Affinage

TRIB3

Tribbles homolog 3 · UniProt Q96RU7

Length
358 aa
Mass
39.6 kDa
Annotated
2026-06-10
100 papers in source corpus 32 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/7 claims corpus-supported (86%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TRIB3 is a stress-inducible pseudokinase scaffold that integrates ER stress, insulin/AKT, Wnt/β-catenin, autophagy, and ubiquitin-proteasome signaling by physically recruiting, stabilizing, or destabilizing regulatory proteins in a context-dependent manner (PMID:12736262, PMID:34066165, PMID:27207527). Originally identified as an NF-κB-inducible protein (SINK) that binds the p65 transactivator and blocks its PKA-mediated phosphorylation to suppress NF-κB transcription while sensitizing cells to TNF/TRAIL apoptosis (PMID:12736262), TRIB3 negatively regulates the ER-stress transcription factor ATF4, with which it colocalizes on chromatin at C/EBP-ATF motifs (PMID:34066165). TRIB3 is itself induced by ATF4/CHOP, establishing recurrent feedback circuits in which the pathways it modulates also drive its expression (PMID:29520103, PMID:31844113, PMID:34729304, PMID:37150773). A dominant theme is its control of protein stability: TRIB3 stabilizes oncoproteins by blocking their ubiquitination—PML-RARα (also suppressing sumoylation) (PMID:28486108), MYC (against UBE3B) (PMID:33298911), TWIST1 (PMID:31235507), TAZ (against β-TrCP) (PMID:32157210), EGFR (with PKCα/WWP1-driven juxtamembrane modification enhancing recycling) (PMID:32694521), and PLIN2 (against TEB4) (PMID:38561354)—while conversely recruiting E3 ligases to destabilize tumor suppressors and metabolic regulators, driving TRIM8-dependent K48 polyubiquitination of HNF4α (PMID:38237865), COP1-dependent FOXO1 degradation (PMID:40211872), and degradation of PPARα/PPARγ (PMID:32929351, PMID:32621919). TRIB3 also impairs autophagic flux by binding SQSTM1/p62 and blocking its LC3 interaction, causing p62 accumulation that suppresses degradation of tumor-promoting factors and promotes liver fibrosis (PMID:26301314, PMID:31286822). As a transcriptional adaptor it potentiates Wnt/β-catenin-TCF4 (PMID:30365932, PMID:31562867, PMID:38429254), SMAD3 (by recruiting KAT5 to sustain SMAD3 acetylation) (PMID:29520103), AKT-FOXO1-SOX2 (PMID:31844113), and STAT3-VEGFA (PMID:36245025) programs. In metabolic tissue TRIB3 is required for glucose-induced insulin resistance upstream of AKT in skeletal muscle (PMID:27207527), and a gain-of-function variant (p.Q84R) worsens hepatic steatosis via enhanced HNF4α degradation (PMID:38237865).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2003 High

    Established TRIB3's first molecular role: how an NF-κB target gene feeds back to restrain NF-κB signaling, identifying TRIB3 as a transcriptional brake and apoptotic sensitizer.

    Evidence Co-IP, in vitro PKA kinase assay, and NF-κB reporter assays in overexpression systems

    PMID:12736262

    Open questions at the time
    • Mechanism by which TRIB3 blocks PKA access to p65 not structurally defined
    • Physiological NF-κB contexts beyond TNF/TRAIL untested
  2. 2012 Medium

    Showed TRIB3 supports immune cell survival and effector function, broadening its role beyond transcriptional suppression to cytokine-dependent cell fate.

    Evidence Trib3-knockout mouse-derived BMMCs assayed for IL-3 deprivation survival, degranulation, and cytokine mRNA

    PMID:23261831

    Open questions at the time
    • Molecular partners mediating mast cell survival not identified
    • Link to IL-3 signaling components undefined
  3. 2015 High

    Defined two distinct TRIB3 mechanisms—an autophagy block via SQSTM1/p62 and a prodeath neuronal axis via Parkin—revealing context-dependent pro-tumor versus pro-death outputs.

    Evidence Co-IP, autophagic flux assays with peptide competition, and genetic epistasis in tumor and neuronal models plus postmortem PD tissue

    PMID:26224857 PMID:26301314

    Open questions at the time
    • How the same scaffold yields opposite cell-fate outcomes across tissues unresolved
    • Whether Parkin reduction is degradative or transcriptional unclear
  4. 2016 High

    Established TRIB3 as a required, nutrient-regulated mediator of glucose toxicity upstream of AKT in skeletal muscle, anchoring its physiological role in metabolic homeostasis.

    Evidence Muscle-specific TRIB3 overexpression and knockout mice with insulin signaling and metabolic phenotyping

    PMID:27207527

    Open questions at the time
    • Direct molecular target in muscle AKT pathway not pinned down
    • Relationship to TRIB3-AKT-FOXO1 interaction defined later not integrated
  5. 2016 High

    Showed TRIB3 abundance is governed by mRNA translation and protein stability, and that TRIB3 suppresses CHAC1 within the ATF4 pathway to control glutathione and stress survival.

