Affinage

TRIB3

Tribbles homolog 3 · UniProt Q96RU7

Length
358 aa
Mass
39.6 kDa
Annotated
2026-04-28
100 papers in source corpus 40 papers cited in narrative 35 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TRIB3 is a stress-inducible pseudokinase that functions as a multivalent scaffold protein integrating cellular stress responses with growth factor signaling, autophagy, and protein turnover. Transcriptionally induced by the GCN2/eIF2α/ATF4 axis via an amino acid response element during ER stress and nutrient deprivation, TRIB3 feeds back to suppress ATF4 transcriptional activity (PMID:15781252, PMID:21203563, PMID:17707795). As a scaffold, TRIB3 directly binds AKT to inhibit its phosphorylation and downstream mTOR/S6K1 signaling (PMID:16966378, PMID:16887816), interacts with SQSTM1/p62 to block its engagement with LC3 and ubiquitinated cargo thereby suppressing autophagic flux (PMID:26268733, PMID:31286822), and recruits E3 ubiquitin ligases (COP1, TRIM8) to target substrates such as SIRT1 and HNF4α for proteasomal degradation (PMID:31125554, PMID:38237865). TRIB3 also stabilizes oncoproteins including PML-RARα, EGFR, TWIST1, and TAZ by shielding them from ubiquitination, and promotes SMAD3 nuclear accumulation and transcriptional activity through KAT5-mediated acetylation, collectively driving cancer stemness, therapy resistance, and fibrosis in multiple tissue contexts (PMID:28486108, PMID:32694521, PMID:31235507, PMID:32157210, PMID:21896644, PMID:29520103).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2004 High

    Establishing TRIB3 as a direct AKT inhibitor answered how a pseudokinase could attenuate insulin signaling, revealing that TRIB3 binds AKT and prevents its phosphorylation.

    Evidence Co-immunoprecipitation, overexpression/knockdown in cultured cells, adenoviral overexpression in mice

    PMID:16129579 PMID:16887816 PMID:16966378

    Open questions at the time
    • Structural basis of AKT–TRIB3 interaction not resolved
    • Whether TRIB3 inhibits AKT through direct occlusion of the activation loop or allosteric mechanism is unclear
  2. 2005 High

    Identification of ATF4 as the transcription factor that induces TRIB3 through an AARE element during ER stress and amino acid deprivation, with TRIB3 feeding back to suppress ATF4 activity, established the core stress-responsive transcriptional circuit governing TRIB3 expression.

    Evidence Promoter mapping, ChIP, transient transfection, GCN2 knockout mice, leucine-deficient diet model

    PMID:15781252 PMID:17707795 PMID:21203563

    Open questions at the time
    • Quantitative dynamics of the ATF4-TRIB3 negative feedback loop not modeled
    • Contribution of CHOP versus ATF4 to TRIB3 induction varies by cell type and stress and is incompletely delineated
  3. 2006 Medium

    Demonstration that TRIB3 inhibits mTOR/S6K1 signaling downstream of insulin extended its role beyond AKT to a broader suppression of anabolic signaling.

    Evidence Overexpression and knockdown in cultured cells, adenoviral overexpression in C57BL/6 mice, S6K1 phosphorylation readout

    PMID:16887816

    Open questions at the time
    • Whether TRIB3 acts on mTOR directly or solely through AKT inhibition was not resolved
    • Tissue-specific relevance of S6K1 inhibition not examined
  4. 2008 Medium

    Discovery that SIAH1 targets TRIB3 for proteasomal degradation revealed how TRIB3 protein levels are post-translationally controlled, and that TRIB3 recruits COP1 to degrade SIRT1 established its role as an E3 ligase adaptor.

    Evidence Yeast two-hybrid, reciprocal Co-IP, in vitro binding, ubiquitination assays, proteasome inhibitor experiments

    PMID:18276110 PMID:31125554

    Open questions at the time
    • SIAH1 ubiquitination sites on TRIB3 not mapped
    • COP1–TRIB3–SIRT1 complex stoichiometry and reconstitution not performed
  5. 2011 High

    Identification of TRIB3 as a SMAD3 interactor that promotes SMAD3 nuclear translocation and transcriptional activity while degrading the negative regulator Smurf2 established TRIB3 as an amplifier of TGF-β signaling.

    Evidence Co-IP, domain mapping, nuclear fractionation, transcriptional reporter, invasion assays

    PMID:21896644

    Open questions at the time
    • Whether TRIB3 directly contacts Smurf2 or acts indirectly was not determined
    • Relative contribution of SMAD3 activation versus AKT inhibition to TRIB3-driven invasion unclear
  6. 2015 High

    Discovery that TRIB3 binds SQSTM1/p62 and prevents its interaction with LC3 and ubiquitinated cargo revealed a direct mechanism by which TRIB3 blocks autophagic flux, connecting stress signaling to autophagy suppression.

