FOXK2

Summary

FOXK2 (forkhead box K2, HGNC:6036) is a protein-coding gene on chromosome 17q25.3, encoding Forkhead box protein K2 (Q01167). Transcriptional regulator involved in different processes such as glucose metabolism, aerobic glycolysis and autophagy.

The protein encoded by this gene contains a fork head DNA binding domain. This protein can bind to the purine-rich motifs of the HIV long terminal repeat (LTR), and to the similar purine-rich motif in the interleukin 2 (IL2) promoter. It may be involved in the regulation of viral and cellular promoter elements.

Source: NCBI Gene 3607 — RefSeq curated summary.

At a glance

• GWAS associations: 18
• Clinical variants (ClinVar): 169 total
• MANE Select transcript: NM_004514

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6036
Approved symbol	FOXK2
Name	forkhead box K2
Location	17q25.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000141568
Ensembl biotype	protein_coding
OMIM	147685
Entrez	3607

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 8 protein_coding, 4 protein_coding_CDS_not_defined, 2 retained_intron, 1 nonsense_mediated_decay, 1 TEC

ENST00000335255, ENST00000473637, ENST00000526383, ENST00000527313, ENST00000529652, ENST00000531030, ENST00000570585, ENST00000571160, ENST00000571989, ENST00000574694, ENST00000575578, ENST00000624186, ENST00000929249, ENST00000949344, ENST00000949345, ENST00000949346

RefSeq mRNA: 1 — MANE Select: NM_004514 NM_004514

CCDS: CCDS11813

Canonical transcript exons

ENST00000335255 — 9 exons

Exon	Start	End
ENSE00001112227	82585904	82586200
ENSE00001112229	82582741	82582934
ENSE00001112230	82587063	82587272
ENSE00001334520	82571724	82571870
ENSE00001362311	82601303	82604602
ENSE00002142812	82519732	82520307
ENSE00003489634	82563354	82563548
ENSE00003528735	82568054	82568201
ENSE00003667493	82584013	82584188

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 95.04.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 41.3068 / max 743.7405, expressed in 1817 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
163524	33.4798	1806
163525	6.2725	1742
163530	1.3305	671
163523	0.1627	69
163527	0.0613	39

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	95.04	gold quality
gastrocnemius	UBERON:0001388	92.53	gold quality
sural nerve	UBERON:0015488	92.40	gold quality
muscle of leg	UBERON:0001383	92.06	gold quality
cortical plate	UBERON:0005343	92.06	gold quality
ganglionic eminence	UBERON:0004023	91.69	gold quality
oocyte	CL:0000023	91.43	gold quality
hindlimb stylopod muscle	UBERON:0004252	91.28	gold quality
ventricular zone	UBERON:0003053	91.21	gold quality
left testis	UBERON:0004533	91.10	gold quality
right testis	UBERON:0004534	90.71	gold quality
gingival epithelium	UBERON:0001949	90.48	gold quality
testis	UBERON:0000473	89.99	gold quality
sperm	CL:0000019	89.97	gold quality
skin of abdomen	UBERON:0001416	89.47	gold quality
muscle organ	UBERON:0001630	89.20	gold quality
skin of leg	UBERON:0001511	89.17	gold quality
popliteal artery	UBERON:0002250	88.96	gold quality
tibial artery	UBERON:0007610	88.96	gold quality
right adrenal gland cortex	UBERON:0035827	88.75	gold quality
tibialis anterior	UBERON:0001385	88.73	silver quality
male germ cell	CL:0000015	88.61	gold quality
adenohypophysis	UBERON:0002196	88.59	gold quality
adrenal gland	UBERON:0002369	88.57	gold quality
left adrenal gland cortex	UBERON:0035825	88.53	gold quality
lower esophagus mucosa	UBERON:0035834	88.50	gold quality
colonic epithelium	UBERON:0000397	88.40	gold quality
stromal cell of endometrium	CL:0002255	88.12	gold quality
muscle layer of sigmoid colon	UBERON:0035805	88.08	gold quality
adrenal cortex	UBERON:0001235	88.05	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.20

