Alternative titles; symbols
HGNC Approved Gene Symbol: FOXK2
Cytogenetic location: 17q25.3 Genomic coordinates (GRCh38): 17:82,519,732-82,604,602 (from NCBI)
FOXK2 belongs to the conserved family of forkhead transcription factors characterized by a winged-helix DNA-binding forkhead domain. These transcription factors control a wide range of cellular processes, including the cell cycle and development (summary by Marais et al., 2010).
Li et al. (1991) cloned ILF from both HeLa and Jurkat cDNA libraries. The deduced 543-amino acids contains an N-terminal nucleotide-binding sequence, followed by a forkhead-type DNA-binding domain, a potential nuclear localization signal, a ubiquitin-mediated degradation signal, and a potential N-glycosylation site. Northern blot analysis suggested ubiquitous ILF expression. ILF appeared to be subject to alternative splicing. In vitro translation resulted in a protein with an apparent molecular mass of 60 kD. Further analysis by Li et al. (1992) demonstrated the existence of 2 ILF mRNA species, both of which encode proteins containing the forkhead DNA-binding domain.
Marais et al. (2010) showed that FOXK2 contains 660 amino acids and has an N-terminal forkhead-associated (FHA) domain, a central forkhead domain, and 3 highly conserved C-terminal regions.
Li et al. (1991) found that ILF bound to purine-rich regulatory motifs in the HIV-1 long terminal repeat and to the interleukin-2 (IL2; 147680) promoter.
Using synchronized human cell lines, Marais et al. (2010) found that FOXK2 was hyperphosphorylated during the cell cycle. FOXK2 phosphorylation peaked at G2-M and correlated with peak cyclin B1 (CCNB1; 123836) expression. FOXK2 was detected in the nucleus of the majority of asynchronously growing cells, but as cells divided and the nuclear envelope broke down, FOXK2 dispersed throughout the cells, then reappeared in the nucleus following cytokinesis. Chromatin immunoprecipitation analysis confirmed that FOXK2 binding to its target MCM3 (602693) was weakest during mitosis. Phosphatase inhibitors and small interfering RNAs revealed that phosphorylation of FOXK2 depended upon cyclin-dependent kinase-1 (CDK1; 116940) and CDK2 (116953) and cyclins A (see CCNA1; 604036) and B1. Mass spectrometric analysis showed that CDK2-cyclin A or CDK1-cyclin B phosphorylated FOXK2 residues ser368 and ser423 in an in vitro kinase assay. Mutation of ser368 to ala (S368A) and ser423 to ala (S423A) reduced, but did not eliminate, FOXK2 phosphorylation during the cell cycle. Phosphorylation of FOXK2 promoted its degradation and consequently reduced its repressive activity. The S368A and S423A mutations stabilized FOXK2, and S368A/S423A mutant FOXK2 reduced the activity of a reporter gene driven by the promoter of the cell cycle regulator p21 (CDKN1A; 116899). S368A/S423A mutant FOXK2 also induced apoptosis in transiently transfected cells. Marais et al. (2010) concluded that FOXK2 functions as a transcriptional repressor during the cell cycle.
Sukonina et al. (2019) reported that the closely related fasting/starvation-induced forkhead transcription factors FOXK1 and FOXK2 induce aerobic glycolysis by upregulating the enzymatic machinery required for this, for example, hexokinase-2 (HK2; 601125), phosphofructokinase (PFKM; 610681), pyruvate kinase (PKM2; see 179050), and lactate dehydrogenase (LDHA; 150000), while at the same time suppressing further oxidation of pyruvate in the mitochondria by increasing the activity of pyruvate dehydrogenase kinase-1 (PDK1; 602524) and -4 (PDK4; 602527). Together with suppression of the catalytic subunit of pyruvate dehydrogenase phosphatase-1 (PDP1; 605993), this leads to increased phosphorylation of the E1-alpha regulatory subunit (PDHA1; 300502) of the pyruvate dehydrogenase complex, which in turn inhibits further oxidation of pyruvate in the mitochondria. Instead, pyruvate is reduced to lactate. Suppression of FOXK1 and FOXK2 induce the opposite phenotype. Both in vitro and in vivo experiments, including studies of primary human cells, showed how FOXK1 and/or FOXK2 are likely to act as important regulators that reprogram cellular metabolism to induce aerobic glycolysis.
By analysis of a panel of mouse/human somatic cell hybrids followed by radioactive in situ hybridization, Li et al. (1992) demonstrated that the ILF gene is located on chromosome 17q25, which is a site of chromosomal translocations in some cases of human acute myelogenous leukemia.
Li, C., Lai, C., Sigman, D. S., Gaynor, R. B. Cloning of a cellular factor, interleukin binding factor, that binds to NFAT-like motifs in the human immunodeficiency virus long terminal repeat. Proc. Nat. Acad. Sci. 88: 7739-7743, 1991. [PubMed: 1909027] [Full Text: https://doi.org/10.1073/pnas.88.17.7739]
Li, C., Lusis, A. J., Sparkes, R., Nirula, A., Gaynor, R. Characterization and chromosomal mapping of the gene encoding the cellular DNA binding protein ILF. Genomics 13: 665-671, 1992. [PubMed: 1339390] [Full Text: https://doi.org/10.1016/0888-7543(92)90139-j]
Marais, A., Ji, Z., Child, E. S., Krause, E., Mann, D. J., Sharrocks, A. D. Cell cycle-dependent regulation of the forkhead transcription factor FOXK2 by CDK-cyclin complexes. J. Biol. Chem. 285: 35728-35739, 2010. [PubMed: 20810654] [Full Text: https://doi.org/10.1074/jbc.M110.154005]
Sukonina, V., Ma, H., Zhang, W., Bartesaghi, S., Subhash, S., Heglind, M., Foyn, H., Betz, M. J., Nilsson, D., Lidell, M. E., Naumann, J., Haufs-Brusberg, S., and 9 others. FOXK1 and FOXK2 regulate aerobic glycolysis. Nature 566: 279-283, 2019. [PubMed: 30700909] [Full Text: https://doi.org/10.1038/s41586-019-0900-5]