FOXK1

Summary

FOXK1 (forkhead box K1, HGNC:23480) is a protein-coding gene on chromosome 7p22.1, encoding Forkhead box protein K1 (P85037). Transcriptional regulator involved in different processes such as glucose metabolism, aerobic glycolysis, muscle cell differentiation and autophagy. It is a selective cancer dependency (DepMap: 15.9% of cell lines).

Enables 14-3-3 protein binding activity; DNA-binding transcription repressor activity, RNA polymerase II-specific; and transcription cis-regulatory region binding activity. Involved in several processes, including intracellular glucose homeostasis; negative regulation of autophagy; and regulation of DNA-templated transcription. Located in cytoplasm and nucleus.

Source: NCBI Gene 221937 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 116 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 15.9% of screened cell lines
• MANE Select transcript: NM_001037165

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23480
Approved symbol	FOXK1
Name	forkhead box K1
Location	7p22.1
Locus type	gene with protein product
Status	Approved
Aliases	IMAGE:5164497
Ensembl gene	ENSG00000164916
Ensembl biotype	protein_coding
OMIM	616302
Entrez	221937

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 retained_intron

ENST00000328914, ENST00000460979, ENST00000496023, ENST00000937603

RefSeq mRNA: 1 — MANE Select: NM_001037165 NM_001037165

CCDS: CCDS34591

Canonical transcript exons

ENST00000328914 — 9 exons

Exon	Start	End
ENSE00001316575	4762184	4771442
ENSE00001425689	4740838	4741023
ENSE00001429534	4682295	4682868
ENSE00002215967	4756994	4757187
ENSE00002222429	4759311	4759595
ENSE00002259588	4755237	4755383
ENSE00002288533	4754459	4754615
ENSE00002317538	4761064	4761288
ENSE00002319975	4759051	4759217

Expression profiles

Bgee: expression breadth ubiquitous, 256 present calls, max score 96.45.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 31.4625 / max 149.2756, expressed in 1808 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
77072	30.2548	1808
77071	0.5888	368
77073	0.3051	128
77077	0.2548	103
77074	0.0591	14

Top tissues by expression

256 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
upper arm skin	UBERON:0004263	96.45	gold quality
tendon of biceps brachii	UBERON:0008188	94.91	gold quality
cerebellar vermis	UBERON:0004720	93.55	gold quality
kidney epithelium	UBERON:0004819	93.34	gold quality
cardiac muscle of right atrium	UBERON:0003379	93.05	gold quality
medial globus pallidus	UBERON:0002477	92.55	gold quality
pons	UBERON:0000988	92.44	gold quality
left ventricle myocardium	UBERON:0006566	92.43	gold quality
middle temporal gyrus	UBERON:0002771	92.37	gold quality
superior vestibular nucleus	UBERON:0007227	91.75	gold quality
globus pallidus	UBERON:0001875	91.54	gold quality
medulla oblongata	UBERON:0001896	91.45	gold quality
dorsal plus ventral thalamus	UBERON:0001897	91.20	gold quality
subthalamic nucleus	UBERON:0001906	91.10	gold quality
Brodmann (1909) area 23	UBERON:0013554	91.04	gold quality
inferior vagus X ganglion	UBERON:0005363	90.90	gold quality
oviduct epithelium	UBERON:0004804	90.78	gold quality
gingival epithelium	UBERON:0001949	90.61	gold quality
saphenous vein	UBERON:0007318	90.58	gold quality
ventral tegmental area	UBERON:0002691	90.40	gold quality
renal medulla	UBERON:0000362	90.35	gold quality
parietal lobe	UBERON:0001872	90.03	gold quality
gingiva	UBERON:0001828	89.93	gold quality
postcentral gyrus	UBERON:0002581	89.81	gold quality
mammary duct	UBERON:0001765	89.58	gold quality
epithelium of mammary gland	UBERON:0003244	89.57	gold quality
pancreatic ductal cell	CL:0002079	89.54	gold quality
esophagus squamous epithelium	UBERON:0006920	89.42	gold quality
lateral nuclear group of thalamus	UBERON:0002736	89.25	gold quality
myocardium	UBERON:0002349	89.13	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.34
E-CURD-112	yes	4.01
E-MTAB-7249	no	2029.28

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

4 targets.