    Evidence Translational control and protein stability assays in cancer cells; Trib3-knockout MEFs with Chac1 promoter reporters and glutathione measurement

    PMID:23185332 PMID:27526673

    Open questions at the time
    • How TRIB3 acts on the Chac1 promoter mechanistically undefined
    • Translation control of TRIB3 in non-anoxic contexts untested
  6. 2018 High

    Revealed TRIB3 as a transcriptional adaptor that enhances Wnt/β-catenin-TCF4 and SMAD3 programs through chromatin recruitment and KAT5-mediated acetylation, embedded in self-reinforcing feedback loops.

    Evidence Co-IP, ChIP, reporter assays, K333 acetylation mutagenesis in colorectal and melanoma models

    PMID:29520103 PMID:30365932

    Open questions at the time
    • Whether TRIB3 directly contacts chromatin or bridges factors unclear
    • Structural basis of KAT5 recruitment to SMAD3 unknown
  7. 2017 High

    Identified the recurrent oncoprotein-stabilization mechanism: TRIB3 binds substrates and blocks their ubiquitin/sumo-dependent degradation, first shown for PML-RARα.

    Evidence Co-IP, ubiquitylation/sumoylation assays, peptide disruption, and APL mouse model

    PMID:28486108

    Open questions at the time
    • Which E3 ligases TRIB3 displaces from PML-RARα not fully resolved
    • Generality across substrates not yet established at this point
  8. 2019 High

    Generalized the stabilization paradigm across oncoproteins (TWIST1, MYC-pending, EGFR) and extended autophagy blockade to fibrosis, while linking TRIB3-AKT to FOXO1-SOX2 stemness circuits.

    Evidence Co-IP, ubiquitination/phosphorylation assays, site-directed mutagenesis, stapled/helical peptide disruption across leukemia, lung, breast, and liver fibrosis models

    PMID:31235507 PMID:31286822 PMID:31844113 PMID:32694521

    Open questions at the time
    • Whether TRIB3 recognizes a shared degron motif across substrates unknown
    • How one scaffold both blocks and recruits E3 ligases mechanistically unresolved
  9. 2020 Medium

    Expanded the dual stabilize/destabilize logic—stabilizing MYC and TAZ while promoting PPARα/γ degradation—and confirmed feedback control via CHOP/ATF4-driven TRIB3 induction in PD.

    Evidence Co-IP, ubiquitination and reporter assays, pharmacological ATF4 inhibition (adaptaquin) across lymphoma, esophageal, leukemia, lung, and PD models

    PMID:31562867 PMID:31911115 PMID:32157210 PMID:32621919 PMID:32929351 PMID:33298911

    Open questions at the time
    • Determinants selecting stabilization versus degradation for a given partner unknown
    • Most substrate findings from single labs without reciprocal cross-validation
  10. 2022 High

    Provided genome-wide evidence that TRIB3 colocalizes with ATF4 on chromatin to restrain its transcription, and showed TRIB3 is itself stabilized by P300 acetylation while suppressing antitumor immunity via EGFR/STAT1/CXCL10.

    Evidence Endogenous Flag-tagged TRIB3 ChIP-Seq, transcriptomics, P300 acetylation/degradation assays, and CRC mouse models

    PMID:34066165 PMID:34985967 PMID:36142452 PMID:36245025 PMID:36555349

    Open questions at the time
    • Whether TRIB3 binds DNA directly or via ATF4 unresolved
    • Mechanism of MLL complex interference at PPARG locus not structurally defined
  11. 2024 High

    Reconstituted TRIB3 as an E3-ligase adaptor driving substrate degradation, defining TRIM8-mediated K48 ubiquitination of HNF4α at K470 and a disease-causing gain-of-function variant, alongside COP1-FOXO1 and TEB4-PLIN2 axes.

    Evidence Co-IP, mass spectrometry, in vivo/in vitro ubiquitination, K470 mutagenesis, peptide disruption, and mouse NAFLD/HCC/RCC models

    PMID:38237865 PMID:38429254 PMID:38561354 PMID:40211872

    Open questions at the time
    • How TRIB3 chooses to recruit versus exclude specific E3 ligases unknown
    • Structural basis of the TRIB3-TRIM8-HNF4α complex not solved

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown what structural feature of the TRIB3 pseudokinase scaffold dictates whether a given partner is stabilized or targeted for degradation, and whether a unifying recognition motif governs substrate selection across its many contexts.
  • No structure of TRIB3 bound to any partner reported in the corpus
  • No common degron or binding motif identified across substrates
  • Tissue-specific determinants of opposing outputs uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0140096 catalytic activity, acting on a protein 4 GO:0098772 molecular function regulator activity 3 GO:0140110 transcription regulator activity 3 GO:0003677 DNA binding 1
Localization
GO:0005634 nucleus 3 GO:0000228 nuclear chromosome 2 GO:0005829 cytosol 2
Pathway
R-HSA-392499 Metabolism of proteins 5 R-HSA-1430728 Metabolism 4 R-HSA-162582 Signal Transduction 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1643685 Disease 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-9612973 Autophagy 2
Partners
ATF4CTNNB1EGFRHNF4AMYCRELASMAD3SQSTM1
Complex memberships
TRIB3-TRIM8-HNF4α ubiquitination complexTRIB3-β-catenin-TCF4 complex