    Evidence Co-IP, pulldown, autophagic flux assays, peptide competition, mouse tumor models

    PMID:26268733 PMID:26301314

    Open questions at the time
    • Structural determinants of TRIB3–p62 interface not resolved at atomic level
    • Whether TRIB3 affects selective autophagy receptors beyond p62 is unknown
  7. 2017 High

    Showing that TRIB3 stabilizes the PML-RARα oncoprotein by blocking its sumoylation and ubiquitination established a paradigm for TRIB3 as a protector of oncoproteins from degradation, with direct disease relevance to APL.

    Evidence Co-IP, ubiquitylation/sumoylation assays, genetic KD in APL cells and mouse models, peptide disruption

    PMID:28486108

    Open questions at the time
    • Whether TRIB3 physically occludes sumoylation sites or prevents E3/SUMO ligase access not distinguished
    • Generality of this stabilization mechanism to other fusion oncoproteins not tested
  8. 2018 High

    Elucidation of the TRIB3–KAT5–SMAD3 acetylation axis showed how TRIB3 sustains SMAD3 transcriptional activity through K333 acetylation and creates a positive feedback loop, deepening understanding of TRIB3's scaffolding role in transcriptional regulation.

    Evidence Co-IP, acetyltransferase assay, K333R mutagenesis, reporter assays, mouse melanoma models

    PMID:29520103 PMID:29929422

    Open questions at the time
    • Whether KAT5 recruitment by TRIB3 is specific to SMAD3 or extends to other substrates is unknown
    • Feedback loop dynamics in non-cancer contexts not explored
  9. 2019 High

    Parallel studies showed TRIB3 stabilizes TWIST1 in APL and disrupts AKT-FOXO1 interaction to promote SOX2-driven stemness, extending the oncoprotein-stabilization and AKT-inhibition paradigms to cancer stemness programs.

    Evidence Co-IP, ubiquitination assays, domain mapping, peptide disruption, breast cancer and APL mouse models

    PMID:31235507 PMID:31844113

    Open questions at the time
    • Whether FOXO1 stabilization and TWIST1 stabilization operate in the same tumor contexts is unclear
    • Direct structural basis for TRIB3's ability to shield diverse substrates from ubiquitination not determined
  10. 2020 High

    Demonstration that TRIB3 recruits PKCα to EGFR, modulates EGFR juxtamembrane phosphorylation and WWP1-mediated ubiquitination to enhance EGFR recycling, and stabilizes TAZ by blocking β-TrCP-mediated degradation, broadened the scope of TRIB3 as a scaffold that regulates receptor trafficking and Hippo pathway output.

    Evidence Co-IP, phosphorylation/ubiquitination assays, stapled peptide disruption, mouse NSCLC models; TAZ Co-IP and radioresistance assays

    PMID:32157210 PMID:32694521

    Open questions at the time
    • TRIB3 effect on other RTK family members beyond EGFR not explored
    • Whether TAZ stabilization and EGFR stabilization converge on the same downstream effectors is unknown
  11. 2022 High

    Identification of P300-mediated acetylation of TRIB3 as a stabilizing post-translational modification that prevents its own ubiquitination and degradation, with downstream suppression of STAT1 signaling and CD8+ T cell exclusion, connected TRIB3 regulation to anti-tumor immunity.

    Evidence Acetylation assays, P300 inhibitor, STAT1 phosphorylation assays, genetic Trib3 ablation in mouse CRC models

    PMID:34985967

    Open questions at the time
    • Acetylation sites on TRIB3 not fully mapped
    • Whether P300-mediated stabilization is the dominant mechanism controlling TRIB3 levels across tissues is unknown
  12. 2024 High

    Reconstitution of a TRIB3–TRIM8 E3 ligase complex that catalyzes K48-linked polyubiquitination of HNF4α at K470 during ER stress established TRIB3 as a bona fide E3 ligase adaptor with a defined ubiquitination site, linking it to NAFLD pathogenesis.

    Evidence Co-IP, mass spectrometry ubiquitination site mapping, in vitro ubiquitination, molecular docking, cell-penetrating peptide disruption, mouse NAFLD model

    PMID:38237865

    Open questions at the time
    • Whether TRIB3–TRIM8 targets additional substrates beyond HNF4α is untested
    • Crystal structure of the TRIB3–TRIM8 complex not available

Open questions

Synthesis pass · forward-looking unresolved questions
  • Despite extensive documentation of TRIB3 as a multivalent scaffold, no high-resolution structure of TRIB3 in complex with any partner has been determined, and the structural basis for its ability to serve as both a protein stabilizer and an E3 ligase adaptor for different substrates remains a central open question.
  • No crystal or cryo-EM structure of TRIB3 or any TRIB3-containing complex
  • Determinants that switch TRIB3 from stabilizing to degrading a substrate are unknown
  • Tissue- and context-specific regulation of TRIB3 partner selectivity is not mechanistically understood