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
IL2	Unknown
SIN3A	Unknown

JASPAR motifs

Motif	Name	Family
MA1103.1	FOXK2	FOX
MA1103.2	FOXK2	FOX
MA1103.3	FOXK2	FOX

JASPAR matrix evidence (PMIDs): PMID:26578569

miRNA regulators (miRDB)

112 targeting FOXK2, 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-5692A	100.00	74.40	6850
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-6793-5P	99.97	65.95	758
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-4782-3P	99.88	73.31	735
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942

Literature-anchored findings (GeneRIF, showing 29)

• FOXK2 is a G/T-mismatch DNA-binding protein and a deaminated DNA-binding protein (PMID:20097901)
• Data show that FOXK2 is subject to control by cell cycle-regulated hyperphosphorylation occurring in CDK).cyclin-dependent manner with CDK1.cyclin B as the major kinase complex. (PMID:20810654)
• FOXK2 can promote transcriptional activation and is required for the efficient recruitment of AP-1 components to chromatin. (PMID:22083952)
• BAP1 deficiency causes increased expression of FoxK2 target genes in a Ring1B-Bmi1-dependent manner (PMID:25451922)
• FOXK2 might act as a negative regulator of ERalpha, and its association with both ERalpha and BRCA1/BARD1 could lead to the down-regulation of ERalpha transcriptional activity, effectively regulating the function of ERalpha. (PMID:25740706)
• FOXK1 and FOXK2 positively regulate Wnt/beta-catenin signaling by translocating dishevelled proteins into the nucleus. (PMID:25805136)
• FOXO3-dependent gene regulation is generally mediated not through uniquely bound regions but through regions occupied by both FOXK2 and FOXO3 where both factors play a regulatory role. (PMID:26578569)
• SOX9 transcriptionally activated FOXK2 was involved in the pathogenesis of colorectal cancer.FOXK2 is highly expressed in colorectal cancer tissues. (PMID:28007600)
• Results show that Foxk2 expression was downregulated in lung adenocarcinoma tissues and non-small cell lung cancer cell (NSCLC) lines. Its overexpression suppresses epithelial-mesenchymal transition in NSCLC cells and inhibits cell migration and invasion. Also, the expression of Foxk2 seems to be regulated by miR-1271. (PMID:28260088)
• FOXK2, regulted by miR-1271-5p, promotes cell growth and indicates unfavorable prognosis in hepatocellular carcinoma (PMID:28506857)
• our results indicate that FOXK2 inhibits the malignant phenotype of clear-cell renal cell carcinoma and acts as a tumor suppressor possibly through the inhibition of EGFR. (PMID:29368368)
• the findings of the present study demonstrated that FOXK2 functions as a tumor suppressor in gastric cancer; the loss of FOXK2 may induce the growth and invasion of gastric cancer cells. (PMID:30221666)
• 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)
• Forkhead box K2 promotes human colorectal cancer metastasis by upregulating ZEB1 and EGFR. (PMID:31281520)
• Results identified FOXK2 as a functional target for miR-602 and its expression downregulated which is inversely correlated with that of miR-602 in esophageal squamous cell carcinoma (ESCC) tissue samples. (PMID:31401147)
• CHK2-FOXK axis promotes transcriptional control of autophagy programs. (PMID:31911943)
• Circular RNA Circ-ITCH Inhibits the Malignant Behaviors of Cervical Cancer by microRNA-93-5p/FOXK2 Axis. (PMID:31993998)
• CircFOXK2 Promotes Growth and Metastasis of Pancreatic Ductal Adenocarcinoma by Complexing with RNA-Binding Proteins and Sponging MiR-942. (PMID:32217695)
• Tumor-derived neomorphic mutations in ASXL1 impairs the BAP1-ASXL1-FOXK1/K2 transcription network. (PMID:32683582)
• The forkhead transcription factor FOXK2 premarks lineage-specific genes in human embryonic stem cells for activation during differentiation. (PMID:33434264)
• CircRNA circFOXK2 facilitates oncogenesis in breast cancer via IGF2BP3/miR-370 axis. (PMID:34329193)
• FOXK2 transcriptionally activating VEGFA induces apatinib resistance in anaplastic thyroid cancer through VEGFA/VEGFR1 pathway. (PMID:34489549)
• Long non-coding RNA tumor protein 53 target gene 1 promotes cervical cancer development via regulating microRNA-33a-5p to target forkhead box K2. (PMID:35090377)
• FOXK2 promotes ovarian cancer stemness by regulating the unfolded protein response pathway. (PMID:35349489)
• FOXK2 affects cancer cell response to chemotherapy by promoting nucleotide de novo synthesis. (PMID:36682222)
• CircFOXK2 promotes hepatocellular carcinoma progression and leads to a poor clinical prognosis via regulating the Warburg effect. (PMID:36922872)
• FOXK2 regulates PFKFB3 in promoting glycolysis and tumorigenesis in multiple myeloma. (PMID:37356282)
• FOXK2 targeting by the SCF-E3 ligase subunit FBXO24 for ubiquitin mediated degradation modulates mitochondrial respiration. (PMID:38735474)
• FOXK2 amplification promotes breast cancer development and chemoresistance. (PMID:38901667)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	foxk2b	ENSDARG00000011609
danio_rerio	foxk2a	ENSDARG00000030583
mus_musculus	Foxk2	ENSMUSG00000039275
rattus_norvegicus	Foxk2	ENSRNOG00000036663

