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FLASH GENE

Symbol

TRIB3

contributors: mct/npt/pgu - updated : 16-08-2013

HGNC name	tribbles homolog 3 (Drosophila)
HGNC id	16228

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

EXPRESSION

Type

widely

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive esophagus       highly   liver         Lymphoid/Immune tonsils       highly Reproductive female system uterus cervix   highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Muscular striatum skeletal   highly

cell lineage
cell lines	lung cancer, breast cancer, colon cancer
fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	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

HOMOLOGY

interspecies	homolog to murine TRB-3
	homolog to rattus Rn.22325
	homolog to Drosophila Tribbles

intraspecies

homolog to C8FW

Homologene

FAMILY	BZIP family
	protein kinase superfamily
	CAMK Ser/Thr protein kinase family
	tribbles subfamily

CATEGORY

enzyme , regulatory , protooncogene , signaling

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm,cytosolic
	intracellular,nucleus

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

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

carbohydrate

signaling

signal transduction

a component

binds DNA as a homo- or heterodimer

INTERACTION

DNA	DNA binding

RNA

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

REGULATION

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

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein 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

Marker

Therapy target

ANIMAL & CELL MODELS