{"gene":"TKT","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2019,"finding":"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.","method":"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":"Journal of experimental & clinical cancer research : CR","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (NLS mutagenesis, cross-linking Co-IP/MS, pharmacological rescue) in a single rigorous study establishing nuclear localization with functional consequence","pmids":["30971297"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Co-IP, DSB repair assays (NHEJ and HR reporters), PARylation assays, TKT knockdown in vitro and mouse xenograft models","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction shown, enzymatic activity modulation demonstrated, multiple DSB repair assays and in vivo validation in a single study","pmids":["38216672"],"is_preprint":false},{"year":2022,"finding":"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).","method":"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","journal":"Basic research in cardiology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO mice, Co-IP, ChIP, and luciferase assay provide multiple orthogonal methods; single lab","pmids":["35380314"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Intestinal epithelial cell-specific TKT knockout mice; metabolite profiling; ATP assay; apoptosis and barrier function assays","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Moderate — tissue-specific KO with defined metabolic and cellular phenotypes and mechanistic metabolite measurements","pmids":["34535624"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Whole-exome sequencing; enzymatic activity assay in patient samples; metabolite profiling of urine and plasma","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — enzymatic confirmation in patient samples combined with genetic and metabolic evidence across three independent families","pmids":["27259054"],"is_preprint":false},{"year":2024,"finding":"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.","method":"ChIP assay, co-IP, transcriptome sequencing, metabolomic analysis, TKT inhibitor (oxythiamine) treatment, conditional HMGA1 knockout mice","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and Co-IP demonstrate HMGA1-SP1-TKT promoter axis; single lab with multiple orthogonal methods","pmids":["39080260"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Co-IP and mass spectrometry; PI3K/AKT pathway activity assays; glucose uptake and lactate production assays","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single Co-IP/MS interaction and pathway assays, single lab","pmids":["37817120"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Co-IP, western blotting, cycloheximide-chase and ubiquitination assays, immunofluorescence, RNA-seq, orthotopic VX2 rabbit TACE model","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical assays (Co-IP, ubiquitination, cycloheximide chase) in a single lab study","pmids":["42014677"],"is_preprint":false},{"year":2025,"finding":"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.","method":"TKT overexpression and knockdown; RBKS pathway assays; proliferation, migration, invasion assays; EMT marker analysis","journal":"Journal of bioenergetics and biomembranes","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, no direct binding demonstrated for TKT-RBKS; epistasis inferred from knockdown phenotypes without biochemical interaction","pmids":["40531362"],"is_preprint":false},{"year":2025,"finding":"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.","method":"TKT and PKM2 knockdown; glycolysis assays; proliferation and invasion assays","journal":"Cell death discovery","confidence":"Low","confidence_rationale":"Tier 3 / Weak — functional epistasis via knockdown without direct biochemical interaction data; single lab","pmids":["41253799"],"is_preprint":false},{"year":2026,"finding":"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.","method":"ChIP, dual luciferase reporter assay, Western blot, metabolic assays (glucose uptake, ATP, lactate), xenograft mouse model","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase reporter directly link SETD2 to TKT promoter; rescue experiment; single lab","pmids":["41868666"],"is_preprint":false},{"year":2026,"finding":"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.","method":"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":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain and loss of function with pathway rescue (AKT inhibition) and in vivo model; single lab","pmids":["41928272"],"is_preprint":false},{"year":2024,"finding":"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.","method":"CUT&TAG