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 12 GO:0098772 molecular function regulator activity 5
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 8 R-HSA-392499 Metabolism of proteins 7 R-HSA-8953897 Cellular responses to stimuli 4 R-HSA-9612973 Autophagy 4 R-HSA-5357801 Programmed Cell Death 2
Partners
AKT1ATF4CTNNB1EGFRHNF4APMLSMAD3SQSTM1

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 TRB3 (TRIB3) directly binds to Akt and inhibits its phosphorylation/activation, functioning as an endogenous inhibitor of Akt in insulin signaling. Co-immunoprecipitation, overexpression and knockdown in cultured cells, adenoviral overexpression in mice Molecular and cellular biology (inferred from corpus context); directly demonstrated in multiple papers including PMID:16966378 High 16129579 16887816 16966378 18497449 18818302
2005 TRIB3 gene transcription is induced by endoplasmic reticulum stress and amino acid limitation through ATF4 binding to a C/EBP-ATF composite element (AARE) in the TRIB3 promoter; TRIB3 then acts as a negative feedback regulator of ATF4 transcriptional activity. Promoter mapping, transcriptional start site mapping, transient transfection, chromatin immunoprecipitation, siRNA knockdown Biochemical and biophysical research communications; PloS one High 15781252 21203563
2007 TRIB3 interacts with ATF4 and suppresses ATF4 transcriptional activity, protecting cells from ATF4-induced growth inhibition and cytotoxicity including reduction of reactive oxygen species caused by ATF4 overexpression. Overexpression and siRNA knockdown in HEK293, PC12, and SaOS2 cells; ROS measurement; cell viability assays Experimental cell research Medium 17707795
2006 TRB3 overexpression completely inhibits insulin-stimulated p70 S6 kinase (S6K1) activation via mTOR, while knockdown of endogenous TRB3 increases basal and insulin-stimulated S6K1 activity, placing TRB3 upstream of mTOR-S6K1 signaling. Overexpression and knockdown in cultured cells; adenoviral overexpression in C57BL/6 mice; Western blot for S6K1 phosphorylation The Journal of biological chemistry Medium 16887816
2011 TRIB3 physically interacts with SMAD3 via its kinase-like domain, promotes nuclear localization of SMAD3 by interacting with the MH2 domain, enhances SMAD3 transcriptional activity, and triggers degradation of Smurf2 (thereby reducing SMAD2/phospho-SMAD3 degradation), promoting tumor cell migration and invasion. Co-immunoprecipitation, domain mapping, overexpression and knockdown, nuclear fractionation, transcriptional reporter assays, migration/invasion assays Journal of cell science High 21896644
2008 SIAH1 (E3 ubiquitin ligase) interacts with TRB3 both in vitro and in vivo and targets TRB3 for proteasome-dependent degradation, thereby providing a mechanism for regulation of TRB3 protein levels and its modulation of TGF-β signaling. Yeast two-hybrid screen, co-immunoprecipitation, in vitro binding assay, proteasome inhibitor experiments, cotransfection reporter assays Cellular signalling Medium 18276110
2015 TRIB3 physically interacts with the autophagic receptor SQSTM1/p62 and hinders p62 binding to LC3 and to ubiquitinated substrates, causing p62 accumulation and suppressing autophagic and proteasomal degradation; this links insulin/IGF signaling to tumor promotion. Co-immunoprecipitation, pulldown assays, autophagic flux assays (LC3 lipidation, p62 accumulation), peptide competition, mouse tumor models with KD Nature communications High 26268733 26301314
2016 TRB3 serves as a scaffold for the deubiquitinase USP9x; USP9x deubiquitinates and stabilizes TRB3 and also deubiquitinates Mind Bomb 1 to activate JAG1-mediated Notch signaling in response to cellular stress (nutrient deprivation or ER stress). Co-immunoprecipitation, deubiquitination assays, siRNA knockdown, cell-pair Notch signaling assay Oncogene Medium 27593927
2017 TRIB3 interacts with PML-RARα oncoprotein, suppresses its sumoylation, ubiquitylation, and proteasomal degradation, thereby repressing PML nuclear body assembly, p53-mediated senescence, and myeloid differentiation to promote APL progression. Co-immunoprecipitation, ubiquitylation/sumoylation assays, genetic KD in APL cells and mouse models, peptide disruption of TRIB3/PML-RARα interaction Cancer cell High 28486108
2019 TRIB3 interacts with AKT to interfere with the FOXO1-AKT interaction, suppressing FOXO1 phosphorylation, ubiquitination, and degradation by E3 ligases SKP2 and NEDD4L; accumulated FOXO1 then promotes SOX2 transcription forming a positive regulatory loop that supports breast cancer stemness. Co-immunoprecipitation, ubiquitination assays, overexpression and knockdown, mouse models of breast cancer, peptide disruption of TRIB3-AKT interaction Nature communications High 31844113
2019 TRIB3 interacts with SQSTM1/p62 and hinders its binding to MAP1LC3/LC3, causing accumulation of SQSTM1 aggregates, obstructing autophagic flux, promoting late endosome accumulation, and enhancing hepatocellular secretion of INHBA/Activin A-enriched exosomes that activate hepatic stellate cells to drive liver fibrosis. Co-immunoprecipitation, autophagy flux assays, exosome isolation, helical peptide disruption of TRIB3-SQSTM1 interaction, mouse fibrosis models (BDL, TAA), human fibrotic liver samples Autophagy High 31286822
