TRIB3

Summary

TRIB3 (tribbles pseudokinase 3, HGNC:16228) is a protein-coding gene on chromosome 20p13, encoding Tribbles homolog 3 (Q96RU7). Inactive protein kinase which acts as a regulator of the integrated stress response (ISR), a process for adaptation to various stress.

The protein encoded by this gene is a putative protein kinase that is induced by the transcription factor NF-kappaB. The encoded protein is a negative regulator of NF-kappaB and can also sensitize cells to TNF- and TRAIL-induced apoptosis. In addition, this protein can negatively regulate the cell survival serine-threonine kinase AKT1. Differential promoter usage and alternate splicing result in multiple transcript variants.

Source: NCBI Gene 57761 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cardiomyopathy (Limited, GenCC)
• GWAS associations: 3
• Clinical variants (ClinVar): 87 total
• MANE Select transcript: NM_021158

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16228
Approved symbol	TRIB3
Name	tribbles pseudokinase 3
Location	20p13
Locus type	gene with protein product
Status	Approved
Aliases	dJ1103G7.3, TRB3, SINK
Ensembl gene	ENSG00000101255
Ensembl biotype	protein_coding
OMIM	607898
Entrez	57761

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 17 protein_coding

ENST00000217233, ENST00000422053, ENST00000449710, ENST00000615226, ENST00000714424, ENST00000714425, ENST00000714426, ENST00000714427, ENST00000714428, ENST00000883797, ENST00000883798, ENST00000883799, ENST00000883800, ENST00000883801, ENST00000930143, ENST00000930144, ENST00000969420

RefSeq mRNA: 6 — MANE Select: NM_021158 NM_001301188, NM_001301190, NM_001301193, NM_001301196, NM_001301201, NM_021158

CCDS: CCDS12997, CCDS77554

Canonical transcript exons

ENST00000217233 — 4 exons

Exon	Start	End
ENSE00001042399	380760	381169
ENSE00003753454	391287	391579
ENSE00003755162	388011	388301
ENSE00004023965	396198	397559

Expression profiles

Bgee: expression breadth ubiquitous, 205 present calls, max score 90.87.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 49.9343 / max 897.8773, expressed in 1761 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
183031	40.6253	1741
183027	1.8697	495
183029	1.5996	556
183032	1.5748	891
183028	1.1192	485
183026	1.0207	438
183033	0.7352	341
183037	0.4887	243
183030	0.3980	187
183036	0.3830	183

Top tissues by expression

268 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	90.87	gold quality
pancreatic ductal cell	CL:0002079	90.62	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.49	gold quality
islet of Langerhans	UBERON:0000006	88.45	gold quality
liver	UBERON:0002107	86.41	gold quality
lower esophagus mucosa	UBERON:0035834	85.52	gold quality
stromal cell of endometrium	CL:0002255	84.61	gold quality
upper lobe of left lung	UBERON:0008952	84.37	gold quality
upper lobe of lung	UBERON:0008948	83.80	gold quality
epithelial cell of pancreas	CL:0000083	83.63	silver quality
pancreas	UBERON:0001264	83.50	gold quality
cranial nerve II	UBERON:0000941	82.89	gold quality
esophagus mucosa	UBERON:0002469	82.80	gold quality
body of pancreas	UBERON:0001150	81.85	gold quality
parotid gland	UBERON:0001831	81.80	gold quality
adenohypophysis	UBERON:0002196	81.76	gold quality
skin of leg	UBERON:0001511	81.75	gold quality
cartilage tissue	UBERON:0002418	81.52	gold quality
left adrenal gland cortex	UBERON:0035825	80.23	gold quality
pituitary gland	UBERON:0000007	80.18	gold quality
left adrenal gland	UBERON:0001234	80.10	gold quality
granulocyte	CL:0000094	80.04	gold quality
skin of abdomen	UBERON:0001416	80.03	gold quality
spleen	UBERON:0002106	79.49	gold quality
zone of skin	UBERON:0000014	79.17	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.78	gold quality
minor salivary gland	UBERON:0001830	78.52	gold quality
saliva-secreting gland	UBERON:0001044	78.39	gold quality
adrenal cortex	UBERON:0001235	78.27	gold quality
right adrenal gland	UBERON:0001233	78.21	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-98556	yes	633.30
E-ANND-3	yes	4.62
E-MTAB-6075	no	679.25
E-MTAB-7249	no	213.50
E-MTAB-6058	no	116.32

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

3 targets.