for NRF2 binding to TKT locus; gene interference and overexpression; transcriptome analysis; proliferation assays in mouse granulosa cells","journal":"Journal of advanced research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CUT&TAG directly shows NRF2 binding at TKT locus; functional rescue by overexpression; single lab","pmids":["39341455"],"is_preprint":false},{"year":2025,"finding":"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.","method":"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","journal":"Biology direct","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP directly demonstrates m6A modification of TKT mRNA by METTL7B; ChIP and luciferase for upstream regulation; single lab","pmids":["40045399"],"is_preprint":false},{"year":1998,"finding":"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.","method":"5' RACE, primer extension, promoter-CAT reporter transfection in cornea and lens cell lines, H2O2/diamide/light treatment of mouse tissues","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter functional assays with reporter genes and oxidative stress induction; single lab","pmids":["9521875"],"is_preprint":false}],"current_model":"TKT is a thiamine diphosphate-dependent enzyme of the non-oxidative pentose phosphate pathway that, beyond its canonical metabolic role linking PPP to glycolysis, translocates to the nucleus under stress where it interacts with PARP1 (facilitating its cleavage and activating AIF-mediated apoptosis in cardiomyocytes, or undergoing PARP1-mediated PARylation to promote DNA DSB repair in cancer), interacts with EGFR and MAPK3 to drive non-metabolic oncogenic signaling, acts upstream of AKT in cardiac fibroblast activation, is transcriptionally regulated by KLF5, SP1/HMGA1, NRF2, and SETD2, and has its mRNA stability controlled by METTL7B-mediated m6A modification; loss-of-function mutations in humans cause a syndrome of short stature, developmental delay, and congenital heart defects due to impaired PPP flux."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":1998,"claim":"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","pmids":["9521875"],"confidence":"Medium","gaps":["Specific stress-responsive elements and trans-acting factors not identified","Findings in mouse promoters; human regulatory architecture not addressed"]},{"year":2016,"claim":"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","pmids":["27259054"],"confidence":"High","gaps":["Tissue-specific basis of short stature, developmental delay and heart defects not mechanistically dissected","Genotype-phenotype correlations across mutation types unresolved"]},{"year":2019,"claim":"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","pmids":["30971297"],"confidence":"High","gaps":["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"]},{"year":2021,"claim":"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","pmids":["34535624"],"confidence":"High","gaps":["Apoptotic effector pathway downstream of ATP depletion not defined","Whether non-metabolic TKT functions contribute not tested"]},{"year":2022,"claim":"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","pmids":["35380314"],"confidence":"High","gaps":["Molecular trigger linking TKT to PARP1 cleavage not defined","Apparent opposite effect on PARP1 (cleavage vs. auto-PARylation) versus cancer context not reconciled"]},{"year":2024,"claim":"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","pmids":["38216672"],"confidence":"High","gaps":["How TKT mechanistically enhances PARP1 activity not resolved","Direct repair-step targeted by TKT not identified"]},{"year":2024,"claim":"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","pmids":["39080260","39341455","40045399"],"confidence":"Medium","gaps":["Whether these regulators act in the same or distinct cellular contexts not integrated","Relative contribution of each input to TKT expression unquantified"]},{"year":2025,"claim":"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","pmids":["42014677","37817120","41928272"],"confidence":"Medium","gaps":["Direct vs. scaffolding role of TKT in RAF1/AKT activation unclear","Whether kinase signaling requires nuclear or cytosolic TKT not defined"]},{"year":2026,"claim":"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","pmids":["41868666"],"confidence":"Medium","gaps":["Mechanism of SETD2-mediated promoter repression not resolved","Generality beyond lung adenocarcinoma untested"]},{"year":null,"claim":"How TKT switches between metabolic and non-metabolic (nuclear, signaling) functions, and what stimuli and structural determinants govern this partitioning across