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 TRIB3 (identified as SINK) is an NF-κB-inducible protein that specifically interacts with the NF-κB transactivator p65 and inhibits p65 phosphorylation by the catalytic subunit of protein kinase A (PKA), thereby suppressing NF-κB-dependent transcription without blocking NF-κB nuclear translocation or DNA binding. TRIB3 also sensitizes cells to TNF- and TRAIL-induced apoptosis. Co-immunoprecipitation, in vitro kinase assay, NF-κB reporter assay, overexpression studies The Journal of biological chemistry High 12736262
2015 TRIB3 physically interacts with Parkin, a prosurvival E3 ubiquitin ligase associated with Parkinson's disease. Elevated TRIB3 reduces Parkin expression in cultured neurons; Parkin knockdown abolishes the neuroprotective effect of TRIB3 downregulation, placing TRIB3 upstream of Parkin in a prodeath pathway. TRIB3 induction in PD models is substantially mediated by transcription factors CHOP and ATF4. Co-immunoprecipitation (physical interaction), siRNA knockdown, overexpression, genetic epistasis (double knockdown), immunostaining in postmortem PD brain tissue The Journal of neuroscience High 26224857
2015 TRIB3 physically interacts with the autophagy receptor SQSTM1/p62 and hinders SQSTM1 binding to LC3 and ubiquitinated proteins, causing SQSTM1 accumulation and blockade of autophagic flux, which suppresses autophagic and proteasomal degradation of tumor-promoting factors and links insulin-IGF1 signaling to malignant promotion. Co-immunoprecipitation, autophagy flux assays, peptide competition (helical peptide from SQSTM1), siRNA knockdown, xenograft tumor models Autophagy High 26301314
2017 TRIB3 interacts with the oncoprotein PML-RARα and suppresses its sumoylation, ubiquitylation, and proteasomal degradation, thereby repressing PML nuclear body assembly, p53-mediated senescence, and myeloid differentiation to support APL-initiating cell self-renewal. Co-immunoprecipitation, ubiquitylation assay, sumoylation assay, genetic knockdown/overexpression, peptide disruption of TRIB3/PML-RARα interaction, APL mouse model Cancer cell High 28486108
2018 TRIB3 physically interacts with β-catenin and TCF4, increasing recruitment of β-catenin and TCF4 to promoters of Wnt target genes, enhancing their transcription and supporting colorectal cancer stem cell features; activated β-catenin in turn increases TRIB3 expression, forming a positive feedback loop. Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), dual luciferase reporter assay, shRNA knockdown, overexpression, ApcMin/J mouse model, organoid assays, xenograft models Gastroenterology High 30365932
2018 TRIB3 acts as an adaptor to recruit lysine acetyltransferase KAT5 to SMAD3, inducing phosphorylation-dependent K333 acetylation of SMAD3, which sustains SMAD3 transcriptional activity and subsequently enhances TRIB3 transcription, forming a positive feedback loop. Metformin suppresses SMAD3 phosphorylation and disrupts the KAT5/SMAD3 interaction to break this loop. Co-immunoprecipitation, in vivo acetylation assay, site-directed mutagenesis (K333), reporter assays, knockdown/overexpression, mouse melanoma models Oncogene High 29520103
2019 TRIB3 interacts with AKT to interfere with the FOXO1-AKT interaction, suppressing FOXO1 phosphorylation and its ubiquitination and degradation by E3 ligases SKP2 and NEDD4L; accumulated FOXO1 promotes SOX2 transcription, which in turn activates FOXO1 transcription, forming a positive regulatory loop supporting breast cancer stemness. Co-immunoprecipitation, ubiquitination assay, siRNA/shRNA knockdown, overexpression, luciferase reporter assay, mouse breast cancer models Nature communications High 31844113
2019 TRIB3 interacts with SQSTM1/p62 and hinders its binding to MAP1LC3/LC3, causing accumulation of SQSTM1 aggregates and obstruction of autophagic flux. TRIB3-mediated autophagy impairment promotes hepatocellular secretion of INHBA/Activin A-enriched exosomes that activate hepatic stellate cells, driving liver fibrosis. Co-immunoprecipitation, autophagic flux assays, transmission electron microscopy, helical peptide disruption, AAV-mediated Trib3 knockdown, bile duct ligation and TAA mouse models Autophagy High 31286822
2019 TRIB3 interacts with TWIST1 via the TWIST1 WR domain and contributes to TWIST1 stabilization by inhibiting its ubiquitination, supporting APL cell survival and ATRA resistance. Co-immunoprecipitation, ubiquitination assay, gain- and loss-of-function experiments, peptide disruption of TRIB3/TWIST1 interaction, in vivo APL models Clinical cancer research Medium 31235507
2020 TRIB3 interacts with EGFR and recruits PKCα to induce Thr654 phosphorylation and WWP1-induced Lys689 ubiquitination in the EGFR juxtamembrane region, which enhances EGFR recycling, stability, downstream signaling activity, and NSCLC stemness. Co-immunoprecipitation, phosphorylation assay, ubiquitination assay, site-specific mutagenesis (Thr654, Lys689), stapled peptide disruption, overexpression/knockdown, NSCLC mouse models Nature communications High 32694521