Paralogs (41): FOXP3 (ENSG00000049768), FOXC1 (ENSG00000054598), FOXJ2 (ENSG00000065970), FOXF1 (ENSG00000103241), FOXN1 (ENSG00000109101), FOXM1 (ENSG00000111206), FOXP1 (ENSG00000114861), FOXO3 (ENSG00000118689), FOXA2 (ENSG00000125798), FOXA1 (ENSG00000129514), FOXJ1 (ENSG00000129654), FOXO1 (ENSG00000150907), FOXH1 (ENSG00000160973), FOXQ1 (ENSG00000164379), FOXK1 (ENSG00000164916), 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 K2 — Q01167 (reviewed: Q01167)

Alternative names: G/T-mismatch specific binding protein, Interleukin enhancer-binding factor 1

All UniProt accessions (4): E9PM37, E9PPI7, Q01167, I3L4U8

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional regulator involved in different processes such as glucose metabolism, aerobic glycolysis 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 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. 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. 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. 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. Also able to bind to a minimal DNA heteroduplex containing a G/T-mismatch with 5’-TRT[G/T]NB-3’ sequence. Binds to NFAT-like motifs (purine-rich) in the IL2 promoter. Positively regulates WNT/beta-catenin signaling by translocating DVL proteins into the nucleus. Also binds to HIV-1 long terminal repeat. May be involved in both positive and negative regulation of important viral and cellular promoter elements. Accessory component of the polycomb repressive deubiquitinase (PR-DUB) complex; recruits the PR-DUB complex to specific FOXK2-bound genes.

Subunit / interactions. Component of SIN3A-, but not SIN3B-, containing multiprotein complexes. Interacts with DVL1, DVL2 (when phosphorylated) and DVL3; the interaction induces DVL2 nuclear translocation. Interacts with SUDS3. Interacts with BAP1 (when phosphorylated); leading to recruit the PR-DUB complex and repress FOXK2 target genes. 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. Interacts with FBXO24.

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. Expressed in both lymphoid and non-lymphoid cells.

Post-translational modifications. Hyperphosphorylated during mitosis by CDK1 and, to a lower extent, CDK2. Phosphorylation at Ser-373 and Ser-428 affects stability by promoting degradation. Ubiquitinated by the SCF-FBXO24 E3 ubiquitin ligase, leading to proteasomal degradation.

Domain organisation. The C-terminal part of the DNA-binding domain may contribute to DNA recognition specificity.

