Affinage

TKT

Discoidin domain-containing receptor 2 · UniProt Q16832

Length
855 aa
Mass
96.7 kDa
Annotated
2026-06-10
31 papers in source corpus 15 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TKT is a thiamine diphosphate-dependent transketolase of the non-oxidative pentose phosphate pathway (PPP) whose metabolic flux links pentose-phosphate intermediates to glycolysis, and whose loss disrupts cellular energy balance: tissue-specific deletion in intestinal epithelium causes accumulation of PPP metabolites, depletion of glycolytic metabolites and ATP, driving apoptosis and barrier failure (PMID:34535624). In humans, loss-of-function mutations confirmed by reduced enzymatic activity and accumulation of erythritol, arabitol, ribitol and pentose-5-phosphates cause a syndrome of short stature, developmental delay and congenital heart defects through impaired non-oxidative PPP flux (PMID:27259054). Beyond catalysis, TKT carries nuclear localization sequences that mediate stress-induced nuclear translocation, where it performs enzyme-independent functions: nuclear TKT interacts with EGFR and MAPK3 to support EGF-driven proliferation independently of its catalytic activity (PMID:30971297), and engages PARP1 in a DNA-damage-dependent manner, enhancing PARP1 auto-PARylation (while being PARylated and catalytically inhibited itself) to promote NHEJ and HR repair and radioresistance in hepatocellular carcinoma (PMID:38216672); under ischemic stress in cardiomyocytes the same TKT-PARP1 axis instead facilitates PARP1 cleavage and AIF-mediated apoptosis (PMID:35380314). TKT also feeds oncogenic kinase signaling, associating with RAF1 to promote c-Raf Ser338 phosphorylation, ERK activation and c-Myc stabilization in a c-Myc-TKT feedback loop (PMID:42014677), and acting upstream of AKT phosphorylation in TGF-β1-induced cardiac fibroblast activation (PMID:41928272). TKT expression is set by multiple transcriptional inputs—activated by KLF5 (PMID:35380314), the HMGA1-SP1 axis (PMID:39080260) and NRF2 (PMID:39341455), repressed by SETD2 (PMID:41868666), and stabilized post-transcriptionally via METTL7B-mediated m6A modification of TKT mRNA (PMID:40045399).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1998 Medium

    Establishing how TKT transcription is organized and regulated answered whether the gene is constitutively expressed or responsive to physiological cues, revealing tissue-specific promoter usage and oxidative-stress inducibility.

    Evidence 5' RACE, primer extension and promoter-CAT reporter assays in cornea and lens cell lines with H2O2/diamide/light treatment of mouse tissues

    PMID:9521875

    Open questions at the time
    • Specific stress-responsive elements and trans-acting factors not identified
    • Findings in mouse promoters; human regulatory architecture not addressed
  2. 2016 High

    Identifying biallelic TKT mutations in patients answered whether TKT deficiency causes human disease, establishing it as the genetic basis of a multisystem syndrome driven by impaired non-oxidative PPP flux.

    Evidence Whole-exome sequencing, enzymatic activity assay in patient samples, and urine/plasma metabolite profiling across three families

    PMID:27259054

    Open questions at the time
    • Tissue-specific basis of short stature, developmental delay and heart defects not mechanistically dissected
    • Genotype-phenotype correlations across mutation types unresolved
  3. 2019 High

    Mapping TKT's nuclear localization sequences and nuclear interactors answered whether TKT has functions beyond catalysis, demonstrating an enzyme-independent nuclear role in EGFR/MAPK3-driven proliferation.

    Evidence GFP-tagged NLS mapping, cross-linking Co-IP/MS, enzyme-dead and NLS-mutant rescue, and erlotinib treatment in HCC cells

    PMID:30971297

    Open questions at the time
    • Direct vs. indirect nature of nuclear TKT-EGFR association not resolved
    • Stimulus that drives nuclear translocation in cancer not defined
    • Structural basis of EGFR/MAPK3 binding unknown
  4. 2021 High

    Tissue-specific deletion answered how TKT loss affects cellular physiology, linking PPP metabolite accumulation and ATP deficit to apoptosis and barrier failure in intestine.