2020 TRIB3 interacts with MYC to suppress E3 ubiquitin ligase UBE3B-mediated MYC ubiquitination and degradation, thereby enhancing MYC transcriptional activity and promoting lymphoma cell proliferation and self-renewal. Co-immunoprecipitation, ubiquitination assay, peptide disruption of TRIB3-MYC interaction, overexpression/knockdown, MycEμ mouse model, patient-derived xenografts Nature communications High 33298911
2020 TRIB3 interacts with TAZ and impedes β-TrCP-mediated TAZ ubiquitination and degradation, thereby stabilizing TAZ and conferring radiotherapy resistance in esophageal squamous cell carcinoma cells. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, overexpression, in vitro and in vivo radioresistance assays Oncogene Medium 32157210
2020 TRIB3 interacts with PML-RARα to inhibit PPARγ activity by interfering with the PPARγ/RXR interaction and promoting PPARγ degradation, causing lipid metabolism disorder and dyslipidemia in APL. During arsenic/ATRA therapy, elevated TRIB3 disrupts the PPARγ/RXR dimer, exacerbating dyslipidemia. Co-immunoprecipitation, luciferase reporter assay, western blot, PML-RARα transgenic and APL cell-transplanted mouse models Theranostics Medium 32929351
2020 TRIB3 interacts with β-catenin and activates β-catenin signaling, increasing recruitment of β-catenin to promoters of Wnt-target genes and promoting lung cancer progression including EMT and stemness. Co-immunoprecipitation, ChIP assay, siRNA knockdown, overexpression, rescue with β-catenin reactivation European journal of pharmacology Medium 31562867
2020 TRIB3 destabilizes PPARα by promoting its ubiquitination and proteasomal degradation in acute myeloid leukemia cells; TRIB3 physically interacts with PPARα as shown by co-immunoprecipitation and immunofluorescence, and in vivo ubiquitination assays confirmed TRIB3-enhanced PPARα ubiquitination. Co-immunoprecipitation, immunofluorescence co-localization, in vivo ubiquitination assay, siRNA knockdown, pharmacological rescue Life sciences Medium 32621919
2021 TRIB3 interacts with GSK-3β and stabilizes GSK-3β from ubiquitination and degradation; elevated GSK-3β then phosphorylates A20 to inhibit its ubiquitin-editing activity, causing C/EBPβ accumulation and profibrotic factor production in alveolar macrophages. Activated C/EBPβ in turn transcriptionally upregulates TRIB3 and GSK-3β, forming a positive feedback loop. Co-immunoprecipitation, ubiquitination assay, knockdown/overexpression, pharmacological disruption of TRIB3-GSK-3β interaction, bleomycin mouse model Acta pharmaceutica Sinica. B Medium 34729304
2022 TRIB3 is acetylated by the acetyltransferase P300, which inhibits ubiquitination and subsequent proteasomal degradation of TRIB3. Ectopically expressed TRIB3 inhibits STAT1 activation and STAT1-mediated CXCL10 transcription by enhancing EGFR signaling, reducing CD8+ T cell infiltration in colorectal cancer. Co-immunoprecipitation, P300 inhibitor treatment, TRIB3 degradation assays, STAT1/CXCL10 reporter assays, CRC mouse models, genetic ablation of Trib3 Science translational medicine High 34985967
2022 TRIB3 interacts with STAT3 and enhances STAT3-mediated transcriptional activity; through this interaction TRIB3 cooperates with STAT3 to increase VEGFA expression and promote cancer angiogenesis. Co-immunoprecipitation, ChIP assay, qPCR, western blot, in vitro angiogenesis assays, in vivo tumor models Current medical science Medium 36245025
2022 TRIB3 interferes with the MLL histone methyltransferase complex and reduces MLL-mediated H3K4 trimethylation at the PPARG locus, thereby reducing PPARγ mRNA expression and blunting the antiproliferative effect of PPARγ ligands in breast cancer cells. Proteomics, phosphoproteomics, co-immunoprecipitation, histone methylation assays (H3K4me3 ChIP), overexpression/knockdown, proliferation assays International journal of molecular sciences Medium 36142452
2022 TRIB3 negatively regulates ATF4 transcriptional activity; TRIB3 protein predominantly colocalizes with ATF4 on chromatin at C/EBP-ATF motif-containing genomic regions (demonstrated by ChIP-Seq using endogenous Flag-tagged TRIB3), and TRIB3 disruption increases ATF4-driven transcription and sensitizes hepatoma cells to bortezomib. ChIP-Seq with endogenously Flag-tagged TRIB3, CRISPR knock-in, transcriptome profiling, overexpression/disruption of TRIB3 Cancers High 34066165
2022 TRIB3 mediates fibroblast activation and fibrosis through interaction with ATF4; TRIB3 expression markedly inhibits ATF4 promoter-driven transcription and downregulates ATF4 expression, placing TRIB3 as a negative regulator of ATF4 in the context of pulmonary fibrosis. Overexpression/knockdown, ATF4 promoter-reporter assay, co-culture system, western blot International journal of molecular sciences Low 36555349
2024 TRIB3 directly interacts with HNF4α and recruits the E3 ubiquitin ligase TRIM8 to form a complex that catalyzes K48-linked polyubiquitination of HNF4α on lysine 470, leading to HNF4α proteasomal degradation and NAFLD progression. A TRIB3 gain-of-function variant (p.Q84R) reduces HNF4α levels and worsens hepatic steatosis. Co-immunoprecipitation, mass spectrometry, in vivo and in vitro ubiquitination assays, site-directed mutagenesis (K470), molecular docking, cell-penetrating peptide disruption, mouse NAFLD model Journal of hepatology High 38237865