Isoforms (3)

UniProt ID	Names	Canonical?
Q01167-1	1	yes
Q01167-2	2
Q01167-3	3

RefSeq proteins (1): NP_004505* (*=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
IPR047397	FH_FOXK2	Domain
IPR047398	FHA_FOXK2	Domain

Pfam: PF00250, PF00498

UniProt features (81 total): mutagenesis site 32, region of interest 9, modified residue 9, compositionally biased region 6, strand 5, binding site 4, cross-link 4, helix 4, splice variant 3, initiator methionine 1, chain 1, domain 1, DNA-binding region 1, sequence conflict 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
2C6Y	X-RAY DIFFRACTION	2.4
1JXS	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q01167-F1	58.09	0.26

Functional residue map

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

Ligand- & substrate-binding residues (4): 310; 311; 313; 316

Post-translational modifications (13): 2, 30, 144, 239, 373, 398, 424, 428, 599, 161, 164, 527, 633

Mutagenesis-validated functional residues (32):

Position	Phenotype
58	reduced interaction with bap1.
129	no effect on interaction with dvl2.
130	no effect on interaction with dvl2.
131	no effect on interaction with dvl2.
133	no effect on interaction with dvl2.
136	no effect on interaction with dvl2.
137	abolishes interaction with dvl2 and suds3 as well as dvl2 nuclear translocation.
138	no effect on interaction with dvl2.
141	no effect on interaction with dvl2.
142	no effect on interaction with dvl2.
145	abolishes interaction with dvl2 and suds3 as well as dvl2 nuclear translocation.
146	highly reduces interaction with dvl2.
147	no effect on interaction with dvl2.
148	no effect on interaction with dvl2.
150	no effect on interaction with dvl2.
151	no effect on interaction with dvl2.
152	no effect on interaction with dvl2.
154	abolishes interaction with dvl2 and suds3 as well as dvl2 nuclear translocation.
155	no effect on interaction with dvl2.
157	no effect on interaction with dvl2.
258	decreases dna-binding to 40%.
300	decreases dna-binding to 20%.
305	decreases dna-binding to 70%.
307	abolishes dna-binding.
308	no effect on interaction with dvl2.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5689603	UCH proteinases

MSigDB gene sets: 218 (showing top): SHEPARD_BMYB_MORPHOLINO_UP, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, GOBP_MONOSACCHARIDE_CATABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, GOBP_NEGATIVE_REGULATION_OF_AUTOPHAGY, CATTTCA_MIR203, GOBP_REGULATION_OF_CATABOLIC_PROCESS

GO Biological Process (11): intracellular glucose homeostasis (GO:0001678), regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357), negative regulation of autophagy (GO:0010507), regulation of glucose metabolic process (GO:0010906), response to starvation (GO:0042594), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), canonical glycolysis (GO:0061621), negative regulation of transcription by RNA polymerase II (GO:0000122)

GO Molecular Function (11): magnesium ion binding (GO:0000287), 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 activator activity, RNA polymerase II-specific (GO:0001228), DNA-binding transcription factor activity (GO:0003700), sequence-specific DNA binding (GO:0043565), DNA binding (GO:0003677), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (5): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), mitochondrion (GO:0005739), 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
RNA polymerase II transcription regulatory region sequence-specific DNA binding	4
DNA-templated transcription	3
transcription by RNA polymerase II	3
regulation of transcription by RNA polymerase II	3
cellular anatomical structure	3
DNA-binding transcription factor activity, RNA polymerase II-specific	2
intracellular membrane-bounded organelle	2
glucose homeostasis	1
intracellular chemical homeostasis	1
regulation of gene expression	1
regulation of RNA biosynthetic process	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
response to stress	1
response to nutrient levels	1
negative regulation of RNA biosynthetic process	1
positive regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	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
metal ion binding	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 repressor activity	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
transcription cis-regulatory region binding	1
transcription regulator activity	1

Protein interactions and networks

STRING

1916 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FOXK2	SIN3A	Q96ST3	856
FOXK2	ASXL2	Q76L83	785
FOXK2	HCFC1	P51610	643
FOXK2	OGT	O15294	579
FOXK2	GTF2E1	P29083	563
FOXK2	ASXL1	Q8IXJ9	558
FOXK2	GTF2B	Q00403	551
FOXK2	Q08EI0	Q08EI0	547
FOXK2	ANKRD17	O75179	511
FOXK2	DCAF7	P61962	502
FOXK2	GTF2E2	P29084	498
FOXK2	NCOR2	Q9Y618	473
FOXK2	FOXK1	P85037	463
FOXK2	REST	Q13127	451
FOXK2	BBX	Q8WY36	439