    Evidence Intestinal epithelial cell-specific TKT knockout mice with metabolite profiling, ATP and apoptosis/barrier assays

    PMID:34535624

    Open questions at the time
    • Apoptotic effector pathway downstream of ATP depletion not defined
    • Whether non-metabolic TKT functions contribute not tested
  5. 2022 High

    Showing stress-induced nuclear TKT-PARP1 binding answered how TKT contributes to ischemic cardiomyocyte death, revealing an enzyme-independent pro-apoptotic axis transcriptionally driven by KLF5.

    Evidence Subcellular fractionation/IF for nuclear redistribution, Co-IP for TKT-PARP1, ChIP and luciferase for KLF5-Tkt, and cardiomyocyte-specific conditional KO mice

    PMID:35380314

    Open questions at the time
    • Molecular trigger linking TKT to PARP1 cleavage not defined
    • Apparent opposite effect on PARP1 (cleavage vs. auto-PARylation) versus cancer context not reconciled
  6. 2024 High

    Characterizing the DNA-damage-dependent TKT-PARP1 interaction answered how nuclear TKT influences genome maintenance, establishing reciprocal regulation (PARP1 PARylates and inhibits TKT; TKT enhances PARP1 auto-PARylation) that promotes DSB repair and radioresistance.

    Evidence Co-IP, NHEJ/HR reporter assays, PARylation assays, TKT knockdown in vitro and in xenografts

    PMID:38216672

    Open questions at the time
    • How TKT mechanistically enhances PARP1 activity not resolved
    • Direct repair-step targeted by TKT not identified
  7. 2024 Medium

    Defining HMGA1-SP1, NRF2, and METTL7B-m6A inputs answered how TKT levels are tuned across tissues, showing transcriptional and post-transcriptional control coupling TKT to nucleotide synthesis and proliferation.

    Evidence ChIP/Co-IP (HMGA1-SP1), CUT&TAG (NRF2), and MeRIP/ChIP/luciferase (METTL7B-m6A, HOXB4) with gain/loss-of-function and metabolomics across ESCC, granulosa, and HCC models

    PMID:39080260 PMID:39341455 PMID:40045399

    Open questions at the time
    • Whether these regulators act in the same or distinct cellular contexts not integrated
    • Relative contribution of each input to TKT expression unquantified
  8. 2025 Medium

    Identifying TKT associations with RAF1 and upstream AKT/PI3K signaling answered how TKT promotes oncogenic and fibrotic kinase cascades, including a c-Myc-TKT positive feedback loop.

    Evidence Co-IP, ubiquitination and cycloheximide-chase assays (RAF1/c-Myc), PI3K/AKT and glycolysis assays, and TKT gain/loss with AKT-inhibition rescue across HCC, gastric cancer, and cardiac fibroblast models

    PMID:37817120 PMID:41928272 PMID:42014677

    Open questions at the time
    • Direct vs. scaffolding role of TKT in RAF1/AKT activation unclear
    • Whether kinase signaling requires nuclear or cytosolic TKT not defined
  9. 2026 Medium

    Defining SETD2 as a transcriptional repressor of TKT answered how chromatin regulators constrain TKT-driven glycolysis, linking SETD2 loss to enhanced malignancy and reduced chemosensitivity.

    Evidence ChIP, dual-luciferase reporter, metabolic assays, and TKT-overexpression rescue with xenografts in lung adenocarcinoma

    PMID:41868666

    Open questions at the time
    • Mechanism of SETD2-mediated promoter repression not resolved
    • Generality beyond lung adenocarcinoma untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TKT switches between metabolic and non-metabolic (nuclear, signaling) functions, and what stimuli and structural determinants govern this partitioning across tissues, remains unresolved.
  • No unifying model for context-dependent pro-survival vs. pro-apoptotic TKT-PARP1 outcomes
  • Structural basis of non-metabolic protein interactions undetermined
  • Direct binding for several inferred epistatic partners (RBKS, PKM2) not demonstrated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 2 GO:0016829 lyase activity 1
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 1
Pathway
R-HSA-1430728 Metabolism 2 R-HSA-162582 Signal Transduction 2 R-HSA-73894 DNA Repair 1
Partners
EGFRMAPK3MND1PARP1RAF1

