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Symbol TRIB3 contributors: mct/npt/pgu - updated : 16-08-2013
HGNC name tribbles homolog 3 (Drosophila)
HGNC id 16228
  • a Ser/Thr protein kinase domain
  • a BZIP domain
  • a single kinase domain without enzymatic activity
  • a kinase-like domain (KD) responsible for the interaction with SMAD3 and the regulation of SMAD3-mediated transcriptional activity
  • a C-terminal domain necessary for protein degradation, and in this region, a typical D-box motif, which is a critical sequence for the anaphase-promoting complex/cyclosome (APC/C) dependent proteolysis
  • conjugated PhosphoP
    interspecies homolog to murine TRB-3
    homolog to rattus Rn.22325
    homolog to Drosophila Tribbles
    intraspecies homolog to C8FW
  • BZIP family
  • protein kinase superfamily
  • CAMK Ser/Thr protein kinase family
  • tribbles subfamily
  • CATEGORY enzyme , regulatory , protooncogene , signaling
    SUBCELLULAR LOCALIZATION     plasma membrane
    basic FUNCTION
  • having a serine/threonine kinase activity
  • may play a role in tumor cell growth and neuronal cell death
  • NF-kappaB-inducible protein, inhibiting AKT1 activity by preventing its phosphorylation
  • involved in a novel negative feedback control pathway of NF-kappaB-induced gene expression
  • may function as a negative feedback regulator of ATF4
  • novel target of DDIT3/ATF4 and downregulates its own induction by repression of DDIT3/ATF4 functions, and is involved in DDIT3-dependent cell death during ER stress
  • acting as a potent negative regulator of PPARgamma, a master regulator of adipocyte differentiation, and tightly controls adipogenesis
  • key in determining cell fate while responding to environmental challenges
  • protects cells against the growth inhibitory and cytotoxic effect of ATF4
  • scaffold-like regulator of various signal transducers and has been implicated in several processes including insulin signaling, NF-kappaB signaling, lipid metabolism and BMP signaling
  • stress-inducible protein, and is an unstable protein regulated by the ubiquitin-proteasome system
  • TRIB3 is a regulator for adjusting the expression level of CDC25A both in a normal and a genotoxic conditions
  • is independently associated with poor prognosis of breast cancer patients, possibly through its association with tumor cell hypoxia
  • acts as a novel SMAD3-interacting protein to participate in the positive regulation of TGFB-SMAD-mediated cellular biological functions
  • potent physiological regulator of insulin sensitivity and mitochondrial glucose oxidation under conditions of nutrient deprivation and excess
  • is a stress-inducible nuclear protein, which has recently been shown to be involved in ER stress-induced apoptosis
  • through its own cleavage, functions as a molecular switch between the cell survival and apoptotic pathways under stressful conditions
  • emerges as an important guardian of genome integrity
  • may serve as a negative regulator of pro-inflammatory cytokines and chemokines, controlling the extent of the inflammatory response
  • scaffold protein activated under hypoxic conditions and involved in several cell survival and proliferation pathways
  • pseudokinase implicated in the cellular stress response and has been linked to inflammation in certain situations
  • potential role in the modulation of the immune response
  • TRIB3 and IGFBP2, both of which are known to be overexpressed in several types of cancers, are pro-survival modulators of cell viability in nutrient-deficient microenvironments
  • CELLULAR PROCESS cell life, cell death/apoptosis
    protein, degradation
    metabolism carbohydrate
    signaling signal transduction
    a component
  • binds DNA as a homo- or heterodimer
    DNA DNA binding
    small molecule nucleotide,
  • ATP
  • protein
  • binding to ATF4, AKT1 (negatively regulate the cell survival serine-threonine kinase AKT1)
  • interacts with activating transcription factor 4 (ATF4) and may function as a negative feedback regulator of ATF4
  • could interact with SIAH1(SIAH1 targeted TRB3 for proteasome-dependent degradation)
  • APC/C coactivator protein FZR1 is involved in ubiquitination and down-regulating the stability of TRIB3 protein
  • regulates the stability of cell division cycle 25 A (CDC25A), an essential activator of cyclin dependent kinases (CDKs)
  • SMAD3-interacting protein
  • trigger the degradation of SMAD ubiquitin regulatory factor 2 (SMURF2), which resulted in a decrease in the degradation of SMAD2 and phosphorylated SMAD3
  • binding to and inhibiting AKT1, a key mediator of insulin signaling
  • might prevent cytoplasmic activation of CASP3 by promoting proCASP3 entry into the nucleus, and thereby inhibit apoptosis
  • interactor for APOBEC3A and APOBEC3C
  • IGFBP2 is the gene most substantially upregulated by TRIB3
  • cell & other
    induced by hypoxia,glucocorticoides,fasting,cAMP agonists
    PPARA for promoting insulin resistance in the liver through PPARGC1
    by the transcription factor NF-kappaB
    hypoxia and is involved in multiple cellular pathways involved in cell survival
    Other up-regulated in stressed cells by the induction of translationally efficient mRNA containing a truncated 5'UTR
    stable protein which levels are predominantly regulated by translational control of TRIB3 mRNA transcript
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --over  
    in breast, colon and lung cancer
    constitutional     --over  
    observed in the liver, adipose tissue, skeletal muscle, and pancreatic beta-cells of individuals with insulin resistance and/or T2DM
    Susceptibility to glucose intolerance, type 2 diabete (T2DM)
    Variant & Polymorphism other
  • R84 variant is associated with early-onset T2D
  • polymorphism (rs2295490/Q84R) in exon 2 of the pseudokinase-encoding gene tribbles 3 (TRIB3) is associated with an increased risk for T2DM
  • Candidate gene
    Therapy target