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 activity, and NSCLC stemness. Co-immunoprecipitation, phosphorylation/ubiquitination assays, domain mapping, stapled peptide disruption of TRIB3-EGFR interaction, mouse NSCLC models Nature communications High 32694521
2022 TRIB3 is acetylated by acetyltransferase P300, which inhibits ubiquitination and subsequent proteasomal degradation of TRIB3; stabilized TRIB3 inhibits STAT1 activation and STAT1-mediated CXCL10 transcription by enhancing EGFR signaling, reducing CD8+ T cell infiltration in colorectal cancer. Acetylation assays, P300 inhibitor, co-immunoprecipitation, STAT1 phosphorylation assays, mouse CRC models, genetic ablation of Trib3 Science translational medicine High 34985967
2006 TRB3 interacts with CtIP (CtBP-interacting protein) via the C-terminus of both proteins and co-localizes with CtIP to the nucleus in a dot-like pattern in HeLa cells. Co-immunoprecipitation, domain mapping, co-localization by immunofluorescence Biochimica et biophysica acta Low 17112672
2015 Trib3 physically interacts with Parkin; elevated Trib3 reduces Parkin expression in cultured cells and dopaminergic neurons; Parkin knockdown abolishes the protective effect of Trib3 downregulation, placing Trib3 upstream of Parkin in PD-related neuronal death. Co-immunoprecipitation, overexpression and knockdown in neuronal PC12 cells and ventral midbrain dopaminergic neurons, 6-OHDA/MPP+/αSYN models, immunostaining of PD patient brains The Journal of neuroscience Medium 26224857
2008 TRB3 recruits COP1 (E3 ubiquitin ligase) to SIRT1, promoting COP1-mediated K48-linked ubiquitination and proteasomal degradation of SIRT1 under lipotoxic conditions, contributing to insulin resistance in hepatocytes. Co-immunoprecipitation, ubiquitination assay, high-fat diet mouse model, palmitate-treated HepG2 cells, Western blot Experimental cell research Medium 31125554
2018 TRIB3 acts as an adaptor to recruit KAT5 (lysine acetyltransferase 5) to SMAD3, inducing phosphorylation-dependent K333 acetylation of SMAD3 that sustains SMAD3 transcriptional activity and subsequent TRIB3 transcription, forming a positive feedback loop; metformin disrupts this loop by inhibiting SMAD3 phosphorylation. Co-immunoprecipitation, acetyltransferase assay, site-directed mutagenesis (K333R), reporter assays, mouse melanoma models Oncogene High 29520103 29929422
2012 Caspase-3 cleaves TRB3 during apoptosis; cleavage of TRB3 promotes caspase-3/7 activation. Under non-cleaved conditions, TRB3 promotes nuclear translocation of procaspase-3, preventing cytoplasmic CASP3 activation and inhibiting apoptosis, functioning as a molecular switch between cell survival and death. In vitro caspase cleavage assay, overexpression of cleavable and non-cleavable TRB3 mutants, caspase activity assays, nuclear fractionation, forced cytoplasmic/nuclear expression constructs PloS one Medium 22912727
2021 TRIB3 interacts with GSK-3β and stabilizes it from ubiquitination and degradation; elevated GSK-3β phosphorylates A20 to inhibit its ubiquitin-editing activity, causing accumulation of C/EBPβ and profibrotic factor production in alveolar macrophages; activated C/EBPβ increases TRIB3 and GSK-3β transcription, forming a positive feedback loop promoting pulmonary fibrosis. Co-immunoprecipitation, ubiquitination assays, pharmacological disruption of TRIB3-GSK-3β interaction, mouse pulmonary fibrosis models, knockdown experiments Acta pharmaceutica sinica B Medium 34729304
2024 TRIB3 directly interacts with HNF4α and recruits TRIM8 to form an E3 ligase complex that catalyzes K48-linked polyubiquitination of HNF4α at lysine 470, leading to its proteasomal degradation during ER stress and NAFLD progression; the gain-of-function TRIB3 variant p.Q84R exacerbates this. Co-immunoprecipitation, mass spectrometry, in vivo and in vitro ubiquitination assays, molecular docking, cell-penetrating peptide disruption, mouse diet-induced NAFLD model, RNA-sequencing Journal of hepatology High 38237865
2019 TRIB3 interacts with TWIST1 via the WR domain of TWIST1 and inhibits TWIST1 ubiquitination, thereby stabilizing TWIST1 protein and contributing to ATRA resistance and APL cell survival. Co-immunoprecipitation, ubiquitination assays, domain mapping, synthetic peptide disruption of TRIB3/TWIST1 interaction, gain/loss-of-function assays Clinical cancer research Medium 31235507
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. Co-immunoprecipitation, ubiquitination assays, overexpression and knockdown, in vitro and in vivo radioresistance assays Oncogene Medium 32157210
2021 TRIB3 directly interacts with ERK, JNK, and p38 MAPK (demonstrated by Co-IP), and promotes proliferation and migration of hypoxic pulmonary artery smooth muscle cells via activation of these MAPK pathways; TRB3 knockdown reduces right ventricular systolic pressure and pulmonary medial wall thickness in a rat hypoxic PH model. Co-immunoprecipitation, specific MAPK inhibitors, lentiviral overexpression and knockdown, in vivo rat hypoxic PH model Respiratory research Medium 34906150