2024 TRIB3 interacts with TCF4 and β-catenin forming a heterotrimeric complex that directly suppresses ALOXE3 promoter activity, thereby inhibiting ferroptosis in head and neck squamous cell carcinoma. Co-immunoprecipitation, ChIP (ALOXE3 promoter), TRIB3 knockdown, ALOXE3 knockdown rescue, ferroptosis assays, hesperidin inhibitor Cell death & disease Medium 38429254
2024 TRIB3 interacts with PLIN2 and abrogates TEB4-mediated PLIN2 ubiquitination and degradation, maintaining higher PLIN2 levels, facilitating lipid accumulation, preserving ER homeostasis, and driving renal cell carcinoma progression. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, overexpression, bioinformatics analysis, in vitro functional assays Cell death & disease Medium 38561354
2025 MET transcriptionally activates TRIB3 via the ERK/SP1 axis; TRIB3 then recruits the E3 ubiquitin ligase COP1 to facilitate ubiquitination and degradation of the tumor suppressor transcription factor FOXO1, upregulating MET, CCND1, and TWIST1 to promote hepatocellular carcinoma development. Co-immunoprecipitation, ubiquitination assay, qRT-PCR, western blot, immunofluorescence, in vitro and in vivo HCC models, AAV8-shTRIB3 liver-specific knockdown Clinical and molecular hepatology Medium 40211872
2016 TRIB3 expression in skeletal muscle mediates glucose-induced insulin resistance; muscle-specific TRIB3 overexpression exacerbates glucose-induced insulin resistance and decreases AKT phosphorylation, while muscle-specific TRIB3 knockout prevents these effects, establishing TRIB3 as a required mediator of glucose toxicity upstream of AKT in skeletal muscle insulin signaling. Muscle-specific TRIB3 overexpressing (MOE) and knockout (MKO) mouse models, insulin signaling assays (AKT phosphorylation), glucose tolerance tests, in vivo metabolic phenotyping Diabetes High 27207527
2016 TRIB3 expression in skeletal muscle is regulated by nutrient availability (decreased under fasting, increased under nutrient excess), indicating a physiological role in metabolic homeostasis beyond pathological insulin resistance. Muscle-specific TRIB3 MOE and MKO mouse models, substrate metabolism assays, energy expenditure measurements Diabetes Medium 27207527
2012 Trib3 mRNA expression in bone marrow-derived mast cells (BMMCs) is positively regulated by IL-3; Trib3-deficient BMMCs show delayed recovery after transient IL-3 deprivation, accelerated death during prolonged IL-3 starvation, and impaired IgE-dependent and pharmacologically induced degranulation, as well as reduced activation-induced cytokine mRNA expression. Trib3 knockout mouse-derived BMMCs, IL-3 deprivation assays, degranulation assays, cytokine mRNA measurement Cellular immunology Medium 23261831
2016 TRIB3 expression in cells is regulated at the level of mRNA translation; during anoxia, TRIB3 mRNA translation is profoundly inhibited, producing a discordance between TRIB3 mRNA and protein levels. TRIB3 protein is stable with levels not controlled by rapid protein breakdown. Translational control assays, anoxia treatment, miRNA-24 manipulation, protein stability assays in breast cancer cell lines and patient specimens PloS one Medium 23185332
2016 TRIB3 suppresses Chac1 (a glutathione-degrading enzyme) expression during arsenite stress; Trib3-deficient cells show markedly elevated CHAC1 expression, accelerated glutathione consumption, and increased susceptibility to arsenite-induced cell death. This suppression is mediated through regulatory elements in the Chac1 promoter and operates within the ATF4 pathway. Trib3 knockout mouse embryonic fibroblasts, Chac1 promoter reporter assays, siRNA knockdown of Chac1, glutathione measurement, cell death assays Biochimica et biophysica acta High 27526673
2020 TRIB3 induction in PD models is driven by the transcription factor complex CHOP/ATF4; the drug adaptaquin inhibits ATF4-dependent transcription, suppresses Trib3 induction, preserves Parkin levels, and protects dopaminergic neurons in both cellular and 6-OHDA mouse models of PD. Neuronal PC12 cells, ventral midbrain dopaminergic neuron cultures, 6-OHDA mouse model, adaptaquin pharmacological treatment, ATF4/CHOP level measurement, Trib3 and Parkin quantification Neurobiology of disease Medium 31911115
2023 ATF4 binds to a specific region of the TRIB3 promoter to transcriptionally upregulate TRIB3 in hepatic stellate cells under mitochondrial stress; TRIB3 in turn promotes HSC activation, and AAV8-shRNA-Atf4 alleviates liver fibrosis in rats by reducing TRIB3 expression. ChIP assay (ATF4 binding to TRIB3 promoter), AAV8-shRNA knockdown, CCl4 rat fibrosis model, PDGF-BB in vitro model, western blot Journal of gastroenterology Medium 37150773
2024 OC-derived TGF-β1 activates SMAD3 phosphorylation in adipocytes, which upregulates TRIB3; TRIB3 then suppresses phosphorylation of C/EBPβ, driving adipocyte dedifferentiation into cancer-associated adipocytes that remodel the extracellular matrix to form a pre-metastatic niche for ovarian cancer. Co-immunoprecipitation-based pathway analysis, pharmacological TGF-β1/SMAD3 inhibition, western blot, in vitro co-culture, in vivo metastasis models Cell death & disease Low 39719444