Target	Regulation
CTSA	Unknown
EIF3K
SCN5A	Repression
TNF	Activation

JASPAR motifs

Motif	Name	Family
MA0852.2	FOXK1	FOX
MA0852.3	FOXK1	FOX

JASPAR matrix evidence (PMIDs): PMID:16624804

Upstream regulators (CollecTRI, top): SOX15

miRNA regulators (miRDB)

287 targeting FOXK1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-1229-3P	99.97	66.49	906
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-4666A-3P	99.96	71.71	3434

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 15.9% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• crystallographic analysis of the FOXK1a-DNA complex (PMID:16624804)
• FOXK1 binds to the promoter and regulates expression of DHFR, TYMS, GSDMD, and the E2F binding partner TFDP1. (PMID:22740631)
• FOXK1 and FOXK2 positively regulate Wnt/beta-catenin signaling by translocating dishevelled proteins into the nucleus. (PMID:25805136)
• Overall, these results demonstrate a novel role for FOXK1 in regulating the expression of antiviral genes via Nup98, from insects to humans. (PMID:25852164)
• FOXK1 protein levels and activity are regulated by associating with JLP and PLK1 (PMID:26468278)
• The higher expression of FOXK1 could indicate a poor prognosis in colorectal carcinoma (CRC) patients since FOXK1 induces epithelial-mesenchymal transition and promotes CRC cell invasion in vitro and in vivo. (PMID:27223064)
• These findings implicate FOXK1 as a cell cycle and growth modulator that inhibits apoptosis in colon cancer cells. FOXK1-shRNA may serve as a novel and potent therapeutic agent, alone or with 5-FU, against colon cancer (PMID:27571921)
• c-jun promoted FOXK1-mediated proliferation and metastasis via orthotopic implantation. (PMID:27882939)
• For FOXK1 and KCNA7, the age effect on the sperm epigenome was replicated in an independent cohort of 188 sperm samples. (PMID:28171595)
• Results demonstrated that knockdown of FOXK1 inhibited the proliferation and metastasis of prostate cancer, at least in part, through suppressing the Wnt/beta-catenin signaling pathway. (PMID:28267429)
• Knockdown of FOXK1 significantly inhibited hepatocellular carcinoma cell proliferation, migration and invasion. (PMID:28551547)
• our results uncovered a novel, unexpected regulatory function of RUFY3. We identified FOXK1 as a new RUFY3-binding protein. This study shed light on the critical role of RUFY3 in inducing EMT and in the migration and invasion phenotypes caused by abnormal FOXK1 expression. (PMID:28623323)
• FOXK1 was overexpressed in esophageal cancer (EC) tissues compared with corresponding non-tumor tissues using immunohistochemistry. And high FOXK1 expression was related to poor differentiation of EC. The Kaplan-Meier curve indicated that high FOXK1 expression may result in poor prognosis of EC patients. (PMID:29050933)
• demonstrated that circMAN2B2 acts as an oncogenic role in lung cancer through promoting FOXK1 expression by sponging miR-1275 (PMID:29550475)
• Authors show that a nuclear-cytoplasmic transport system is necessary for the mTORC1-FOXK1 signal transduction. This reaction is mediated by a shuttling protein B56, which is a regulatory subunit of PP2A and plays an essential role in the mTORC1-dependent dephosphorylation of FOXK1. (PMID:29845697)
• LINC02163 regulates growth and epithelial-to-mesenchymal transition phenotype via miR-593-3p/FOXK1 axis in gastric cancer cells (PMID:29893595)
• Knockdown of FOXK1 reduced cell viability and HK2 expression, decreased glucose consumption and lactate production in liver cancer cells. Furthermore, FOXK1 knockdown suppressed the activation of Akt/mTOR pathway. Inhibition of Akt/mTOR pathway reduced cell viability and glycolysis of liver cancer cells. (PMID:30312701)