Target	Regulation
ATF4	Repression
SMAD3	Unknown
TRIB3	Repression

Upstream regulators (CollecTRI, top): AHR, AP1, AR, ATF1, ATF2, ATF4, BCL11B, BCL6, CDX2, CEBPB, CEBPG, CREB1, CUX1, DDIT3, DNMT1, E2F1, EGR1, EGR2, ELK1, ESR1, ESR2, ETS1, FOS, FOXC1, FOXO1, FOXO4, GLI1, HES1, HHEX, HIF1A, HNF1A, HNF4A, HNRNPK, HOXA9, ID1, IER2, INSM1, IRF3, IRF6, ISL1

miRNA regulators (miRDB)

35 targeting TRIB3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-629-3P	99.85	67.99	1875
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-3136-3P	99.57	66.59	781
HSA-MIR-7155-3P	99.57	66.48	794
HSA-MIR-5571-5P	99.49	66.99	1764
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-3911	99.38	66.95	1087
HSA-MIR-940	99.37	66.14	2064
HSA-MIR-584-3P	99.35	67.69	1082
HSA-MIR-6808-5P	99.31	66.23	2150
HSA-MIR-6893-5P	99.31	66.25	2119
HSA-MIR-5582-5P	99.27	71.42	1879
HSA-MIR-3191-5P	99.24	66.52	1722
HSA-MIR-4279	99.19	66.70	2437
HSA-MIR-146A-3P	99.13	68.99	1881
HSA-MIR-7851-3P	98.72	64.88	980
HSA-MIR-7977	98.65	66.18	2590
HSA-MIR-1178-3P	98.57	67.09	890
HSA-MIR-3130-5P	98.14	66.00	711
HSA-MIR-6867-3P	98.12	66.07	1305
HSA-MIR-5087	98.01	69.09	965
HSA-MIR-5681A	97.99	67.17	1658
HSA-MIR-4423-3P	97.98	69.66	912

Literature-anchored findings (GeneRIF, showing 40)