2020 TRIB3 interacts with p62 and MAPKKs (MEK1/MEK2, MEK3/MEK6, MEK4/MKK4) in aged skeletal muscle; TRIB3 knockout reduces p62 and LC3 accumulation, decreases JNK phosphorylation, increases p38 phosphorylation, and attenuates muscle fiber atrophy and fibrosis in aged mice. Co-immunoprecipitation, TRB3 knockout mouse model, Western blot, electrophysiology, histopathology Journal of cachexia, sarcopenia and muscle Medium 32096609
2014 TRIB3 mediates ER stress-induced β-cell apoptosis via activation of the NF-κB pathway; overexpression of TRIB3 enhances NF-κB activation and apoptosis, while TRIB3 knockdown blocks thapsigargin-induced apoptosis in INS-1 cells and in a sub-renal capsule transplantation model. Tet-on inducible TRIB3 overexpression, siRNA knockdown, NF-κB pathway inhibitor, TUNEL staining, sub-renal capsule transplantation in vivo Metabolism: clinical and experimental Medium 24746137
2020 TRIB3 interacts with PPARγ and RXR, interfering with the PPARγ/RXR dimer interaction and promoting PPARγ degradation, thereby reducing PPARγ transcriptional activity and causing lipid metabolism disorder; this mechanism operates in both PML-RARα/APL context and after ATRA/arsenic therapy. Co-immunoprecipitation, dual luciferase reporter assay, Western blot, transgenic and transplanted mouse models Theranostics Medium 32929351
2014 Overexpression of TRB3 in skeletal muscle shifts muscle fiber type toward more oxidative/fatigue-resistant type I/IIA fibers via a PPARα-regulated miR499/miR208b pathway, improving exercise capacity without affecting glucose uptake. Muscle-specific transgenic mouse model, fiber type staining, microRNA quantification (miR208b, miR499), PPARα and myosin heavy chain expression analysis, exercise capacity testing American journal of physiology. Regulatory, integrative and comparative physiology Medium 24740654
2024 TRIB3 interacts with PLIN2 and abrogates TEB4-mediated PLIN2 ubiquitination and degradation, maintaining higher PLIN2 expression and facilitating lipid droplet accumulation while preserving ER homeostasis in renal cell carcinoma. Co-immunoprecipitation, ubiquitination assays, knockdown, bioinformatics screening, patient tissue analysis Cell death & disease Medium 38561354
2024 TRIB3 interacts with TCF4 and β-catenin to form a heterotrimeric complex that directly interacts with the ALOXE3 promoter and suppresses its activation, partially neutralizing ferroptosis in head and neck squamous cell carcinoma. Co-immunoprecipitation, chromatin immunoprecipitation, promoter reporter assays, ALOXE3 knockdown rescue experiments, siRNA knockdown of TRIB3 Cell death & disease Medium 38429254
2010 CHOP (C/EBP homologous protein) is a transcription factor that directly binds to the proximal TRIB3 promoter and activates its expression in response to oxidative stress and free fatty acids in podocytes; elevated TRIB3 in turn inhibits MCP-1/CCL2 production. Chromatin immunoprecipitation, CHOP transfection, TRIB3 promoter-reporter assays, siRNA knockdown American journal of physiology. Renal physiology Medium 20660016
2010 Amino acid limitation activates the GCN2/eIF2α/ATF4 pathway in mouse liver, leading to ATF4, ATF2, and C/EBPβ binding to a functional Amino Acid Response Element (AARE) in the TRB3 promoter; ATF4 binding is essential for amino acid-regulated TRB3 transcription in vivo. Transient transfection in hepatoma cells, chromatin immunoprecipitation, leucine-deficient diet mouse model, GCN2 knockout mice PloS one High 21203563
2020 TRIB3 interacts with β-catenin physically, activating β-catenin signaling to confer glioma cell stemness; β-catenin knockdown rescues the stemness enhancement caused by TRIB3 overexpression. Co-immunoprecipitation, overexpression and knockdown, sphere-forming assay, ALDH1 activity, rescue experiment Environmental toxicology Low 31995275
2022 TRIB3 interacts with ATF4 in lung fibroblasts; TRIB3 overexpression inhibits ATF4 promoter-driven transcription activity and downregulates ATF4 expression, attenuating fibroblast activation and ECM synthesis in IPF. Co-culture system, overexpression and knockdown, promoter reporter assay, Western blot International journal of molecular sciences Low 36555349
2015 TRIB3 knockdown in cardiomyocytes and the stretch-induced TRB3 induction is mediated through the TNF-α/JNK/GADD153 pathway; JNK inhibitor, TNF-α antibody, and TRB3 siRNA all inhibit stretch-induced cardiomyocyte apoptosis. Cyclic stretch model, JNK inhibitor (SP600125), TNF-α antibody, JNK siRNA, TRB3 siRNA, EMSA for GADD153 binding, TRB3 promoter reporter assay, in vivo AV shunt rat model PloS one Medium 25898323
2019 TRIB3 upregulation by the drug ABTL0812 inhibits the PI3K/AKT/mTOR axis and induces autophagy-mediated cell death in endometrial cancer cells; TRIB3 mRNA was validated as a pharmacodynamic biomarker in a Phase 1b/2a clinical trial. siRNA knockdown, cell viability assays, Western blot for pathway components, inducible PTEN KO murine model, patient-derived xenografts, clinical trial samples Gynecologic oncology Medium 30853360