IntAct

161 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
TULP3	FOXK2	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
FOXK2	IRF2	psi-mi:“MI:0915”(physical association)	0.770
BAP1	OGT	psi-mi:“MI:0914”(association)	0.730
HDAC1	ZNF609	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
FOXK2	DVL2	psi-mi:“MI:0914”(association)	0.640
SINHCAF	TNRC18	psi-mi:“MI:0914”(association)	0.640
TFAP4	ANGPTL7	psi-mi:“MI:0914”(association)	0.640
KANSL1	FOXK2	psi-mi:“MI:0914”(association)	0.640
TULP3	GGPS1	psi-mi:“MI:0914”(association)	0.640
PDGFRB	PIK3R2	psi-mi:“MI:0914”(association)	0.610
FOXK2	MAX	psi-mi:“MI:0915”(physical association)	0.580
MAX	FOXK2	psi-mi:“MI:0915”(physical association)	0.580
KANSL1	PHF20L1	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
IRF2	CTSS	psi-mi:“MI:0914”(association)	0.530
FHL2	CNOT1	psi-mi:“MI:0914”(association)	0.530
DVL2	WWP2	psi-mi:“MI:0914”(association)	0.530

BioGRID (365): FOXK2 (Affinity Capture-MS), FOXK2 (Affinity Capture-MS), SMU1 (Co-fractionation), TEAD1 (Co-fractionation), FOXK2 (Affinity Capture-Western), ESR1 (Affinity Capture-Western), FOXK2 (Two-hybrid), ESR1 (Reconstituted Complex), BARD1 (Affinity Capture-Western), FOXK2 (Affinity Capture-Western), FOXK2 (Affinity Capture-MS), FOXK2 (Affinity Capture-MS), FOXK2 (Affinity Capture-MS), FOXK2 (Affinity Capture-MS), FOXK2 (Affinity Capture-Western)

ESM2 similar proteins: A0A1W2PQ72, A4IFD2, A7MBH3, D3ZXW3, O35260, O35750, O57337, P14003, P15257, P20823, P22361, P35428, P39880, P42128, P53564, P53565, P56524, P81069, P83038, P85037, Q01167, Q01664, Q04666, Q0V8G2, Q14469, Q3UCQ1, Q3ZBG4, Q5R902, Q5ZI27, Q69YI7, Q6NSM8, Q6NZM9, Q6PFD7, Q6ZTZ1, Q7TSZ8, Q7ZX03, Q80ZH1, Q8BIL2, Q8TAK5, Q8UW00

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

5 interactions.

A	Effect	B	Mechanism
CDK1	up-regulates	FOXK2	phosphorylation
CDK2	up-regulates	FOXK2	phosphorylation
SOX8	“up-regulates quantity by expression”	FOXK2	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 195 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
Formation of WDR5-containing histone-modifying complexes	5	10.6×	9e-03
Regulation of PTEN gene transcription	6	8.6×	7e-03
HDACs deacetylate histones	8	7.7×	3e-03
Potential therapeutics for SARS	8	7.3×	3e-03
UCH proteinases	7	7.0×	7e-03

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of stem cell population maintenance	9	39.6×	3e-10
positive regulation of stem cell population maintenance	10	19.8×	2e-08
negative regulation of gene expression, epigenetic	6	13.8×	6e-04
negative regulation of transforming growth factor beta receptor signaling pathway	9	9.0×	1e-04
negative regulation of cell migration	9	5.8×	3e-03
chromatin organization	10	5.7×	1e-03
transcription by RNA polymerase II	11	4.5×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	111
Likely benign	17
Benign	11

Top pathogenic / likely-pathogenic (0)

SpliceAI

4521 predictions. Top by Δscore:

