Molecule Information

General Information of the Molecule (ID: Mol01885)

• Name: Forkhead box K2 (FOXK2) ,Homo sapiens
• Synonyms: FOXK2; ILF; ILF1
• Molecule Type: Protein
• Gene Name: FOXK2
• Gene ID: 3607
• Location: chr17:82,519,713-82,644,662[+]
• Sequence:
  MAAAAAALSGAGTPPAGGGAGGGGAGGGGSPPGGWAVARLEGREFEYLMKKRSVTIGRNS
  SQGSVDVSMGHSSFISRRHLEIFTPPGGGGHGGAAPELPPAQPRPDAGGDFYLRCLGKNG
  VFVDGVFQRRGAPPLQLPRVCTFRFPSTNIKITFTALSSEKREKQEASESPVKAVQPHIS
  PLTINIPDTMAHLISPLPSPTGTISAANSCPSSPRGAGSSGYKVGRVMPSDLNLMADNSQ
  PENEKEASGGDSPKDDSKPPYSYAQLIVQAITMAPDKQLTLNGIYTHITKNYPYYRTADK
  GWQNSIRHNLSLNRYFIKVPRSQEEPGKGSFWRIDPASESKLIEQAFRKRRPRGVPCFRT
  PLGPLSSRSAPASPNHAGVLSAHSSGAQTPESLSREGSPAPLEPEPGAAQPKLAVIQEAR
  FAQSAPGSPLSSQPVLITVQRQLPQAIKPVTYTVATPVTTSTSQPPVVQTVHVVHQIPAV
  SVTSVAGLAPANTYTVSGQAVVTPAAVLAPPKAEAQENGDHREVKVKVEPIPAIGHATLG
  TASRIIQTAQTTPVQTVTIVQQAPLGQHQLPIKTVTQNGTHVASVPTAVHGQVNNAAASP
  LHMLATHASASASLPTKRHNGDQPEQPELKRIKTEDGEGIVIALSVDTPPAAVREKGVQN
• 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.
• Uniprot ID: FOXK2_HUMAN
• Ensembl ID: ENSG00000141568
• HGNC ID: HGNC:6036

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 1 drug(s) in total

YN-968D1

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Anaplastic thyroid cancer [1]

• Resistant Disease: Anaplastic thyroid cancer [ICD-11: 2D10.2]
• Resistant Drug: YN-968D1
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: VEGFA/VEGFR1 signaling pathway; Activation; hsa05205
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• In Vitro Model: HUT78 cells; Lymph; Homo sapiens (Human); CVCL_0337
• In Vitro Model: SH-1-V2 cells; Esophagus; Homo sapiens (Human); N.A.
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: On VEGFR2 blockage by specific targeting agent, such as Apatinib, FOXK2 could rapidly trigger therapeutic resistance. Mechanical analyses revealed that VEGFA transcriptionally induced by FOXK2 could bind to VEGFR1 as a compensation for VEGFR2 blockage, which promoted angiogenesis by activating ERK, PI3K/AKT and P38/MAPK signaling in human umbilical vein endothelial cells (HUVECs). Synergic effect on anti-angiogenesis could be observed when VEGFR1 suppressor AF321 was included in VEGFR2 inhibition system, which clarified the pivot role of FOXK2 in VEGFR2 targeting therapy resistance.

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Thyroid cancer [ICD-11: 2D10]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Thyroid
• The Specified Disease: Thyroid cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 4.87E-01; Fold-change: -1.25E-02; Z-score: -3.61E-02
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 1.88E-01; Fold-change: 6.91E-02; Z-score: 2.35E-01

References

• Ref 1: FOXK2 transcriptionally activating VEGFA induces apatinib resistance in anaplastic thyroid cancer through VEGFA/VEGFR1 pathway .Oncogene. 2021 Oct;40(42):6115-6129. doi: 10.1038/s41388-021-01830-5. Epub 2021 Sep 6. 10.1038/s41388-021-01830-5