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Source to sink: regulation of carotenoid biosynthesis in plants. Trends in plant science 530 20303820
1999 Source-sink regulation by sugar and stress. Current opinion in plant biology 296 10375568
2005 Expression profiling of genes involved in starch synthesis in sink and source organs of rice. Journal of experimental botany 278 16275672
2022 Reactive Oxygen Species in Plants: From Source to Sink. Antioxidants (Basel, Switzerland) 260 35204108
2017 Starch as a source, starch as a sink: the bifunctional role of starch in carbon allocation. Journal of experimental botany 212 28981786
2019 TRIB3 supports breast cancer stemness by suppressing FOXO1 degradation and enhancing SOX2 transcription. Nature communications 181 31844113
2019 Disrupting the TRIB3-SQSTM1 interaction reduces liver fibrosis by restoring autophagy and suppressing exosome-mediated HSC activation. Autophagy 143 31286822
2018 TRIB3 Interacts With β-Catenin and TCF4 to Increase Stem Cell Features of Colorectal Cancer Stem Cells and Tumorigenesis. Gastroenterology 143 30365932
2022 TRIB3 reduces CD8+ T cell infiltration and induces immune evasion by repressing the STAT1-CXCL10 axis in colorectal cancer. Science translational medicine 133 34985967
2022 Phloem Loading and Unloading of Sucrose: What a Long, Strange Trip from Source to Sink. Annual review of plant biology 130 35171647
2018 Sink into the Epigenome: Histones as Repositories That Influence Cellular Metabolism. Trends in endocrinology and metabolism: TEM 106 30001904
2016 Metabolite transport and associated sugar signalling systems underpinning source/sink interactions. Biochimica et biophysica acta 105 27487250
2018 Denitrification as an N2O sink. Water research 102 30616050
2003 SINK is a p65-interacting negative regulator of NF-kappaB-dependent transcription. The Journal of biological chemistry 101 12736262
2020 TRIB3-EGFR interaction promotes lung cancer progression and defines a therapeutic target. Nature communications 97 32694521
2017 TRIB3 Promotes APL Progression through Stabilization of the Oncoprotein PML-RARα and Inhibition of p53-Mediated Senescence. Cancer cell 96 28486108
2017 Systems biology derived source-sink mechanism of BMP gradient formation. eLife 77 28826472
2024 Engineering source-sink relations by prime editing confers heat-stress resilience in tomato and rice. Cell 70 39674177
1998 Molecular determinants of sink strength. Current opinion in plant biology 70 10066584
2017 Emodin induces apoptosis of lung cancer cells through ER stress and the TRIB3/NF-κB pathway. Oncology reports 68 28184934
2014 Source/sink interactions underpin crop yield: the case for trehalose 6-phosphate/SnRK1 in improvement of wheat. Frontiers in plant science 67 25202319
2019 TRIB3 Promotes the Proliferation and Invasion of Renal Cell Carcinoma Cells via Activating MAPK Signaling Pathway. International journal of biological sciences 66 30745845
2018 Plant Fructokinases: Evolutionary, Developmental, and Metabolic Aspects in Sink Tissues. Frontiers in plant science 65 29616058
2022 The CD38 glycohydrolase and the NAD sink: implications for pathological conditions. American journal of physiology. Cell physiology 62 35138178
2007 Metabolic engineering of carotenoid accumulation by creating a metabolic sink. Transgenic research 62 17619157
2022 Auxin regulates source-sink carbohydrate partitioning and reproductive organ development in rice. Proceedings of the National Academy of Sciences of the United States of America 61 36037381
2011 Mitochondria are sources of metabolic sink and arrhythmias. Pharmacology & therapeutics 61 21513732
2014 TRIB3 alters endoplasmic reticulum stress-induced β-cell apoptosis via the NF-κB pathway. Metabolism: clinical and experimental 54 24746137
2015 A carbon sink pathway increases carbon productivity in cyanobacteria. Metabolic engineering 53 25777135
2018 Metformin suppresses melanoma progression by inhibiting KAT5-mediated SMAD3 acetylation, transcriptional activity and TRIB3 expression. Oncogene 52 29520103
2016 Tripping on TRIB3 at the junction of health, metabolic dysfunction and cancer. Biochimie 52 26855171
2008 TRIB3 [corrected] is implicated in glucotoxicity- and endoplasmic reticulum-stress-induced [corrected] beta-cell apoptosis. The Journal of endocrinology 50 18818302
2023 A 'wiring diagram' for sink strength traits impacting wheat yield potential. Journal of experimental botany 49 36334052
2018 Deciphering source and sink responses of potato plants (Solanum tuberosum L.) to elevated temperatures. Plant, cell & environment 49 29869794
2015 Trib3 Is Elevated in Parkinson's Disease and Mediates Death in Parkinson's Disease Models. The Journal of neuroscience : the official journal of the Society for Neuroscience 49 26224857