• Coexpression of FOXK1 and vimentin enhances cell metastasis through the induction of epithelial-mesenchymal transition in gastric cancer cells. (PMID:30483822)
• This work identified that CCDC43 promoted epithelial-mesenchymal transition and was a direct transcriptional target of FOXK1 in colorectal cancer cells. (PMID:30562730)
• in vitro and in vivo experiments, including studies of primary human cells, show how FOXK1 and/or FOXK2 are likely to act as important regulators that reprogram cellular metabolism to induce aerobic glycolysis (PMID:30700909)
• Silencing of FOXK1 expression enhanced the inhibitory effects of miR-186-5p on OS cell proliferation, migration and invasion. (PMID:30897321)
• FOXK1 was overexpressed in human hepatocellular carcinoma and positively correlated with cancer progression. DNA hypomethylation and gene copy number variation contributed to the overexpression of FOXK1. (PMID:31054270)
• the miR-498 was found to target the 3’-UTR of lncRNA CASC11 and FOXK1 mRNA. (PMID:31121483)
• Investigated the role between MCM3AP antisense RNA 1 (MCM3AP-AS1) and miR-138-5p, and between microRNA 138-5p and forkhead box K1 (FOXK1), in pancreatic cancer. (PMID:31830901)
• miR-1294 alleviates epithelial-mesenchymal transition process in gastric cancer by targeting FOXK1. (PMID:31833046)
• CHK2-FOXK axis promotes transcriptional control of autophagy programs. (PMID:31911943)
• Long non-coding RNA HUMT hypomethylation promotes lymphangiogenesis and metastasis via activating FOXK1 transcription in triple-negative breast cancer. (PMID:32138762)
• Nuclear DLC1 exerts oncogenic function through association with FOXK1 for cooperative activation of MMP9 expression in melanoma. (PMID:32214200)
• miR-195-5p Suppresses Lung Cancer Cell Proliferation, Migration, and Invasion Via FOXK1. (PMID:32406336)
• Aurora-A/SOX8/FOXK1 signaling axis promotes chemoresistance via suppression of cell senescence and induction of glucose metabolism in ovarian cancer organoids and cells. (PMID:32550913)
• Tumor-derived neomorphic mutations in ASXL1 impairs the BAP1-ASXL1-FOXK1/K2 transcription network. (PMID:32683582)
• FOXK1 Participates in DNA Damage Response by Controlling 53BP1 Function. (PMID:32783940)
• LINC00460 Enhances Bladder Carcinoma Cell Proliferation and Migration by Modulating miR-612/FOXK1 Axis. (PMID:33027786)
• Forkhead box K1 facilitates growth of papillary thyroid carcinoma cells by regulating connective tissue growth factor expression. (PMID:33098545)
• FOXK1 plays an oncogenic role in the progression of hilar cholangiocarcinoma. (PMID:33300075)
• Hsa_circ_0041103 induces proliferation, migration and invasion in bladder cancer via the miR-107/FOXK1 axis. (PMID:33629298)
• circ-PRKCI targets miR-1294 and miR-186-5p by downregulating FOXK1 expression to suppress glycolysis in hepatocellular carcinoma. (PMID:33880589)
• Circular RNA Eps15-homology domain containing protein 2 motivates proliferation, glycolysis but refrains autophagy in non-small cell lung cancer via crosstalk with microRNA-3186-3p and forkhead box K1. (PMID:35220908)
• TRPM2-AS promotes paclitaxel resistance in prostate cancer by regulating FOXK1 via sponging miR-497-5p. (PMID:35238054)
• FOXK1 regulates epithelial-mesenchymal transition and radiation sensitivity in nasopharyngeal carcinoma via the JAK/STAT3 signaling pathway. (PMID:37043129)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	foxk1	ENSDARG00000037872
mus_musculus	Foxk1	ENSMUSG00000056493
rattus_norvegicus	Foxk1	ENSRNOG00000001104