Variant	Effect	Δscore
17:82563352:A:AG	acceptor_gain	1.0000
17:82563352:AG:A	acceptor_gain	1.0000
17:82563352:AGGT:A	acceptor_gain	1.0000
17:82563353:G:GA	acceptor_gain	1.0000
17:82563353:GG:G	acceptor_gain	1.0000
17:82563353:GGT:G	acceptor_gain	1.0000
17:82563353:GGTG:G	acceptor_gain	1.0000
17:82563353:GGTGC:G	acceptor_gain	1.0000
17:82563544:ATCAG:A	donor_loss	1.0000
17:82563545:TCAG:T	donor_loss	1.0000
17:82563546:CAG:C	donor_loss	1.0000
17:82563547:AG:A	donor_loss	1.0000
17:82563548:GG:G	donor_loss	1.0000
17:82563549:GTGC:G	donor_loss	1.0000
17:82563550:T:G	donor_loss	1.0000
17:82571716:A:AG	acceptor_gain	1.0000
17:82571717:A:G	acceptor_gain	1.0000
17:82571719:TACA:T	acceptor_loss	1.0000
17:82571720:ACAG:A	acceptor_gain	1.0000
17:82571721:CAGG:C	acceptor_loss	1.0000
17:82571722:A:AG	acceptor_gain	1.0000
17:82571722:AG:A	acceptor_gain	1.0000
17:82571722:AGG:A	acceptor_loss	1.0000
17:82571722:AGGAT:A	acceptor_gain	1.0000
17:82571723:G:GG	acceptor_gain	1.0000
17:82571723:GG:G	acceptor_gain	1.0000
17:82571723:GGAT:G	acceptor_gain	1.0000
17:82571723:GGATG:G	acceptor_gain	1.0000
17:82585899:A:AG	acceptor_gain	1.0000
17:82585899:ACCAG:A	acceptor_gain	1.0000

AlphaMissense

4224 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:82520007:T:C	L40P	1.000
17:82520012:G:C	G42R	1.000
17:82520055:T:A	I56N	1.000
17:82520057:G:A	G57S	1.000
17:82520057:G:C	G57R	1.000
17:82520057:G:T	G57C	1.000
17:82520058:G:A	G57D	1.000
17:82520058:G:C	G57A	1.000
17:82520058:G:T	G57V	1.000
17:82520060:C:A	R58S	1.000
17:82520060:C:T	R58C	1.000
17:82520061:G:A	R58H	1.000
17:82520061:G:C	R58P	1.000
17:82520061:G:T	R58L	1.000
17:82520067:C:T	S60L	1.000
17:82520096:G:C	G70R	1.000
17:82520096:G:T	G70C	1.000
17:82520097:G:T	G70V	1.000
17:82520105:A:C	S73R	1.000
17:82520107:C:A	S73R	1.000
17:82520107:C:G	S73R	1.000
17:82520108:T:A	F74I	1.000
17:82520108:T:C	F74L	1.000
17:82520109:T:C	F74S	1.000
17:82520109:T:G	F74C	1.000
17:82520110:C:A	F74L	1.000
17:82520110:C:G	F74L	1.000
17:82520111:A:T	I75F	1.000
17:82520112:T:A	I75N	1.000
17:82520112:T:C	I75T	1.000

dbSNP variants (sampled 300 via entrez): RS1000028723 (17:82554426 C>T), RS1000094005 (17:82519388 G>A), RS1000114848 (17:82560463 G>A), RS1000212058 (17:82569646 C>T), RS1000232736 (17:82597043 C>T), RS1000258218 (17:82575705 C>T), RS1000258335 (17:82559309 T>C), RS1000271866 (17:82530644 G>A), RS1000322462 (17:82564674 T>A), RS1000327211 (17:82601908 G>T), RS1000327572 (17:82530157 A>C), RS1000380400 (17:82535729 C>T), RS1000382189 (17:82597657 CT>C,CTT,CTTT), RS1000428233 (17:82587829 C>CG), RS1000428280 (17:82546522 G>A)

Disease associations

OMIM: gene MIM:147685 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): premature menopause (MONDO:0001119)

Orphanet (0):

HPO phenotypes

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

GWAS associations

18 associations (top):