tissues, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["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":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[3,4]},{"term_id":"GO:0016829","term_label":"lyase activity","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[3,4]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[1]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,7]}],"complexes":[],"partners":["PARP1","EGFR","MAPK3","RAF1","MND1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q16832","full_name":"Discoidin domain-containing receptor 2","aliases":["CD167 antigen-like family member B","Discoidin domain-containing receptor tyrosine kinase 2","Neurotrophic tyrosine kinase, receptor-related 3","Receptor protein-tyrosine kinase TKT","Tyrosine-protein kinase TYRO10"],"length_aa":855,"mass_kda":96.7,"function":"Tyrosine kinase involved in the regulation of tissues remodeling (PubMed:30449416). It functions as a cell surface receptor for fibrillar collagen and regulates cell differentiation, remodeling of the extracellular matrix, cell migration and cell proliferation. Required for normal bone development. Regulates osteoblast differentiation and chondrocyte maturation via a signaling pathway that involves MAP kinases and leads to the activation of the transcription factor RUNX2. Regulates remodeling of the extracellular matrix by up-regulation of the collagenases MMP1, MMP2 and MMP13, and thereby facilitates cell migration and tumor cell invasion. Promotes fibroblast migration and proliferation, and thereby contributes to cutaneous wound healing","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q16832/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TKT","classification":"Not Classified","n_dependent_lines":514,"n_total_lines":1208,"dependency_fraction":0.42549668874172186},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SAR1B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TKT","total_profiled":1310},"omim":[{"mim_id":"618493","title":"HYPOTONIA, HYPOVENTILATION, IMPAIRED INTELLECTUAL DEVELOPMENT, DYSAUTONOMIA, EPILEPSY, AND EYE ABNORMALITIES; HIDEA","url":"https://www.omim.org/entry/618493"},{"mim_id":"617044","title":"SHORT STATURE, DEVELOPMENTAL DELAY, AND CONGENITAL HEART DEFECTS; SDDHD","url":"https://www.omim.org/entry/617044"},{"mim_id":"614584","title":"PROLYL 4-HYDROXYLASE, TRANSMEMBRANE; P4HTM","url":"https://www.omim.org/entry/614584"},{"mim_id":"608901","title":"CORONARY HEART DISEASE, SUSCEPTIBILITY TO, 5","url":"https://www.omim.org/entry/608901"},{"mim_id":"606781","title":"TRANSKETOLASE; TKT","url":"https://www.omim.org/entry/606781"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"},{"location":"Nuclear speckles","reliability":"Additional"},{"location":"Nuclear bodies","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone marrow","ntpm":630.1}],"url":"https://www.proteinatlas.org/search/TKT"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q16832","domains":[{"cath_id":"2.60.120.260","chopping":"31-185","consensus_level":"high","plddt":92.0844,"start":31,"end":185},{"cath_id":"2.60.120.1190","chopping":"190-367","consensus_level":"high","plddt":90.4822,"start":190,"end":367},{"cath_id":"3.30.200.20","chopping":"559-656","consensus_level":"high","plddt":80.9494,"start":559,"end":656},{"cath_id":"1.10.510.10","chopping":"661-672_679-850","consensus_level":"high","plddt":89.0485,"start":661,"end":850}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16832","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q16832-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q16832-F1-predicted_aligned_error_v6.png","plddt_mean":75.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TKT","jax_strain_url":"https://www.jax.org/strain/search?query=TKT"},"sequence":{"accession":"Q16832","fasta_url":"https://rest.uniprot.org/uniprotkb/Q16832.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q16832/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16832"}},"corpus_meta":[{"pmid":"30971297","id":"PMC_30971297","title":"Transketolase (TKT) activity and nuclear localization promote hepatocellular carcinoma in a metabolic and a non-metabolic manner.","date":"2019","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/30971297","citation_count":79,"is_preprint":false},{"pmid":"8247548","id":"PMC_8247548","title":"Structure, expression and chromosomal mapping of TKT from man and mouse: a new subclass of receptor tyrosine kinases with a factor VIII-like domain.","date":"1993","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/8247548","citation_count":70,"is_preprint":false},{"pmid":"27259054","id":"PMC_27259054","title":"Mutations in TKT Are the Cause of a Syndrome Including Short Stature, Developmental Delay, and Congenital Heart Defects.","date":"2016","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27259054","citation_count":40,"is_preprint":false},{"pmid":"34535624","id":"PMC_34535624","title":"TKT maintains intestinal ATP production and inhibits apoptosis-induced colitis.