Paralogs (41): FOXP3 (ENSG00000049768), FOXC1 (ENSG00000054598), FOXJ2 (ENSG00000065970), FOXF1 (ENSG00000103241), FOXN1 (ENSG00000109101), FOXM1 (ENSG00000111206), FOXP1 (ENSG00000114861), FOXO3 (ENSG00000118689), FOXA2 (ENSG00000125798), FOXA1 (ENSG00000129514), FOXJ1 (ENSG00000129654), FOXK2 (ENSG00000141568), FOXO1 (ENSG00000150907), FOXH1 (ENSG00000160973), FOXQ1 (ENSG00000164379), FOXD4 (ENSG00000170122), FOXA3 (ENSG00000170608), FOXB1 (ENSG00000171956), FOXR1 (ENSG00000176302), FOXL1 (ENSG00000176678), FOXC2 (ENSG00000176692), FOXE1 (ENSG00000178919), FOXS1 (ENSG00000179772), FOXL2 (ENSG00000183770), FOXO4 (ENSG00000184481), FOXD4L1 (ENSG00000184492), FOXD4L4 (ENSG00000184659), FOXD2 (ENSG00000186564), FOXI2 (ENSG00000186766), FOXE3 (ENSG00000186790), FOXD3 (ENSG00000187140), FOXD4L3 (ENSG00000187559), FOXR2 (ENSG00000189299), FOXJ3 (ENSG00000198815), FOXO6 (ENSG00000204060), FOXB2 (ENSG00000204612), FOXD4L5 (ENSG00000204779), FOXI3 (ENSG00000214336), FOXL3 (ENSG00000248767), FOXD1 (ENSG00000251493)

Protein

Protein identifiers

Forkhead box protein K1 — P85037 (reviewed: P85037)

Alternative names: Myocyte nuclear factor

All UniProt accessions (2): P85037, U3KQ26

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional regulator involved in different processes such as glucose metabolism, aerobic glycolysis, muscle cell differentiation and autophagy. 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. Together with FOXK2, 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. 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. Probably plays a role in gluconeogenesis during overnight fasting, when lactate from white adipose tissue and muscle is the main substrate. Involved in mTORC1-mediated metabolic reprogramming: in response to mTORC1 signaling, translocates into the nucleus and regulates the expression of genes associated with glycolysis and downstream anabolic pathways, such as HIF1A, thereby regulating glucose metabolism. Together with FOXK2, 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. Acts as a transcriptional regulator of the myogenic progenitor cell population in skeletal muscle. Binds to the upstream enhancer region (CCAC box) of myoglobin (MB) gene, regulating the myogenic progenitor cell population. Promotes muscle progenitor cell proliferation by repressing the transcriptional activity of FOXO4, thereby inhibiting myogenic differentiation. Involved in remodeling processes of adult muscles that occur in response to physiological stimuli. Required to correct temporal orchestration of molecular and cellular events necessary for muscle repair. Represses myogenic differentiation by inhibiting MEFC activity. Positively regulates Wnt/beta-catenin signaling by translocating DVL into the nucleus. Reduces virus replication, probably by binding the interferon stimulated response element (ISRE) to promote antiviral gene expression. Accessory component of the polycomb repressive deubiquitinase (PR-DUB) complex; recruits the PR-DUB complex to specific FOXK1-bound genes. Acts as an indirect positive regulator of ferroptosis following phosphorylation by isoform Beta-II of PRKCB by promoting expression and subsequent secretion of LGALS13.

Subunit / interactions. Interacts with SIN3A and SIN3B (via PAH2) to form a complex which represses transcription. Component of SIN3A-, but not SIN3B-, containing multiprotein complexes. Interacts with FOXO4 and MEF2C; both interactions inhibit FOXO4 and MEF2C transactivation activity. Interacts (when phosphorylated) with YWHAE/14-3-3-epsilon; promotes sequestration in the cytoplasm and leads to impaired ability to bind DNA. Interacts with FHL2. Interacts with SRF. Interacts with DVL2 and DVL3; the interaction induces DVL2 nuclear translocation. Interacts with BAP1 (when phosphorylated). Accessory component of the polycomb repressive deubiquitinase (PR-DUB) complex, at least composed of BAP1, one of ASXL1, ASXL2 or (probably) ASXL3 and one of MBD5 or MBD6. The PR-DUB core associates with a number of accessory proteins, including FOXK1, FOXK2, KDM1B, HCFC1 and OGT.

