncogenic roles elsewhere unreconciled\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established FOXK2 as a master driver of aerobic glycolysis downstream of insulin signaling, with localization gated by Akt-mTOR versus GSK3 reciprocal to FoxO1.\",\n      \"evidence\": \"Knockdown/overexpression in cells and in vivo, metabolic flux assays, and pathway-inhibitor subcellular fractionation/immunofluorescence\",\n      \"pmids\": [\"30700909\", \"30952843\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct nuclear import machinery downstream of mTOR not defined\", \"Tissue-specific metabolic target sets only partially mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated multilayer PTM control of FOXK2 nuclear function and chemosensitivity, and expanded its activator targets to enhancers and angiogenic/stem programs.\",\n      \"evidence\": \"SUMOylation-site mutants with ChIP (Lys527/633); CBP/SIRT1 K223 acetylation with localization and cisplatin assays; dCas9 enhancer blocking at ERN1; VEGFA promoter ChIP-seq; ESC ChIP-seq premarking\",\n      \"pmids\": [\"29540677\", \"34866322\", \"35349489\", \"34489549\", \"33434264\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How distinct PTMs are integrated on a single FOXK2 molecule unknown\", \"Relationship between enhancer premarking and later activation mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified PIAS4 as the SUMO ligase that drives FOXK2 nuclear translocation to activate nucleotide synthesis genes, linking FOXK2 SUMOylation to chemoresistance.\",\n      \"evidence\": \"ChIP-seq, RNA-seq, SUMOylation and luciferase assays with DNA-damage modulation and in vivo 5-FU resistance\",\n      \"pmids\": [\"36682222\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"DNA-damage signal that represses SUMOylation not pinpointed\", \"SUMO-dependent import receptor unidentified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Mapped FOXK2 degradation and an FHA-domain interaction repertoire (kinase, viral, and mitochondrial), broadening its regulatory and effector landscape.\",\n      \"evidence\": \"FBXO24-SCF Co-IP/ubiquitination with mitochondrial localization (mouse model); PDK2 FHA binding/Thr13-Ser30 phosphorylation feedback; KSHV ORF45 FHA-motif binding at viral promoters; SIRT2 rescue of EMT/glycolysis; PPAR\\u03b3 adipogenic activation\",\n      \"pmids\": [\"38735474\", \"38734828\", \"39494902\", \"39287387\", \"38949649\", \"39789420\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role of mitochondrial FOXK2 pool only partly defined\", \"How FHA domain discriminates among diverse phospho-partners unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended FOXK2 to organ regeneration and stem-cell differentiation, showing it drives cardiomyocyte cell-cycle re-entry and controls mitochondrial gene programs via chromatin accessibility.\",\n      \"evidence\": \"Cardiomyocyte- and muscle-stem-cell-specific knockouts with ChIP/ATAC-seq, AAV9 rescue, infarction and differentiation models, plus mTOR/DRP1 lipid-metabolism axis in cancer\",\n      \"pmids\": [\"40128196\", \"40410591\", \"40641601\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect control of mitochondrial gene chromatin not fully separated\", \"Regenerative role tissue-restricted; human translation untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How FOXK2 selects between activating and repressive outputs at a given locus, and how its many PTMs and FHA-mediated interactions are integrated into context-specific programs, remains unresolved.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model integrating PTM state with cofactor choice\", \"Rules governing activator vs corepressor recruitment undefined\", \"Physiological role of mitochondrial FOXK2 unclear\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [3, 8, 12, 16, 24]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 2, 4, 14]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 5, 6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [13, 18, 11, 15]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [19, 25]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 8, 16, 24]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [12, 26]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [4, 5, 25]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [13, 16]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 24]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"complexes\": [\"FOXK2\\u2013BAP1\\u2013HCF-1 (PR-DUB) complex\"],\n    \"partners\": [\"BAP1\", \"SIN3A\", \"BARD1\", \"ER\\u03b1\", \"PDK2\", \"SIRT1\", \"PIAS4\", \"FBXO24\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}