2020 TRIB3 promotes MYC-associated lymphoma development through suppression of UBE3B-mediated MYC degradation. Nature communications 47 33298911
1982 Sorbitol metabolism and sink-source interconversions in developing apple leaves. Plant physiology 47 16662490
2012 Silence of TRIB3 suppresses atherosclerosis and stabilizes plaques in diabetic ApoE-/-/LDL receptor-/- mice. Diabetes 46 22275087
2020 The drug adaptaquin blocks ATF4/CHOP-dependent pro-death Trib3 induction and protects in cellular and mouse models of Parkinson's disease. Neurobiology of disease 45 31911115
2023 CCR7 acts as both a sensor and a sink for CCL19 to coordinate collective leukocyte migration. Science immunology 43 37656776
2012 Sink or swim: lipid rafts in parasite pathogenesis. Trends in parasitology 42 22906512
2011 Birds and longevity: does flight driven aerobicity provide an oxidative sink? Ageing research reviews 38 22198369
2024 TRIB3-TRIM8 complex drives NAFLD progression by regulating HNF4α stability. Journal of hepatology 37 38237865
2020 Feeling the heat: source-sink mismatch as a mechanism underlying the failure of thermal tolerance. The Journal of experimental biology 36 32820058
2016 Skeletal Muscle TRIB3 Mediates Glucose Toxicity in Diabetes and High- Fat Diet-Induced Insulin Resistance. Diabetes 36 27207527
2020 Vernalization Alters Sink and Source Identities and Reverses Phloem Translocation from Taproots to Shoots in Sugar Beet. The Plant cell 35 32769131
2019 Therapeutic potential of the new TRIB3-mediated cell autophagy anticancer drug ABTL0812 in endometrial cancer. Gynecologic oncology 35 30853360
2021 Cytokinin Regulation of Source-Sink Relationships in Plant-Pathogen Interactions. Frontiers in plant science 34 34504504
2019 Cell Wall Invertase 3 Affects Cassava Productivity via Regulating Sugar Allocation From Source to Sink. Frontiers in plant science 33 31114601
2019 TRIB3 promotes lung cancer progression by activating β-catenin signaling. European journal of pharmacology 33 31562867
2018 Metformin reduces TRIB3 expression and restores autophagy flux: an alternative antitumor action. Autophagy 33 29929422
2017 Mammalian Pseudokinase TRIB3 in Normal Physiology and Disease: Charting the Progress in Old and New Avenues. Current protein & peptide science 33 28393700
2022 Visualization and quantification of carbon "rusty sink" by rice root iron plaque: Mechanisms, functions, and global implications. Global change biology 32 35986445
2020 The Cassava Source-Sink project: opportunities and challenges for crop improvement by metabolic engineering. The Plant journal : for cell and molecular biology 32 32502321
2016 Overexpression of TRIB3 promotes angiogenesis in human gastric cancer. Oncology reports 32 27573078
2024 TRIB3 promotes malignancy of head and neck squamous cell carcinoma via inhibiting ferroptosis. Cell death & disease 30 38429254
2020 Interleukin 15 Pharmacokinetics and Consumption by a Dynamic Cytokine Sink. Frontiers in immunology 30 32903632
2015 The TRIB3-SQSTM1 interaction mediates metabolic stress-promoted tumorigenesis and progression via suppressing autophagic and proteasomal degradation. Autophagy 30 26301314
2022 The functions and molecular mechanisms of Tribbles homolog 3 (TRIB3) implicated in the pathophysiology of cancer. International immunopharmacology 29 36527874
2019 TRIB3 Stabilizes High TWIST1 Expression to Promote Rapid APL Progression and ATRA Resistance. Clinical cancer research : an official journal of the American Association for Cancer Research 29 31235507
2017 Photoreceptor outer segment as a sink for membrane proteins: hypothesis and implications in retinal ciliopathies. Human molecular genetics 29 28453661
2020 PML-RARα interaction with TRIB3 impedes PPARγ/RXR function and triggers dyslipidemia in acute promyelocytic leukemia. Theranostics 28 32929351
2012 Regulation of TRIB3 mRNA and protein in breast cancer. PloS one 28 23185332
2022 Alkaline α-galactosidase 2 (CsAGA2) plays a pivotal role in mediating source-sink communication in cucumber. Plant physiology 27 35357489
2021 TRIB3‒GSK-3β interaction promotes lung fibrosis and serves as a potential therapeutic target. Acta pharmaceutica Sinica. B 27 34729304
2020 Treat and trick: common regulation and manipulation of sugar transporters during sink establishment by the plant and the pathogen. Journal of experimental botany 27 32242225
2019 TRIB3 suppresses proliferation and invasion and promotes apoptosis of endometrial cancer cells by regulating the AKT signaling pathway. OncoTargets and therapy 27 30988628
2020 Sp2 promotes invasion and metastasis of hepatocellular carcinoma by targeting TRIB3 protein. Cancer medicine 26 32160655
2022 LncRNA RMRP accelerates autophagy-mediated neurons apoptosis through miR-3142/TRIB3 signaling axis in alzheimer's disease. Brain research 24 35304105