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. Expressed both developing and adult tissues. In adults, significant expression is seen in tumors of the brain, colon and lymph node.

Post-translational modifications. Phosphorylation by GSK3 (GSK3A or GSK3B) promotes interaction with YWHAE/14-3-3-epsilon and retention in the cytoplasm. In response to mTORC1 signaling, phosphorylation by GSK3 is prevented, leading to translocation to the nucleus. Phosphorylation at Ser-441 by isoform Beta-II of PRKCB promotes expression and secretion of LGALS13.

Isoforms (2)

UniProt ID	Names	Canonical?
P85037-1	1, a	yes
P85037-2	2, b

RefSeq proteins (1): NP_001032242* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000253	FHA_dom	Domain
IPR001766	Fork_head_dom	Domain
IPR008984	SMAD_FHA_dom_sf	Homologous_superfamily
IPR018122	TF_fork_head_CS_1	Conserved_site
IPR030456	TF_fork_head_CS_2	Conserved_site
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily
IPR047394	FH_FOXK1	Domain

Pfam: PF00250, PF00498

UniProt features (54 total): modified residue 22, region of interest 6, sequence conflict 6, helix 5, compositionally biased region 3, mutagenesis site 3, strand 3, splice variant 2, initiator methionine 1, chain 1, domain 1, DNA-binding region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
8BZM	X-RAY DIFFRACTION	2.69

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P85037-F1	58.39	0.24

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (22): 2, 101, 161, 191, 213, 223, 239, 243, 245, 247, 253, 257, 295, 299, 416, 420, 422, 428, 436, 441 …

Mutagenesis-validated functional residues (3):

Position	Phenotype
127	reduced interaction with bap1.
355	reduced dna-binding and ability to repress transcription without affecting interaction with srf. no effect on interactio
441	abolished phosphorylation by isoform beta-ii of prkcb.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5689603	UCH proteinases

MSigDB gene sets: 212 (showing top): GOBP_REGULATION_OF_AUTOPHAGY, GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, GOBP_MONOSACCHARIDE_CATABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, chr7p22, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, GOBP_NEGATIVE_REGULATION_OF_AUTOPHAGY, CATTTCA_MIR203, GOBP_MUSCLE_STRUCTURE_DEVELOPMENT, GOBP_REGULATION_OF_CATABOLIC_PROCESS, GOBP_REGULATION_OF_CARBOHYDRATE_METABOLIC_PROCESS

GO Biological Process (12): intracellular glucose homeostasis (GO:0001678), regulation of transcription by RNA polymerase II (GO:0006357), muscle organ development (GO:0007517), negative regulation of autophagy (GO:0010507), regulation of glucose metabolic process (GO:0010906), cell differentiation (GO:0030154), response to starvation (GO:0042594), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of DNA-templated transcription (GO:0045893), canonical glycolysis (GO:0061621), negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (11): transcription cis-regulatory region binding (GO:0000976), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), DNA-binding transcription factor activity (GO:0003700), 14-3-3 protein binding (GO:0071889), sequence-specific double-stranded DNA binding (GO:1990837), RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), DNA binding (GO:0003677), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565)

GO Cellular Component (4): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Deubiquitination	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	4
DNA-templated transcription	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
cellular anatomical structure	3
transcription by RNA polymerase II	2
regulation of transcription by RNA polymerase II	2
transcription cis-regulatory region binding	2
glucose homeostasis	1
intracellular chemical homeostasis	1
animal organ development	1
muscle structure development	1
autophagy	1
negative regulation of catabolic process	1
regulation of autophagy	1
glucose metabolic process	1
regulation of carbohydrate metabolic process	1
regulation of small molecule metabolic process	1
cellular developmental process	1
response to stress	1
response to nutrient levels	1
negative regulation of RNA biosynthetic process	1
positive regulation of RNA biosynthetic process	1
glucokinase activity	1
glyceraldehyde-3-phosphate dehydrogenase (NAD+) (phosphorylating) activity	1
glucose catabolic process	1
glycolytic process through glucose-6-phosphate	1
negative regulation of DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
transcription regulatory region nucleic acid binding	1
sequence-specific double-stranded DNA binding	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
negative regulation of transcription by RNA polymerase II	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription repressor activity	1
transcription regulator activity	1
protein binding	1
double-stranded DNA binding	1