• SINK specifically interacted with the NF-kappaB transactivator p65 and inhibited p65 phosphorylation (PMID:12736262)
• This protein, a novel Drosophila tribbles ortholog, is overexpressed in human tumors and is regulated by hypoxia. (PMID:12743605)
• results suggest that TRB3, a mammalian homolog of Drosophila tribbles, promotes glucose output from liver under fasting conditions by binding to and interfering with Akt phosphorylation in response to residual insulin signaling [Trb3 tribbles homolog 3] (PMID:12791994)
• TRB3 is a novel target of CHOP/ATF4 and downregulates its own induction by repression of CHOP/ATF4 functions and is involved in CHOP-dependent cell death during endoplasmic reticulum stress. (PMID:15775988)
• coexpression of hNIPK inhibits activation of hNIPK promoter in response to the stress-inducing agents and to overexpressed ATF4, and thus NIPK may function as a negative feedback regulator of ATF4 (PMID:15781252)
• The prevalent TRB3 missense Q84R polymorphism is significantly associated with several insulin resistance-related abnormalities and with the presence of a cluster of cardiovascular risk factors. (PMID:16123373)
• We have identified TRB3 as a novel transcriptional target of phosphatidylinositol (PI) 3-kinase.Our data point to an important role of TRB3 in sensing reduced nutrient supplies and in providing survival signals during these periods. (PMID:16129579)
• In cultured cells, overexpression of TRB3 completely inhibits insulin-stimulated hepatic p70 S6 kinase activation by mammalian target of rapamycin. (PMID:16887816)
• LKB1-mediated TRB3 expression provides a novel link between LKB1 and Akt, critical kinases involved in both tumor genesis and cell metabolism. (PMID:16966378)
• Since CtIP plays important roles in cell cycle checkpoint control and it has been implicated in tumorigenesis, our data suggest that TRB3 may be involved in these biological processes through interacting with CtIP. (PMID:17112672)
• TRB3 and ATF4 belong to the same protein complex bound to the sequence involved in the ATF4-dependent regulation of gene expression by amino acid limitation. (PMID:17369260)
• The results indicate that TRB3 protects cells against the growth inhibitory and cytotoxic effect of ATF4. (PMID:17707795)
• the N-terminal portion of CHOP plays a crucial role in its functional regulation and enable us to identify a novel function of TRB3 as an intracellular antagonist of the p300-binding domain of CHOP. (PMID:17872950)
• TRB3 acts as a potent negative regulator of PPARgamma, a master regulator of adipocyte differentiation, and tightly controls adipogenesis (PMID:18187772)
• SIAH1-induced degradation of TRB3 represents a potential regulatory mechanism for TGF-beta signaling. (PMID:18276110)
• Multiple pathways are involved in the anoxia response of SKIP3 including HuR-regulated RNA stability, NF-kappaB and ATF4 (PMID:18408768)
• Data demonstrate that the TRIB3 R84 variant impairs insulin signaling and nitric oxide production in human endothelial cells (PMID:18436806)
• The TRIB3 R84 variant is associated with early-onset type 2 diabetes in whites. Alteration in the insulin secretion/insulin sensitivity interplay appears to underlie this association. (PMID:18984671)
• amino acid substitution is a gain of function mutation with the potential to affect insulin signalling and to increase the risk of insulin resistance and diabetes. [REVIEW] (PMID:19139803)
• These results are the first to demonstrate that TRB3 is present in human chondrocytes, and that the level of TRB3 is increased in osteoarthritis cartilage and in isolated osteoarthritis chondrocytes. (PMID:19180501)
• Q84R variant is associated with insulin resistance among T2DM patients in Chinese population. (PMID:19291425)
• TRB3 in part mediates the macrophage apoptosis induced by ox-LDL, which suggests that TRB3 might be involved in vulnerable atherosclerotic plaque progression (PMID:19389115)
• The TRIB3 R84 allele especially predisposes to carotid atherosclerosis in part through the effects of abdominal obesity, hypertriglyceridemia, and insulin resistance. (PMID:19389818)
• increased transcription as well as altered usage of 5’-UTR variants contributes to the upregulation of hTRB3 protein synthesis in stressful conditions. (PMID:19505541)
• study showed TRIB3 is expressed at higher levels in colorectal cancer (CRC) than corresponding normal regions & is expressed in gastrointestinal cancer cell lines; data suggest usefulness of TRIB3 as a marker for predicting prognosis of CRC patients (PMID:19904274)
• These results suggest that APC/C(Cdh1) is involved in ubiquitination and down-regulating the stability of TRB3 protein. (PMID:20064487)
• TRB3 as a bile acid responsive gene, downregulated in Barrett’s oesophagus, which regulates NF-kappaB activation and cytokine levels. (PMID:20139130)
• Data confirm that the TRIB3 R84 variant affects glucose homeostasis and suggest this effect is due to an alteration of the interplay between insulin sensitivity and secretion. (PMID:20393693)
• Study have found evidence for a role of aberrant hepatic TRIB3 transcript levels in insulin resistance in obese humans and identified potential transcriptional pathways involved in regulation of TRIB3 gene expression in the liver. (PMID:20461355)
• The pseudokinase tribbles homolog 3 interacts with ATF4 to negatively regulate insulin exocytosis in human and mouse beta cells. (PMID:20592469)
• The TRIB3 R84 variant is associated with increased carotid IMT also in Caucasians, thus replicating previous data obtained in Asians. In addition, in HUVECs, this variant is associated with unbalanced insulin signalling. (PMID:20693163)
• the GCN2/eIF2alpha/ATF4 pathway is essential for the induction of the TRB3 gene transcription (PMID:21203563)
• Helicobacter pylori infection is associated with decreased expression of TRIB3 in human gastric epithelial cell lines and tissue samples. (PMID:21220698)
• HHcy impairs hepatic glycogen synthesis by inducing the expression of TRB3 (PMID:21435438)
• TRB3 Q84R polymorphism is associated with obesity and especially glucose metabolism and not associated with polycystic ovary syndrome because of compositional characteristics of phenotype in Chinese PCOS women. (PMID:21492415)
• TRIB3 protein is associated with a good prognosis in human breast cancer patients, possibly due to the fact that TRIB3 is involved in hypoxia tolerance. (PMID:21704407)
• TRIB3 is independently associated with poor prognosis of breast cancer patients, possibly through its association with tumor cell hypoxia (PMID:21864376)
• knockdown of endogenous TRB3 expression inhibited the migration and invasion of tumor cells in vitro (PMID:21896644)
• TRB3 is a critical molecule in the homocysteine-mediated cell-cycle arrest in endothelial cells. (PMID:21935927)
• Studies indicate tribbles 1 and tribbles 3 as regulators of lipid level and disease susceptibility genes in metabolic syndrome and type 2 diabetes. (PMID:22274752)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	trib3	ENSDARG00000016200
mus_musculus	Trib3	ENSMUSG00000032715
rattus_norvegicus	Trib3	ENSRNOG00000007319
drosophila_melanogaster	trbl	FBGN0028978

Paralogs (3): TRIB2 (ENSG00000071575), TRIB1 (ENSG00000173334), STK40 (ENSG00000196182)