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2019 TKT localizes to the nucleus in HCC cells via identified nuclear localization sequences (NLS); NLS mutations decreased the pro-tumor function of TKT independently of its enzymatic activity. Nuclear TKT interacts with EGFR and MAPK3 (identified by cross-linking Co-IP/MS), and EGF-stimulated cell viability/proliferation was dependent on nuclear TKT but not enzymatic TKT activity, and could be blocked by EGFR inhibitor erlotinib. GFP-tagged TKT truncations/mutants for NLS mapping; cross-linking Co-IP/MS for nuclear interaction partners; enzyme-inactivating and NLS mutant rescue experiments; EGFR inhibitor treatment Journal of experimental & clinical cancer research : CR High 30971297
2024 TKT interacts with PARP1 in a DNA damage-dependent manner; PARP1 PARylates TKT (inhibiting its enzymatic activity), and TKT enhances PARP1 auto-PARylation in response to DNA double-strand breaks. TKT depletion reduces both NHEJ and HR-mediated DSB repair and mitigates radioresistance in HCC. Co-IP, DSB repair assays (NHEJ and HR reporters), PARylation assays, TKT knockdown in vitro and mouse xenograft models Oncogene High 38216672
2022 Under ischemic stress, TKT redistributes into cardiomyocyte nuclei. Nuclear TKT binds full-length PARP1, facilitates its cleavage, and activates apoptosis-inducing factor (AIF), promoting cardiomyocyte apoptosis independently of its metabolic function. Tkt is a direct transcriptional target of KLF5 (validated by luciferase assay and ChIP). Luciferase assay and ChIP for KLF5-Tkt axis; Co-IP for Tkt-Parp1 interaction; lentivirus-mediated knockdown and overexpression; inducible cardiomyocyte-specific Tkt knockout mice; subcellular fractionation/immunofluorescence for nuclear redistribution Basic research in cardiology High 35380314
2021 TKT deletion in intestinal epithelial cells causes accumulation of PPP metabolites and reduction of glycolytic metabolites, thereby reducing ATP production. This ATP deficit leads to excessive apoptosis and defective intestinal barrier function, establishing TKT as essential for maintaining intestinal integrity. Intestinal epithelial cell-specific TKT knockout mice; metabolite profiling; ATP assay; apoptosis and barrier function assays Cell death & disease High 34535624
2016 Loss-of-function mutations in TKT (homozygous in-frame insertion; compound heterozygous nonsense/missense) confirmed by enzymatic testing showing significantly reduced transketolase activity. Affected individuals accumulate erythritol, arabitol, ribitol, and pent(ul)ose-5-phosphates, establishing TKT as the causative gene for a syndrome with short stature, developmental delay, and congenital heart defects via impaired non-oxidative PPP flux. Whole-exome sequencing; enzymatic activity assay in patient samples; metabolite profiling of urine and plasma American journal of human genetics High 27259054
2024 HMGA1 promotes TKT transcription by interacting with transcription factor SP1 and enhancing SP1 binding to the TKT promoter, thereby upregulating the non-oxidative pentose phosphate pathway and nucleotide synthesis in ESCC cells. ChIP assay, co-IP, transcriptome sequencing, metabolomic analysis, TKT inhibitor (oxythiamine) treatment, conditional HMGA1 knockout mice Cell death & disease Medium 39080260
2023 MND1 physically interacts with TKT (shown by Co-IP/MS), and TKT activates the PI3K/AKT signaling axis to enhance glucose uptake and lactate production in gastric cancer cells. Co-IP and mass spectrometry; PI3K/AKT pathway activity assays; glucose uptake and lactate production assays Cancer cell international Medium 37817120