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/34535624","citation_count":30,"is_preprint":false},{"pmid":"10906192","id":"PMC_10906192","title":"Upregulation of tyrosine kinase TKT by the Epstein-Barr virus transactivator Zta.","date":"2000","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/10906192","citation_count":26,"is_preprint":false},{"pmid":"29563135","id":"PMC_29563135","title":"Identification of CRKII, CFL1, CNTN1, NME2, and TKT as Novel and Frequent T-Cell Targets in Human IDH-Mutant Glioma.","date":"2018","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/29563135","citation_count":26,"is_preprint":false},{"pmid":"38216672","id":"PMC_38216672","title":"TKT-PARP1 axis induces radioresistance by promoting DNA double-strand break repair in hepatocellular carcinoma.","date":"2024","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/38216672","citation_count":25,"is_preprint":false},{"pmid":"8353127","id":"PMC_8353127","title":"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.","date":"1993","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/8353127","citation_count":22,"is_preprint":false},{"pmid":"8241274","id":"PMC_8241274","title":"Nucleotide sequence of the Escherichia coli K-12 transketolase (tkt) gene.","date":"1993","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/8241274","citation_count":22,"is_preprint":false},{"pmid":"9521875","id":"PMC_9521875","title":"The mouse transketolase (TKT) gene: cloning, characterization, and functional promoter analysis.","date":"1998","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/9521875","citation_count":19,"is_preprint":false},{"pmid":"35380314","id":"PMC_35380314","title":"Nuclear Tkt promotes ischemic heart failure via the cleaved Parp1/Aif axis.","date":"2022","source":"Basic research in cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/35380314","citation_count":19,"is_preprint":false},{"pmid":"15968503","id":"PMC_15968503","title":"RpoS-mediated growth-dependent expression of the Escherichia coli tkt genes encoding transketolases isoenzymes.","date":"2005","source":"Current microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/15968503","citation_count":16,"is_preprint":false},{"pmid":"39080260","id":"PMC_39080260","title":"HMGA1 promotes the progression of esophageal squamous cell carcinoma by elevating TKT-mediated upregulation of pentose phosphate pathway.","date":"2024","source":"Cell death & 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Research","url":"https://pubmed.ncbi.nlm.nih.gov/29502067","citation_count":11,"is_preprint":false},{"pmid":"32659474","id":"PMC_32659474","title":"Genetic variants in TKT and DERA in the nicotinamide adenine dinucleotide phosphate pathway predict melanoma survival.","date":"2020","source":"European journal of cancer (Oxford, England : 1990)","url":"https://pubmed.ncbi.nlm.nih.gov/32659474","citation_count":5,"is_preprint":false},{"pmid":"40045399","id":"PMC_40045399","title":"HOXB4/METTL7B cascade mediates malignant phenotypes of hepatocellular carcinoma through TKT m6A modification.","date":"2025","source":"Biology direct","url":"https://pubmed.ncbi.nlm.nih.gov/40045399","citation_count":5,"is_preprint":false},{"pmid":"38805171","id":"PMC_38805171","title":"Prolactin receptor potentiates chemotherapy through miRNAs-induced G6PD/TKT inhibition in pancreatic cancer.","date":"2024","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/38805171","citation_count":4,"is_preprint":false},{"pmid":"29236388","id":"PMC_29236388","title":"Inhibition of IRE1 modifies hypoxic regulation of G6PD, GPI, TKT, TALDO1, PGLS and RPIA genes expression in U87 glioma cells.","date":"2017","source":"Ukrainian biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/29236388","citation_count":3,"is_preprint":false},{"pmid":"39341455","id":"PMC_39341455","title":"A novel effect of sulforaphane on promoting mouse granulosa cells proliferation via the NRF2-TKT pathway.","date":"2024","source":"Journal of advanced research","url":"https://pubmed.ncbi.nlm.nih.gov/39341455","citation_count":3,"is_preprint":false},{"pmid":"38455402","id":"PMC_38455402","title":"Regulating TKT activity inhibits proliferation of human acute lymphoblastic leukemia cells.","date":"2024","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/38455402","citation_count":2,"is_preprint":false},{"pmid":"41253799","id":"PMC_41253799","title":"TKT drives renal cell carcinoma progression through