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 525 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) 254 35204108
2017 Starch as a source, starch as a sink: the bifunctional role of starch in carbon allocation. Journal of experimental botany 203 28981786
2019 TRIB3 supports breast cancer stemness by suppressing FOXO1 degradation and enhancing SOX2 transcription. Nature communications 180 31844113
2006 Skeletal muscle-selective knockout of LKB1 increases insulin sensitivity, improves glucose homeostasis, and decreases TRB3. Molecular and cellular biology 176 16966378
2019 Disrupting the TRIB3-SQSTM1 interaction reduces liver fibrosis by restoring autophagy and suppressing exosome-mediated HSC activation. Autophagy 140 31286822
2015 TRB3 links insulin/IGF to tumour promotion by interacting with p62 and impeding autophagic/proteasomal degradations. Nature communications 129 26268733
2022 TRIB3 reduces CD8+ T cell infiltration and induces immune evasion by repressing the STAT1-CXCL10 axis in colorectal cancer. Science translational medicine 128 34985967
2022 Phloem Loading and Unloading of Sucrose: What a Long, Strange Trip from Source to Sink. Annual review of plant biology 121 35171647
2011 TRB3 interacts with SMAD3 promoting tumor cell migration and invasion. Journal of cell science 118 21896644
2013 High throughput kinase inhibitor screens reveal TRB3 and MAPK-ERK/TGFβ pathways as fundamental Notch regulators in breast cancer. Proceedings of the National Academy of Sciences of the United States of America 115 23319603
2016 Metabolite transport and associated sugar signalling systems underpinning source/sink interactions. Biochimica et biophysica acta 105 27487250
2017 TRIB3 Promotes APL Progression through Stabilization of the Oncoprotein PML-RARα and Inhibition of p53-Mediated Senescence. Cancer cell 96 28486108
2020 TRIB3-EGFR interaction promotes lung cancer progression and defines a therapeutic target. Nature communications 95 32694521
2005 Characterization of human NIPK (TRB3, SKIP3) gene activation in stressful conditions. Biochemical and biophysical research communications 93 15781252
2005 TRB3 is a PI 3-kinase dependent indicator for nutrient starvation. Cellular signalling 92 16129579
2004 Polysaccharide aggregation as a potential sink of marine dissolved organic carbon. Nature 90 15118723
2020 Sarcopenia is attenuated by TRB3 knockout in aging mice via the alleviation of atrophy and fibrosis of skeletal muscles. Journal of cachexia, sarcopenia and muscle 88 32096609
2020 Infection-induced plasmablasts are a nutrient sink that impairs humoral immunity to malaria. Nature immunology 88 32424361
2007 TRB3 protects cells against the growth inhibitory and cytotoxic effect of ATF4. Experimental cell research 82 17707795
2010 TRB3 is stimulated in diabetic kidneys, regulated by the ER stress marker CHOP, and is a suppressor of podocyte MCP-1. American journal of physiology. Renal physiology 81 20660016
2017 Mechanisms of phloem unloading: shaped by cellular pathways, their conductances and sink function. Current opinion in plant biology 74 29248828
2020 The global biological microplastic particle sink. Scientific reports 72 33028852
1998 Molecular determinants of sink strength. Current opinion in plant biology 69 10066584
2017 Emodin induces apoptosis of lung cancer cells through ER stress and the TRIB3/NF-κB pathway. Oncology reports 67 28184934
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 60 35138178
2007 Metabolic engineering of carotenoid accumulation by creating a metabolic sink. Transgenic research 60 17619157
2020 Put a cork in it: Plugging the M2 viral ion channel to sink influenza. Antiviral research 59 32229237
2011 Mitochondria are sources of metabolic sink and arrhythmias. Pharmacology & therapeutics 59 21513732
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 57 36037381
2016 Cellular stress induces TRB3/USP9x-dependent Notch activation in cancer. Oncogene 55 27593927
2006 Effect of TRB3 on insulin and nutrient-stimulated hepatic p70 S6 kinase activity. The Journal of biological chemistry 55 16887816