Protein interactions and networks

STRING

1939 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FOXK1	OGT	O15294	943
FOXK1	ASXL1	Q8IXJ9	918
FOXK1	SIN3A	Q96ST3	905
FOXK1	HCFC1	P51610	883
FOXK1	Q08EI0	Q08EI0	829
FOXK1	BAP1	Q92560	798
FOXK1	SIN3B	O75182	791
FOXK1	ASXL2	Q76L83	768
FOXK1	MBD5	Q9P267	634
FOXK1	ABO	P16442	603
FOXK1	YY1	P25490	538
FOXK1	BBX	Q8WY36	497
FOXK1	FOXP2	O15409	488
FOXK1	BRCA1	P38398	469
FOXK1	DYRK1A	Q13627	464

IntAct

217 interactions, top by confidence:

A	B	Type	Score
HDAC1	CDK2AP1	psi-mi:“MI:0914”(association)	0.840
RBBP7	CDK2AP1	psi-mi:“MI:0914”(association)	0.840
HDAC1	TNRC18	psi-mi:“MI:0914”(association)	0.790
RFXANK	RFXAP	psi-mi:“MI:0914”(association)	0.780
TP63	TP73	psi-mi:“MI:0914”(association)	0.770
PDGFRB	PDGFRA	psi-mi:“MI:0914”(association)	0.770
BAP1	OGT	psi-mi:“MI:0914”(association)	0.730
RBBP7	HAT1	psi-mi:“MI:0914”(association)	0.730
TANC2	TAX1BP3	psi-mi:“MI:0914”(association)	0.690
SINHCAF	TNRC18	psi-mi:“MI:0914”(association)	0.640
TFAP4	ANGPTL7	psi-mi:“MI:0914”(association)	0.640
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
YWHAB	BLTP3B	psi-mi:“MI:2364”(proximity)	0.610
PDGFRB	PIK3R2	psi-mi:“MI:0914”(association)	0.610
DCAF7	PFDN6	psi-mi:“MI:0914”(association)	0.570
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
RABGGTB	PIPSL	psi-mi:“MI:0914”(association)	0.530
GPS2	DCTN6	psi-mi:“MI:0914”(association)	0.530
DVL3	DVL2	psi-mi:“MI:0914”(association)	0.530
TRAK2	OGT	psi-mi:“MI:0914”(association)	0.530
IRF2	CTSS	psi-mi:“MI:0914”(association)	0.530
FHL2	CNOT1	psi-mi:“MI:0914”(association)	0.530

BioGRID (351): FOXK1 (Affinity Capture-MS), FOXK1 (Affinity Capture-MS), FOXK1 (Affinity Capture-MS), FOXK1 (Affinity Capture-MS), FOXK1 (Affinity Capture-MS), FOXK1 (Affinity Capture-MS), FOXK1 (Affinity Capture-MS), FOXK1 (Affinity Capture-MS), FOXK1 (Affinity Capture-MS), FOXK1 (Co-fractionation), FOXK1 (Co-fractionation), FOXK1 (Co-fractionation), NAA10 (Co-fractionation), FOXK1 (Affinity Capture-MS), FOXK1 (Affinity Capture-MS)

ESM2 similar proteins: A1L1I3, A5PKW4, O08919, O70405, O75385, O75420, O75553, P16554, P42128, P49757, P53814, P85037, P97318, P98081, Q04637, Q2LC84, Q3UCQ1, Q4KMP7, Q5DTT2, Q5I1X5, Q5RBR0, Q5VZ18, Q69ZH9, Q69ZI1, Q7TN02, Q7Z6J0, Q80VC9, Q80XI3, Q80Z38, Q86V15, Q8BGT6, Q8BHL3, Q8BSD5, Q8C120, Q8CI12, Q8IY33, Q8K4J6, Q8N3F8, Q8TEH3, Q8TEJ3