metabolic reprogramming and synergistic interaction with PKM2.","date":"2025","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/41253799","citation_count":1,"is_preprint":false},{"pmid":"9182394","id":"PMC_9182394","title":"[Validation of TKT medium for detection of Streptococcus agalactiae in bulk milk samples].","date":"1997","source":"Veterinarni medicina","url":"https://pubmed.ncbi.nlm.nih.gov/9182394","citation_count":1,"is_preprint":false},{"pmid":"40531362","id":"PMC_40531362","title":"TKT regulates the pentose phosphate pathway via RBKS to promote epithelial-mesenchymal transition during AML progression.","date":"2025","source":"Journal of bioenergetics and biomembranes","url":"https://pubmed.ncbi.nlm.nih.gov/40531362","citation_count":0,"is_preprint":false},{"pmid":"41097326","id":"PMC_41097326","title":"Structural and Computational Insights into Transketolase-like 1 (TKTL-1): Distinction from TKT and Implications for Cancer Metabolism and Therapeutic Targeting.","date":"2025","source":"Molecules (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/41097326","citation_count":0,"is_preprint":false},{"pmid":"42098867","id":"PMC_42098867","title":"Single-cell and machine learning-integrated bulk RNA-seq analysis reveals TKT as an oxidative stress-associated diagnostic biomarker in acute myocardial infarction.","date":"2026","source":"Human genomics","url":"https://pubmed.ncbi.nlm.nih.gov/42098867","citation_count":0,"is_preprint":false},{"pmid":"40615820","id":"PMC_40615820","title":"CRISPRi knockdown of mycobacterial tkt gene potentiates the anti-mycobacterial activity of phyto-compounds from selected medicinal plants.","date":"2025","source":"BMC complementary medicine and therapies","url":"https://pubmed.ncbi.nlm.nih.gov/40615820","citation_count":0,"is_preprint":false},{"pmid":"41868666","id":"PMC_41868666","title":"Histone methyltransferase SETD2 regulates TKT expression and mediates glycolysis to suppress lung adenocarcinoma progression and improve chemosensitivity.","date":"2026","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/41868666","citation_count":0,"is_preprint":false},{"pmid":"41928272","id":"PMC_41928272","title":"TKT inhibition attenuates cardiac fibrosis in myocardial infarction through deactivating AKT signaling pathway.","date":"2026","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41928272","citation_count":0,"is_preprint":false},{"pmid":"42014677","id":"PMC_42014677","title":"A positive feedback loop between TKT and c-Myc drives TACE resistance in hepatocellular carcinoma.","date":"2026","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/42014677","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.01.02.25319933","title":"Identifying Potential Drug Targets for Prostate Cancer from a Genetic Perspective: A Mendelian Randomization Study","date":"2025-01-03","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.02.25319933","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":18760,"output_tokens":3776,"usd":0.05646,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11547,"output_tokens":3782,"usd":0.076143,"stage2_stop_reason":"end_turn"},"total_usd":0.132603,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (NLS mutagenesis, cross-linking Co-IP/MS, pharmacological rescue) in a single rigorous study establishing nuclear localization with functional consequence\",\n      \"pmids\": [\"30971297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP, DSB repair assays (NHEJ and HR reporters), PARylation assays, TKT knockdown in vitro and mouse xenograft models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction shown, enzymatic activity modulation demonstrated, multiple DSB repair assays and in vivo validation in a single study\",\n      \"pmids\": [\"38216672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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).\",\n      \"method\": \"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\",\n      \"journal\": \"Basic research in cardiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO mice, Co-IP, ChIP, and luciferase assay provide multiple orthogonal methods; single lab\",\n      \"pmids\": [\"35380314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Intestinal epithelial cell-specific TKT knockout mice; metabolite profiling; ATP assay; apoptosis and barrier function assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific KO with defined metabolic and cellular phenotypes and mechanistic metabolite measurements\",\n      \"pmids\": [\"34535624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Whole-exome sequencing; enzymatic activity assay in patient samples; metabolite profiling of urine and