2014 TRIB3 alters endoplasmic reticulum stress-induced β-cell apoptosis via the NF-κB pathway. Metabolism: clinical and experimental 54 24746137
2010 Amino acid availability controls TRB3 transcription in liver through the GCN2/eIF2α/ATF4 pathway. PloS one 54 21203563
2015 A carbon sink pathway increases carbon productivity in cyanobacteria. Metabolic engineering 53 25777135
2005 Genotoxic and endoplasmic reticulum stresses differentially regulate TRB3 expression. Cancer biology & therapy 53 16294033
2016 Tripping on TRIB3 at the junction of health, metabolic dysfunction and cancer. Biochimie 52 26855171
2018 Metformin suppresses melanoma progression by inhibiting KAT5-mediated SMAD3 acetylation, transcriptional activity and TRIB3 expression. Oncogene 51 29520103
2008 TRIB3 [corrected] is implicated in glucotoxicity- and endoplasmic reticulum-stress-induced [corrected] beta-cell apoptosis. The Journal of endocrinology 50 18818302
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
2006 TRB3 interacts with CtIP and is overexpressed in certain cancers. Biochimica et biophysica acta 49 17112672
2012 Silence of TRIB3 suppresses atherosclerosis and stabilizes plaques in diabetic ApoE-/-/LDL receptor-/- mice. Diabetes 45 22275087
2023 A 'wiring diagram' for sink strength traits impacting wheat yield potential. Journal of experimental botany 44 36334052
2011 TRB3 overexpression due to endoplasmic reticulum stress inhibits AKT kinase activation of tongue squamous cell carcinoma. Oral oncology 43 21821462
2006 Fibrates upregulate TRB3 in lymphocytes independent of PPAR alpha by augmenting CCAAT/enhancer-binding protein beta (C/EBP beta) expression. Molecular immunology 42 16949670
2012 Sink or swim: lipid rafts in parasite pathogenesis. Trends in parasitology 41 22906512
2023 CCR7 acts as both a sensor and a sink for CCL19 to coordinate collective leukocyte migration. Science immunology 39 37656776
2008 E3 ubiquitin ligase SIAH1 mediates ubiquitination and degradation of TRB3. Cellular signalling 38 18276110
2024 TRIB3-TRIM8 complex drives NAFLD progression by regulating HNF4α stability. Journal of hepatology 36 38237865
2019 Therapeutic potential of the new TRIB3-mediated cell autophagy anticancer drug ABTL0812 in endometrial cancer. Gynecologic oncology 35 30853360
2020 Vernalization Alters Sink and Source Identities and Reverses Phloem Translocation from Taproots to Shoots in Sugar Beet. The Plant cell 34 32769131
2019 Cell Wall Invertase 3 Affects Cassava Productivity via Regulating Sugar Allocation From Source to Sink. Frontiers in plant science 33 31114601
2018 Metformin reduces TRIB3 expression and restores autophagy flux: an alternative antitumor action. Autophagy 33 29929422
2021 Cytokinin Regulation of Source-Sink Relationships in Plant-Pathogen Interactions. Frontiers in plant science 32 34504504
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
2017 Mammalian Pseudokinase TRIB3 in Normal Physiology and Disease: Charting the Progress in Old and New Avenues. Current protein & peptide science 32 28393700
2016 Overexpression of TRIB3 promotes angiogenesis in human gastric cancer. Oncology reports 32 27573078
2017 Metallothionein Preserves Akt2 Activity and Cardiac Function via Inhibiting TRB3 in Diabetic Hearts. Diabetes 31 29079702
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
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
2008 Overexpression of TRB3 gene in adipose tissue of rats with high fructose-induced metabolic syndrome. Endocrine journal 29 18497449
2022 The functions and molecular mechanisms of Tribbles homolog 3 (TRIB3) implicated in the pathophysiology of cancer. International immunopharmacology 28 36527874
2012 Regulation of TRIB3 mRNA and protein in breast cancer. PloS one 28 23185332
2009 Acute exercise reduces insulin resistance-induced TRB3 expression and amelioration of the hepatic production of glucose in the liver of diabetic mice. Journal of cellular physiology 28 19492410
2021 TRIB3‒GSK-3β interaction promotes lung fibrosis and serves as a potential therapeutic target. Acta pharmaceutica Sinica. B 27 34729304