Study	Trait	p-value
GCST004619_205	Reticulocyte fraction of red cells	4.000000e-09
GCST004621_200	Red cell distribution width	3.000000e-14
GCST004622_63	Reticulocyte count	4.000000e-09
GCST006804_33	Red cell distribution width	5.000000e-15
GCST006979_260	Heel bone mineral density	4.000000e-21
GCST008153_49	Lean body mass	9.000000e-06
GCST009311_4	Letter-number span reordering	6.000000e-06
GCST90000025_624	Appendicular lean mass	4.000000e-19
GCST90002385_332	High light scatter reticulocyte count	2.000000e-19
GCST90002386_81	High light scatter reticulocyte percentage of red cells	3.000000e-20
GCST90002390_545	Mean corpuscular hemoglobin	8.000000e-19
GCST90002392_35	Mean corpuscular volume	1.000000e-18
GCST90002395_276	Mean platelet volume	3.000000e-13
GCST90002396_681	Mean reticulocyte volume	8.000000e-18
GCST90002397_378	Mean spheric corpuscular volume	1.000000e-11
GCST90002404_187	Red cell distribution width	1.000000e-28
GCST90002405_560	Reticulocyte count	1.000000e-17
GCST90002406_507	Reticulocyte fraction of red cells	6.000000e-19

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0007986	reticulocyte count
EFO:0009188	Red cell distribution width
EFO:0009270	heel bone mineral density
EFO:0004995	lean body mass
EFO:0004874	memory performance
EFO:0004980	appendicular lean mass
EFO:0004527	mean corpuscular hemoglobin
EFO:0010701	mean reticulocyte volume