plasma\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — enzymatic confirmation in patient samples combined with genetic and metabolic evidence across three independent families\",\n      \"pmids\": [\"27259054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP assay, co-IP, transcriptome sequencing, metabolomic analysis, TKT inhibitor (oxythiamine) treatment, conditional HMGA1 knockout mice\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and Co-IP demonstrate HMGA1-SP1-TKT promoter axis; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"39080260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP and mass spectrometry; PI3K/AKT pathway activity assays; glucose uptake and lactate production assays\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single Co-IP/MS interaction and pathway assays, single lab\",\n      \"pmids\": [\"37817120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP, western blotting, cycloheximide-chase and ubiquitination assays, immunofluorescence, RNA-seq, orthotopic VX2 rabbit TACE model\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical assays (Co-IP, ubiquitination, cycloheximide chase) in a single lab study\",\n      \"pmids\": [\"42014677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"TKT overexpression and knockdown; RBKS pathway assays; proliferation, migration, invasion assays; EMT marker analysis\",\n      \"journal\": \"Journal of bioenergetics and biomembranes\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, no direct binding demonstrated for TKT-RBKS; epistasis inferred from knockdown phenotypes without biochemical interaction\",\n      \"pmids\": [\"40531362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"TKT and PKM2 knockdown; glycolysis assays; proliferation and invasion assays\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional epistasis via knockdown without direct biochemical interaction data; single lab\",\n      \"pmids\": [\"41253799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP, dual luciferase reporter assay, Western blot, metabolic assays (glucose uptake, ATP, lactate), xenograft mouse model\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase reporter directly link SETD2 to TKT promoter; rescue experiment; single lab\",\n      \"pmids\": [\"41868666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain and loss of function with pathway rescue (AKT inhibition) and in vivo model; single lab\",\n      \"pmids\": [\"41928272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"CUT&TAG for NRF2 binding to TKT locus; gene interference and overexpression; transcriptome analysis; proliferation assays in mouse granulosa cells\",\n      \"journal\": \"Journal of advanced research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CUT&TAG directly shows NRF2 binding at TKT locus; functional rescue by overexpression; single lab\",\n      \"pmids\": [\"39341455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Biology direct\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP directly demonstrates m6A modification of TKT mRNA by METTL7B; ChIP and luciferase for upstream regulation; single lab\",\n      \"pmids\": [\"40045399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"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.\",\n      \"method\": \"5' RACE, primer extension, promoter-CAT reporter transfection in cornea and lens cell lines, H2O2/diamide/light treatment of mouse tissues\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter functional assays with reporter genes and oxidative stress induction; single lab\",\n      \"pmids\": [\"9521875\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TKT is a thiamine diphosphate-dependent enzyme of the non-oxidative pentose phosphate pathway that, beyond its canonical metabolic role linking PPP to glycolysis, translocates to the nucleus under stress where it interacts with PARP1 (facilitating its cleavage and activating AIF-mediated apoptosis in cardiomyocytes, or undergoing PARP1-mediated PARylation to promote DNA DSB repair in cancer), interacts with EGFR and MAPK3 to drive non-metabolic oncogenic signaling, acts upstream of AKT in cardiac fibroblast activation, is transcriptionally regulated by KLF5, SP1/HMGA1, NRF2, and SETD2, and has its mRNA stability controlled by METTL7B-mediated m6A modification; loss-of-function mutations in humans cause a syndrome of short stature, developmental delay, and congenital heart defects due to impaired PPP flux.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#3]. 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 [#4]. 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 [#0], 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 [#1]; under ischemic stress in cardiomyocytes the same TKT-PARP1 axis instead facilitates PARP1 cleavage and AIF-mediated apoptosis [#2]. 