Diamond homologs: A0A078BQN7, A0A1W2PRP0, A0A8V0YY16, A1L1S5, A3KNJ3, A8MTJ6, A8XJN7, B5RHS5, D3Z120, F1R8Z9, O00358, O17617, O43638, O54743, O60129, O88470, P32027, P32028, P32030, P32315, P42128, P55316, P56260, P58012, P79772, P85037, P91278, Q00939, Q01167, Q02360, Q12946, Q12947, Q12948, Q12950, Q12951, Q12952, Q13461, Q19802, Q1A1A1, Q1A1A2

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 227 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Activation of BAD and translocation to mitochondria	6	30.9×	5e-06
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	6	27.2×	7e-06
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	6	27.2×	7e-06
Activation of BH3-only proteins	6	20.1×	3e-05
RHO GTPases activate PKNs	7	15.0×	3e-05
Intrinsic Pathway for Apoptosis	7	13.8×	5e-05
Transcriptional Regulation by E2F6	6	11.9×	5e-04
Translocation of SLC2A4 (GLUT4) to the plasma membrane	8	8.3×	3e-04

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of stem cell population maintenance	9	34.1×	8e-10
positive regulation of stem cell population maintenance	9	15.3×	1e-06
negative regulation of gene expression, epigenetic	6	11.9×	2e-03
protein targeting	6	10.9×	2e-03
negative regulation of neuron differentiation	6	8.1×	9e-03
negative regulation of transforming growth factor beta receptor signaling pathway	9	7.7×	4e-04
negative regulation of cell migration	10	5.5×	2e-03
chromatin remodeling	15	5.4×	2e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

116 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	91
Likely benign	7
Benign	6

Top pathogenic / likely-pathogenic (0)

SpliceAI

2821 predictions. Top by Δscore:

Variant	Effect	Δscore
7:4682866:GCA:G	donor_gain	1.0000
7:4682869:G:GG	donor_gain	1.0000
7:4740834:GCA:G	acceptor_loss	1.0000
7:4740835:CA:C	acceptor_loss	1.0000
7:4740836:A:AG	acceptor_gain	1.0000
7:4740836:AG:A	acceptor_gain	1.0000
7:4740836:AGGT:A	acceptor_gain	1.0000
7:4740837:G:GT	acceptor_gain	1.0000
7:4740837:GG:G	acceptor_gain	1.0000
7:4740837:GGT:G	acceptor_gain	1.0000
7:4740837:GGTG:G	acceptor_gain	1.0000
7:4740837:GGTGT:G	acceptor_gain	1.0000
7:4741020:TCAG:T	donor_gain	1.0000
7:4741024:G:GA	donor_loss	1.0000
7:4741024:G:GG	donor_gain	1.0000
7:4754454:CTCA:C	acceptor_loss	1.0000
7:4754455:TCAGT:T	acceptor_loss	1.0000
7:4754457:A:AC	acceptor_loss	1.0000
7:4754457:A:AG	acceptor_gain	1.0000
7:4754457:AGT:A	acceptor_gain	1.0000
7:4754458:G:GT	acceptor_gain	1.0000
7:4754458:GT:G	acceptor_gain	1.0000
7:4754458:GTG:G	acceptor_gain	1.0000
7:4754458:GTGT:G	acceptor_gain	1.0000
7:4754458:GTGTC:G	acceptor_gain	1.0000
7:4755236:GGAT:G	acceptor_gain	1.0000
7:4761058:CCGCA:C	acceptor_loss	1.0000
7:4761059:CGCAG:C	acceptor_loss	1.0000
7:4761060:GCA:G	acceptor_loss	1.0000
7:4761062:A:AG	acceptor_gain	1.0000