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008594	Menopause, Premature	C12.050.351.500.056.630.250; C12.100.250.056.630.250; G08.686.157.500.500; G08.686.841.249.500.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression, affects expression, decreases methylation	3
Estradiol	affects expression, increases expression	3
Acetaminophen	decreases expression, increases expression	2
Cyclosporine	increases expression	2
FR900359	affects phosphorylation	1
TAK-243	affects sumoylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	affects methylation, increases abundance	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
coumarin	decreases phosphorylation	1
K 7174	increases expression	1
Sunitinib	increases expression	1
Arsenic	affects methylation	1
Caffeine	affects phosphorylation	1
Cannabinoids	affects methylation, increases abundance	1
Carbamazepine	affects expression	1
Demecolcine	decreases expression	1
Dimethyl Sulfoxide	increases expression	1
Dioxins	decreases methylation	1
Doxorubicin	decreases expression	1
Lead	affects methylation	1
Menthol	increases expression	1
Methotrexate	increases expression	1
Phenobarbital	affects expression	1
Retinoids	increases expression, increases reaction	1
Theophylline	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	decreases expression	1
Urethane	increases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_1280	HH [Human lymphoma]	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00417066	PHASE4	COMPLETED	Flexible GnRH Antagonist vs Flare up GnRH Agonist Protocol in Poor Responders
NCT00732693	PHASE4	COMPLETED	Evaluation of Physiologic and Standard Sex Steroid Replacement Regimens in Women With Premature Ovarian Failure
NCT00837616	PHASE4	COMPLETED	Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
NCT01853501	PHASE4	UNKNOWN	Effects of ADSC Therapy in Women With POF
NCT02783937	PHASE4	COMPLETED	Filgrastim for Premature Ovarian Insufficiency
NCT03535480	PHASE4	UNKNOWN	Autologous Bone Marrow Stem Cell Ovarian Transplantation to Restore Ovarian Function in Premature Ovarian Failure
NCT00140998	PHASE3	COMPLETED	Estrogen Treatment (Oral vs. Patches) in Turner Syndrome
NCT00001951	PHASE2	COMPLETED	Hormone Replacement in Young Women With Premature Ovarian Failure
NCT00370019	PHASE2	WITHDRAWN	Effects of an Estrogen Replacement Therapy Skin Patch on Ovulation in Women With Premature Ovarian Failure
NCT00429494	PHASE2	COMPLETED	GnRH Analogue for Ovarian Function Preservation in Hematopoietic Stem Cell Transplantation Patients
NCT03816852	PHASE2	SUSPENDED	The Safety and Efficiency Study of Mesenchymal Stem Cell (19#iSCLife®-POI) in Premature Ovarian Insufficiency
NCT04536467	PHASE2	UNKNOWN	Prevention of Chemotherapy-Induced Ovarian Failure With Goserelin in Premenopausal Lymphoma Patients
NCT06117982	PHASE2	COMPLETED	The Impact of Granulocyte Colony Stimulating Factor on Premature Ovarian Insufficiency
NCT02912104	PHASE1	COMPLETED	A Therapeutic Trial of Human Amniotic Epithelial Cells Transplantation for Primary Ovarian Failure
NCT03178695	PHASE1	COMPLETED	Inovium Ovarian Rejuvenation Trials
NCT04815213	PHASE1	ACTIVE_NOT_RECRUITING	The Use of Expandeded Mesenchymal Stromal Cells (MSC) in Premature Ovarian Failure (POF) in Adult Humans
NCT05138367	PHASE1	COMPLETED	Effects of UCA-PSCs in Women With POF
NCT06132542	PHASE1	UNKNOWN	Autologous ADMSC Transplantation in Patients With POI
NCT00948857	PHASE2/PHASE3	TERMINATED	Dehydroepiandrosterone (DHEA) Treatment and Premature Ovarian Failure (POF)
NCT04031456	PHASE2/PHASE3	RECRUITING	Autologous PRP Infusion May Restore Ovarian Function and May Promote Folliculogenesis in POI Patients
NCT02043743	PHASE1/PHASE2	UNKNOWN	Autologous Stem Cells Transplantation in Patients With Idiopathic and Drug Induced Premature Ovarian Failure
NCT02062931	PHASE1/PHASE2	UNKNOWN	Autologous Mesenchymal Stem Cells Transplantation In Women With Premature Ovarian Failure
NCT02151890	PHASE1/PHASE2	COMPLETED	Pregnancy After Stem Cell Transplantation in Premature Ovarian Failure
NCT02372474	PHASE1/PHASE2	COMPLETED	It is a Real The First Baby Of Autologous Stem Cell Therapy in Premature Ovarian Failure
NCT02603744	PHASE1/PHASE2	UNKNOWN	Autologous Adipose Derived Mesenchymal Stromal Cells Transplantation in Women With Premature Ovarian Failure (POF)
NCT02644447	PHASE1/PHASE2	COMPLETED	Transplantation of HUC-MSCs With Injectable Collagen Scaffold for POF
NCT03069209	PHASE1/PHASE2	UNKNOWN	Autologous Bone Marrow-Derived Stem Cell Transplantation in Patients With Premature Ovarian Failure (POF)
NCT03985462	PHASE1/PHASE2	WITHDRAWN	Very Small Embryonic-like Stem Cells for Ovary
NCT04009473	PHASE1/PHASE2	UNKNOWN	Stem Cell Therapy and Growth Factor Ovarian in Vitro Activation
NCT04071574	PHASE1/PHASE2	COMPLETED	Comparative Study on the Efficacy of Ovarian Stimulation Protocols on the Success Rate of ICSI in Female Infertility
NCT04922398	PHASE1/PHASE2	UNKNOWN	Ovarian Injection of PRP (Platelet -Rich Plasma) Vs Normal Saline in Premature Ovarian Insufficiency
NCT05462379	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Autologous Heterotopic Fresh Ovarian Graft in Woman With LACC Eligible for Pelvic Radiotherapy Treatment.
NCT06202547	PHASE1/PHASE2	UNKNOWN	Intra-ovarian Injection of MSC-EVs in Idiopathic Premature Ovarian Failure
NCT01129947	EARLY_PHASE1	WITHDRAWN	The Use of DHEA in Women With Premature Ovarian Failure
NCT05522634	EARLY_PHASE1	UNKNOWN	A Clinical Study of Chinese Herbal Compound TJAOA101 in the Treatment of Premature Ovarian Insufficiency
NCT07308327	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	The Influence of Gut Microbiota on Ovarian Function: A Single-center, Randomized,Double Blind, Parallel-controlled, Exploratory Clinical Trial
NCT00001275	Not specified	COMPLETED	Ovarian Follicle Function in Patients With Primary Ovarian Failure
NCT00001306	Not specified	COMPLETED	Steroid Therapy in Autoimmune Premature Ovarian Failure
NCT00006156	Not specified	COMPLETED	Feasibility Study for Development of an Early Test for Ovarian Failure
NCT00119925	Not specified	UNKNOWN	‘SPRING’-Study: Subfertility Guidelines: Patient Related Implementation in the Netherlands Among Gynaecologists