2020 TRIB3 destabilizes tumor suppressor PPARα expression through ubiquitin-mediated proteasome degradation in acute myeloid leukemia. Life sciences 24 32621919
2020 Down-regulation of TRIB3 inhibits the progression of ovarian cancer via MEK/ERK signaling pathway. Cancer cell international 24 32874132
2010 UPR-mediated TRIB3 expression correlates with reduced AKT phosphorylation and inability of interleukin 6 to overcome palmitate-induced apoptosis in RINm5F cells. The Journal of endocrinology 24 20488947
2020 TRIB3 confers radiotherapy resistance in esophageal squamous cell carcinoma by stabilizing TAZ. Oncogene 23 32157210
2018 Capsaicin-induced TRIB3 upregulation promotes apoptosis in cancer cells. Cancer management and research 23 30323679
2021 c-MYC-mediated TRIB3/P62+ aggresomes accumulation triggers paraptosis upon the combination of everolimus and ginsenoside Rh2. Acta pharmaceutica Sinica. B 22 35530150
2022 TRIB3 Mediates Fibroblast Activation and Fibrosis though Interaction with ATF4 in IPF. International journal of molecular sciences 21 36555349
2020 TRIB3 facilitates glioblastoma progression via restraining autophagy. Aging 21 33203798
2012 Trib3 is regulated by IL-3 and affects bone marrow-derived mast cell survival and function. Cellular immunology 21 23261831
2024 TRIB3 promotes the progression of renal cell carcinoma by upregulating the lipid droplet-associated protein PLIN2. Cell death & disease 20 38561354
2015 TRIB3 mediates the expression of Wnt5a and activation of nuclear factor-κB in Porphyromonas endodontalis lipopolysaccharide-treated osteoblasts. Molecular oral microbiology 20 25601649
2022 TRIB3 Is Highly Expressed in the Adipose Tissue of Obese Patients and Is Associated With Insulin Resistance. The Journal of clinical endocrinology and metabolism 19 34718616
2021 The Involvement of TRIB3 and FABP1 and Their Potential Functions in the Dynamic Process of Gastric Cancer. Frontiers in molecular biosciences 19 34957220
2017 TRIB3 inhibits proliferation and promotes osteogenesis in hBMSCs by regulating the ERK1/2 signaling pathway. Scientific reports 19 28871113
2021 Sink Strength Maintenance Underlies Drought Tolerance in Common Bean. Plants (Basel, Switzerland) 18 33807580
2020 TRIB3 confers glioma cell stemness via interacting with β-catenin. Environmental toxicology 18 31995275
2021 TRIB3 promotes oral squamous cell carcinoma cell proliferation by activating the AKT signaling pathway. Experimental and therapeutic medicine 17 33717256
2021 Pharmacological or TRIB3-Mediated Suppression of ATF4 Transcriptional Activity Promotes Hepatoma Cell Resistance to Proteasome Inhibitor Bortezomib. Cancers 17 34066165
2016 TRIB3 increases cell resistance to arsenite toxicity by limiting the expression of the glutathione-degrading enzyme CHAC1. Biochimica et biophysica acta 17 27526673
2022 Source-To-Sink Transport of Sugar and Its Role in Male Reproductive Development. Genes 16 35893060
2017 TRIB3 downregulation enhances doxorubicin-induced cytotoxicity in gastric cancer cells. Archives of biochemistry and biophysics 16 28442401
2025 MET promotes hepatocellular carcinoma development through the promotion of TRIB3-mediated FOXO1 degradation. Clinical and molecular hepatology 15 40211872
2022 Perfluorooctanoic acid promotes pancreatic β cell dysfunction and apoptosis through ER stress and the ATF4/CHOP/TRIB3 pathway. Environmental science and pollution research international 15 35788477
2024 Cepharanthine sensitizes gastric cancer cells to chemotherapy by targeting TRIB3-FOXO3-FOXM1 axis to inhibit autophagy. Phytomedicine : international journal of phytotherapy and phytopharmacology 14 39454374
2022 TRIB3 Modulates PPARγ-Mediated Growth Inhibition by Interfering with the MLL Complex in Breast Cancer Cells. International journal of molecular sciences 14 36142452
2022 TRIB3 Interacts with STAT3 to Promote Cancer Angiogenesis. Current medical science 14 36245025
2021 CHOP Increases TRIB3-Dependent miR-208 Expression to Potentiate Vascular Smooth Muscle Cell Proliferation and Migration by Downregulating TIMP3 in Atherosclerosis. Cardiovascular drugs and therapy 14 33856595
2024 TRIB3 knockdown increases the sensitivity of clear cell renal cell carcinoma to sunitinib by inducing ferroptosis. Cellular signalling 13 39299601
2024 Ovarian cancer-derived TGF-β1 induces cancer-associated adipocytes formation by activating SMAD3/TRIB3 pathway to establish pre-metastatic niche. Cell death & disease 13 39719444
2023 Mitochondrial stress induces hepatic stellate cell activation in response to the ATF4/TRIB3 pathway stimulation. Journal of gastroenterology 13 37150773
2023 The chromatin source-sink hypothesis: a shared mode of chromatin-mediated regulations. Development (Cambridge, England) 13 37922125

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