AlphaMissense

4650 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:4682682:T:A	I125N	1.000
7:4682684:G:C	G126R	1.000
7:4682685:G:A	G126D	1.000
7:4682685:G:T	G126V	1.000
7:4682687:C:A	R127S	1.000
7:4682735:T:C	F143L	1.000
7:4682737:C:A	F143L	1.000
7:4682737:C:G	F143L	1.000
7:4682739:T:A	I144N	1.000
7:4682751:A:G	H148R	1.000
7:4682754:T:C	L149P	1.000
7:4682787:T:C	L160P	1.000
7:4682792:T:C	C162R	1.000
7:4682794:C:G	C162W	1.000
7:4682798:G:C	G164R	1.000
7:4682799:G:A	G164D	1.000
7:4682799:G:T	G164V	1.000
7:4682802:A:T	K165M	1.000
7:4682803:G:C	K165N	1.000
7:4682803:G:T	K165N	1.000
7:4682804:A:G	N166D	1.000
7:4682805:A:T	N166I	1.000
7:4682806:C:A	N166K	1.000
7:4682806:C:G	N166K	1.000
7:4682807:G:C	G167R	1.000
7:4682807:G:T	G167C	1.000
7:4682808:G:A	G167D	1.000
7:4682808:G:T	G167V	1.000
7:4682811:T:A	V168D	1.000
7:4682828:T:C	F174L	1.000

dbSNP variants (sampled 300 via entrez): RS1000023255 (7:4713153 T>C,G), RS1000038840 (7:4735460 T>C,G), RS1000044813 (7:4682985 G>A,C), RS1000057272 (7:4681750 A>G,T), RS1000059766 (7:4697789 GTTTC>G), RS1000138426 (7:4726306 C>T), RS1000193786 (7:4741934 G>A,T), RS1000199489 (7:4765180 A>C), RS1000214134 (7:4760314 C>G), RS1000239632 (7:4708839 C>T), RS1000241946 (7:4750235 G>A,C), RS1000245560 (7:4763246 G>A), RS1000281660 (7:4765443 C>G), RS1000315308 (7:4691671 C>A,G,T), RS1000320518 (7:4692866 A>G)

Disease associations

OMIM: gene MIM:616302 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST003075_129	Cognitive decline rate in late mild cognitive impairment	1.000000e-06
GCST003075_20	Cognitive decline rate in late mild cognitive impairment	6.000000e-07
GCST004861_91	Itch intensity from mosquito bite	1.000000e-08
GCST004863_92	Mosquito bite size	9.000000e-09
GCST005359_13	Disease progression in age-related macular degeneration	4.000000e-06
GCST006630_9	Diastolic blood pressure	2.000000e-09
GCST006979_722	Heel bone mineral density	1.000000e-09
GCST007880_6	Emotional lability in attention deficit hyperactivity disorder	8.000000e-06
GCST010241_310	Apolipoprotein A1 levels	2.000000e-08

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0007710	cognitive decline measurement
EFO:0008377	mosquito bite reaction itch intensity measurement
EFO:0008378	mosquito bite reaction size measurement
EFO:0008336	disease progression measurement
EFO:0006336	diastolic blood pressure
EFO:0009270	heel bone mineral density
EFO:0008475	mood instability measurement
EFO:0004614	apolipoprotein A 1 measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066443 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.45	Kd	3.587	nM	CHEMBL3752910
8.45	ED50	3.587	nM	CHEMBL3752910

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149862: Binding affinity to human FOXK1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0036	uM

CTD chemical–gene interactions

46 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases methylation, affects cotreatment, decreases expression	5
trichostatin A	affects cotreatment, decreases expression	4
Acetaminophen	decreases expression, increases expression	2
Benzo(a)pyrene	affects methylation, decreases expression	2
GSK-J4	increases expression	1
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
methylmercuric chloride	decreases expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
beta-lapachone	increases expression	1
arsenite	affects binding, decreases reaction	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
ochratoxin A	affects cotreatment, increases expression	1
coumarin	increases phosphorylation	1
methacrylaldehyde	decreases expression, increases abundance, affects cotreatment	1
avobenzone	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Decitabine	affects cotreatment, decreases expression	1
Sunitinib	increases expression	1
Acrolein	affects cotreatment, decreases expression, increases abundance	1
Air Pollutants	affects cotreatment, decreases expression, increases abundance	1
Arsenic	affects methylation	1
Vehicle Emissions	increases methylation	1
Cadmium	decreases expression, increases abundance	1
Caffeine	affects phosphorylation	1
Calcitriol	increases expression	1
Cisplatin	decreases expression	1
Citrinin	affects cotreatment, increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652904	Binding	Binding affinity to human FOXK1 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.