2025 TKT associates with RAF1, promotes phosphorylation of c-Raf at Ser338 and subsequent ERK activation, and stabilizes c-Myc by enhancing Ser62 phosphorylation and reducing ubiquitin-mediated degradation. c-Myc in turn transcriptionally upregulates TKT, forming a positive feedback loop underlying TACE resistance in HCC. Co-IP, western blotting, cycloheximide-chase and ubiquitination assays, immunofluorescence, RNA-seq, orthotopic VX2 rabbit TACE model Cell death discovery Medium 42014677
2025 TKT acts upstream of RBKS and promotes AML cell growth by regulating the pentose phosphate pathway through RBKS, which in turn drives epithelial-mesenchymal transition. TKT overexpression and knockdown; RBKS pathway assays; proliferation, migration, invasion assays; EMT marker analysis Journal of bioenergetics and biomembranes Low 40531362
2025 TKT promotes glycolysis in renal cell carcinoma through coordinated action with PKM2; PKM2 knockdown significantly impaired TKT-mediated increases in glycolysis, cell proliferation, and invasive potential. TKT and PKM2 knockdown; glycolysis assays; proliferation and invasion assays Cell death discovery Low 41253799
2026 SETD2 binds the TKT promoter (shown by ChIP) and suppresses TKT transcription, thereby reducing glycolytic activity in lung adenocarcinoma cells; TKT overexpression partially reversed SETD2-mediated suppression of malignant progression and chemosensitivity. ChIP, dual luciferase reporter assay, Western blot, metabolic assays (glucose uptake, ATP, lactate), xenograft mouse model American journal of cancer research Medium 41868666
2026 TKT inhibition suppresses TGF-β1-induced cardiac fibroblast phenotypic transformation, proliferation, and migration by inhibiting AKT phosphorylation; TKT overexpression promoted these fibroblast functions in response to TGF-β1, which was reversed by AKT phosphorylation inhibition, placing TKT upstream of AKT in cardiac fibroblast activation. TKT inhibitor (oxythiamine) and TKT overexpression in neonatal rat cardiac fibroblasts; western blotting for AKT phosphorylation; EDU, wound healing, Transwell assays; AMI mouse model with Masson/Sirius red staining Journal of translational medicine Medium 41928272
2024 NRF2 activation by sulforaphane promotes TKT transcription (NRF2 translocates to nucleus and activates TKT), driving ribose 5-phosphate production to support granulosa cell proliferation via the non-oxidative pentose phosphate pathway. CUT&TAG for NRF2 binding to TKT locus; gene interference and overexpression; transcriptome analysis; proliferation assays in mouse granulosa cells Journal of advanced research Medium 39341455
2025 METTL7B controls TKT mRNA stability through m6A methylation, with METTL7B overexpression increasing TKT expression and promoting HCC progression; HOXB4 suppresses METTL7B transcription by binding its promoter, thereby indirectly reducing TKT levels. Methylated RNA immunoprecipitation (MeRIP) for m6A on TKT mRNA; dual-luciferase reporter and ChIP for HOXB4-METTL7B promoter; DNA pulldown assays; gain/loss-of-function experiments Biology direct Medium 40045399
1998 The mouse TKT gene has two promoter regions; the proximal promoter (lacking TATA sequence, GC-rich, multiple initiation sites) drives expression in cornea and liver, while a distal TATA-containing promoter is used only in liver. TKT mRNA is induced by oxidative stress (H2O2, diamide, light) consistent with stress-responsive elements in its promoters. 5' RACE, primer extension, promoter-CAT reporter transfection in cornea and lens cell lines, H2O2/diamide/light treatment of mouse tissues Genomics Medium 9521875