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 [#7], and acting upstream of AKT phosphorylation in TGF-\\u03b21-induced cardiac fibroblast activation [#11]. TKT expression is set by multiple transcriptional inputs\\u2014activated by KLF5 [#2], the HMGA1-SP1 axis [#5] and NRF2 [#12], repressed by SETD2 [#10], and stabilized post-transcriptionally via METTL7B-mediated m6A modification of TKT mRNA [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"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.\",\n      \"evidence\": \"5' RACE, primer extension and promoter-CAT reporter assays in cornea and lens cell lines with H2O2/diamide/light treatment of mouse tissues\",\n      \"pmids\": [\"9521875\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific stress-responsive elements and trans-acting factors not identified\", \"Findings in mouse promoters; human regulatory architecture not addressed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"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.\",\n      \"evidence\": \"Whole-exome sequencing, enzymatic activity assay in patient samples, and urine/plasma metabolite profiling across three families\",\n      \"pmids\": [\"27259054\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific basis of short stature, developmental delay and heart defects not mechanistically dissected\", \"Genotype-phenotype correlations across mutation types unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"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.\",\n      \"evidence\": \"GFP-tagged NLS mapping, cross-linking Co-IP/MS, enzyme-dead and NLS-mutant rescue, and erlotinib treatment in HCC cells\",\n      \"pmids\": [\"30971297\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Tissue-specific deletion answered how TKT loss affects cellular physiology, linking PPP metabolite accumulation and ATP deficit to apoptosis and barrier failure in intestine.\",\n      \"evidence\": \"Intestinal epithelial cell-specific TKT knockout mice with metabolite profiling, ATP and apoptosis/barrier assays\",\n      \"pmids\": [\"34535624\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Apoptotic effector pathway downstream of ATP depletion not defined\", \"Whether non-metabolic TKT functions contribute not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"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.\",\n      \"evidence\": \"Subcellular fractionation/IF for nuclear redistribution, Co-IP for TKT-PARP1, ChIP and luciferase for KLF5-Tkt, and cardiomyocyte-specific conditional KO mice\",\n      \"pmids\": [\"35380314\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular trigger linking TKT to PARP1 cleavage not defined\", \"Apparent opposite effect on PARP1 (cleavage vs. auto-PARylation) versus cancer context not reconciled\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, NHEJ/HR reporter assays, PARylation assays, TKT knockdown in vitro and in xenografts\",\n      \"pmids\": [\"38216672\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TKT mechanistically enhances PARP1 activity not resolved\", \"Direct repair-step targeted by TKT not identified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"39080260\", \"39341455\", \"40045399\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether these regulators act in the same or distinct cellular contexts not integrated\", \"Relative contribution of each input to TKT expression unquantified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"42014677\", \"37817120\", \"41928272\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. scaffolding role of TKT in RAF1/AKT activation unclear\", \"Whether kinase signaling requires nuclear or cytosolic TKT not defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"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.\",\n      \"evidence\": \"ChIP, dual-luciferase reporter, metabolic assays, and TKT-overexpression rescue with xenografts in lung adenocarcinoma\",\n      \"pmids\": [\"41868666\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of SETD2-mediated promoter repression not resolved\", \"Generality beyond lung adenocarcinoma untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TKT switches between metabolic and non-metabolic (nuclear, signaling) functions, and what stimuli and structural determinants govern this partitioning across tissues, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0016829\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PARP1\", \"EGFR\", \"MAPK3\", \"RAF1\", \"MND1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}