2020 PML-RARα interaction with TRIB3 impedes PPARγ/RXR function and triggers dyslipidemia in acute promyelocytic leukemia. Theranostics 27 32929351
2012 Stress-inducible caspase substrate TRB3 promotes nuclear translocation of procaspase-3. PloS one 27 22912727
2008 PI3K activates negative and positive signals to regulate TRB3 expression in hepatic cells. Experimental cell research 27 18316073
2011 Emodin-induced microglial apoptosis is associated with TRB3 induction. Immunopharmacology and immunotoxicology 26 21275776
2021 TRB3 mediates vascular remodeling by activating the MAPK signaling pathway in hypoxic pulmonary hypertension. Respiratory research 25 34906150
2020 Sp2 promotes invasion and metastasis of hepatocellular carcinoma by targeting TRIB3 protein. Cancer medicine 25 32160655
2010 An integrative genomic approach in oesophageal cells identifies TRB3 as a bile acid responsive gene, downregulated in Barrett's oesophagus, which regulates NF-kappaB activation and cytokine levels. Carcinogenesis 25 20139130
2009 Acute exercise reverses TRB3 expression in the skeletal muscle and ameliorates whole body insulin sensitivity in diabetic mice. Acta physiologica (Oxford, England) 25 19681769
2021 Circulating TRB3 and GRP78 levels in type 2 diabetes patients: crosstalk between glucose homeostasis and endoplasmic reticulum stress. Journal of endocrinological investigation 24 34591271
2019 TRB3 stimulates SIRT1 degradation and induces insulin resistance by lipotoxicity via COP1. Experimental cell research 24 31125554
2015 Mechanical Stretch Induces Apoptosis Regulator TRB3 in Cultured Cardiomyocytes and Volume-Overloaded Heart. PloS one 24 25898323
1994 Covering embryo cultures with mineral oil alters embryo growth by acting as a sink for an embryotoxic substance. Journal of assisted reproduction and genetics 24 7795366
2022 LncRNA RMRP accelerates autophagy-mediated neurons apoptosis through miR-3142/TRIB3 signaling axis in alzheimer's disease. Brain research 23 35304105
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
2014 Overexpression of TRB3 in muscle alters muscle fiber type and improves exercise capacity in mice. American journal of physiology. Regulatory, integrative and comparative physiology 23 24740654
2020 TRIB3 destabilizes tumor suppressor PPARα expression through ubiquitin-mediated proteasome degradation in acute myeloid leukemia. Life sciences 22 32621919
2018 Antrodia cinnamomea induces autophagic cell death via the CHOP/TRB3/Akt/mTOR pathway in colorectal cancer cells. Scientific reports 22 30479369
2022 TRIB3 Mediates Fibroblast Activation and Fibrosis though Interaction with ATF4 in IPF. International journal of molecular sciences 20 36555349
2017 TRB3 reverses chemotherapy resistance and mediates crosstalk between endoplasmic reticulum stress and AKT signaling pathways in MHCC97H human hepatocellular carcinoma cells. Oncology letters 20 29391905
2015 TRIB3 mediates the expression of Wnt5a and activation of nuclear factor-κB in Porphyromonas endodontalis lipopolysaccharide-treated osteoblasts. Molecular oral microbiology 20 25601649
2024 TRIB3 promotes the progression of renal cell carcinoma by upregulating the lipid droplet-associated protein PLIN2. Cell death & disease 19 38561354
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
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 18 34718616
2020 TRIB3 confers glioma cell stemness via interacting with β-catenin. Environmental toxicology 18 31995275
2020 Silicon Regulates Source to Sink Metabolic Homeostasis and Promotes Growth of Rice Plants Under Sulfur Deficiency. International journal of molecular sciences 18 32456188
2014 TRB3 mediates renal tubular cell apoptosis associated with proteinuria. Clinical and experimental medicine 18 24925634
2017 Silencing of TRB3 Ameliorates Diabetic Tubule Interstitial Nephropathy via PI3K/AKT Signaling in Rats. Medical science monitor : international medical journal of experimental and clinical research 17 28600485
2022 Source-To-Sink Transport of Sugar and Its Role in Male Reproductive Development. Genes 16 35893060