Source papers

Stage 0 corpus · 31 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 Transketolase (TKT) activity and nuclear localization promote hepatocellular carcinoma in a metabolic and a non-metabolic manner. Journal of experimental & clinical cancer research : CR 79 30971297
1993 Structure, expression and chromosomal mapping of TKT from man and mouse: a new subclass of receptor tyrosine kinases with a factor VIII-like domain. Oncogene 70 8247548
2016 Mutations in TKT Are the Cause of a Syndrome Including Short Stature, Developmental Delay, and Congenital Heart Defects. American journal of human genetics 40 27259054
2021 TKT maintains intestinal ATP production and inhibits apoptosis-induced colitis. Cell death & disease 30 34535624
2018 Identification of CRKII, CFL1, CNTN1, NME2, and TKT as Novel and Frequent T-Cell Targets in Human IDH-Mutant Glioma. Clinical cancer research : an official journal of the American Association for Cancer Research 26 29563135
2000 Upregulation of tyrosine kinase TKT by the Epstein-Barr virus transactivator Zta. Journal of virology 26 10906192
2024 TKT-PARP1 axis induces radioresistance by promoting DNA double-strand break repair in hepatocellular carcinoma. Oncogene 25 38216672
1993 Nucleotide sequence of the Escherichia coli K-12 transketolase (tkt) gene. Biochimica et biophysica acta 22 8241274
1993 Two open reading frames adjacent to the Escherichia coli K-12 transketolase (tkt) gene show high similarity to the mannitol phosphotransferase system enzymes from Escherichia coli and various gram-positive bacteria. Biochimica et biophysica acta 22 8353127
2022 Nuclear Tkt promotes ischemic heart failure via the cleaved Parp1/Aif axis. Basic research in cardiology 19 35380314
1998 The mouse transketolase (TKT) gene: cloning, characterization, and functional promoter analysis. Genomics 19 9521875
2005 RpoS-mediated growth-dependent expression of the Escherichia coli tkt genes encoding transketolases isoenzymes. Current microbiology 16 15968503
2024 HMGA1 promotes the progression of esophageal squamous cell carcinoma by elevating TKT-mediated upregulation of pentose phosphate pathway. Cell death & disease 14 39080260
2023 FOXA1/MND1/TKT axis regulates gastric cancer progression and oxaliplatin sensitivity via PI3K/AKT signaling pathway. Cancer cell international 14 37817120
2018 C-MYC, HIF-1α, ERG, TKT, and GSTP1: an Axis in Prostate Cancer? Pathology oncology research : POR 13 30357756
2018 Dual effects for lovastatin in anaplastic thyroid cancer: the pivotal effect of transketolase (TKT) on lovastatin and tumor proliferation. Journal of investigative medicine : the official publication of the American Federation for Clinical Research 11 29502067
2025 HOXB4/METTL7B cascade mediates malignant phenotypes of hepatocellular carcinoma through TKT m6A modification. Biology direct 5 40045399
2020 Genetic variants in TKT and DERA in the nicotinamide adenine dinucleotide phosphate pathway predict melanoma survival. European journal of cancer (Oxford, England : 1990) 5 32659474
2024 Prolactin receptor potentiates chemotherapy through miRNAs-induced G6PD/TKT inhibition in pancreatic cancer. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 4 38805171
2024 A novel effect of sulforaphane on promoting mouse granulosa cells proliferation via the NRF2-TKT pathway. Journal of advanced research 3 39341455
2017 Inhibition of IRE1 modifies hypoxic regulation of G6PD, GPI, TKT, TALDO1, PGLS and RPIA genes expression in U87 glioma cells. Ukrainian biochemical journal 3 29236388
2024 Regulating TKT activity inhibits proliferation of human acute lymphoblastic leukemia cells. American journal of cancer research 2 38455402
2025 TKT drives renal cell carcinoma progression through metabolic reprogramming and synergistic interaction with PKM2. Cell death discovery 1 41253799
1997 [Validation of TKT medium for detection of Streptococcus agalactiae in bulk milk samples]. Veterinarni medicina 1 9182394
2026 Histone methyltransferase SETD2 regulates TKT expression and mediates glycolysis to suppress lung adenocarcinoma progression and improve chemosensitivity. American journal of cancer research 0 41868666
2026 TKT inhibition attenuates cardiac fibrosis in myocardial infarction through deactivating AKT signaling pathway. Journal of translational medicine 0 41928272
2026 A positive feedback loop between TKT and c-Myc drives TACE resistance in hepatocellular carcinoma. Cell death discovery 0 42014677
2026 Single-cell and machine learning-integrated bulk RNA-seq analysis reveals TKT as an oxidative stress-associated diagnostic biomarker in acute myocardial infarction. Human genomics 0 42098867
2025 TKT regulates the pentose phosphate pathway via RBKS to promote epithelial-mesenchymal transition during AML progression. Journal of bioenergetics and biomembranes 0 40531362
2025 CRISPRi knockdown of mycobacterial tkt gene potentiates the anti-mycobacterial activity of phyto-compounds from selected medicinal plants. BMC complementary medicine and therapies 0 40615820
2025 Structural and Computational Insights into Transketolase-like 1 (TKTL-1): Distinction from TKT and Implications for Cancer Metabolism and Therapeutic Targeting. Molecules (Basel, Switzerland) 0 41097326

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