Protein

Protein identifiers

Tribbles homolog 3 — Q96RU7 (reviewed: Q96RU7)

Alternative names: Neuronal cell death-inducible putative kinase, SINK, p65-interacting inhibitor of NF-kappa-B

All UniProt accessions (5): Q96RU7, A0A087WTX3, A0AAQ5BHY5, B0QYQ2, J3KR25

UniProt curated annotations — full annotation on UniProt →

Function. Inactive protein kinase which acts as a regulator of the integrated stress response (ISR), a process for adaptation to various stress. Inhibits the transcriptional activity of DDIT3/CHOP and is involved in DDIT3/CHOP-dependent cell death during ER stress. May play a role in programmed neuronal cell death but does not appear to affect non-neuronal cells. Acts as a negative feedback regulator of the ATF4-dependent transcription during the ISR: while TRIB3 expression is promoted by ATF4, TRIB3 protein interacts with ATF4 and inhibits ATF4 transcription activity. Disrupts insulin signaling by binding directly to Akt kinases and blocking their activation. May bind directly to and mask the ‘Thr-308’ phosphorylation site in AKT1. Interacts with the NF-kappa-B transactivator p65 RELA and inhibits its phosphorylation and thus its transcriptional activation activity. Interacts with MAPK kinases and regulates activation of MAP kinases. Can inhibit APOBEC3A editing of nuclear DNA.

Subunit / interactions. Interacts with AKT1, AKT2, MAP2K1 and MAP2K7. Interacts with ATF4. Interacts with DDIT3/CHOP and inhibits its interaction with EP300/P300. Interacts with APOBEC3C. Interacts (via N-terminus) with APOBEC3A. Interacts with RELA.

Subcellular location. Nucleus.

Tissue specificity. Highest expression in liver, pancreas, peripheral blood leukocytes and bone marrow. Also highly expressed in a number of primary lung, colon and breast tumors. Expressed in spleen, thymus, and prostate and is undetectable in other examined tissues, including testis, ovary, small intestine, colon, leukocyte, heart, brain, placenta, lung, skeletal muscle, and kidney.

Domain organisation. The protein kinase domain is predicted to be catalytically inactive.

Induction. By hypoxia, TNF, and by nutrient starvation. Expression is PI 3-kinase and/or NF-kappa-B-dependent. Induced by ER stress via ATF4-DDIT3/CHOP pathway and can down-regulate its own induction by repression of ATF4-DDIT3/CHOP functions.

Similarity. Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. Tribbles subfamily.

RefSeq proteins (6): NP_001288117, NP_001288119, NP_001288122, NP_001288125, NP_001288130, NP_066981* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR024104	Tribbles/Ser_Thr_kinase_40	Family

Pfam: PF00069

UniProt features (15 total): sequence variant 5, sequence conflict 4, region of interest 2, chain 1, domain 1, compositionally biased region 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96RU7-F1	77.51	0.64

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 12

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-165158	Activation of AKT2
R-HSA-1989781	PPARA activates gene expression
R-HSA-199418	Negative regulation of the PI3K/AKT network
R-HSA-389357	CD28 dependent PI3K/Akt signaling
R-HSA-5218920	VEGFR2 mediated vascular permeability
R-HSA-9633012	Response of EIF2AK4 (GCN2) to amino acid deficiency
R-HSA-9648895	Response of EIF2AK1 (HRI) to heme deficiency

MSigDB gene sets: 375 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_UP, GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_UP, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_MONOCYTE_UP, REACTOME_SIGNALING_BY_INSULIN_RECEPTOR, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_CARBOHYDRATE_TRANSPORT, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_REGULATION_OF_FAT_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, TSENG_IRS1_TARGETS_UP, GOBP_REGULATION_OF_PHOSPHORYLATION, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_NEGATIVE_REGULATION_OF_LIPID_METABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_FAT_CELL_DIFFERENTIATION

GO Biological Process (16): negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of autophagy (GO:0010506), regulation of D-glucose transmembrane transport (GO:0010827), positive regulation of protein ubiquitination (GO:0031398), positive regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032436), cellular response to insulin stimulus (GO:0032869), response to endoplasmic reticulum stress (GO:0034976), regulation of MAP kinase activity (GO:0043405), negative regulation of MAPK cascade (GO:0043409), negative regulation of fat cell differentiation (GO:0045599), negative regulation of fatty acid biosynthetic process (GO:0045717), negative regulation of DNA-templated transcription (GO:0045892), negative regulation of insulin receptor signaling pathway (GO:0046627), intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress (GO:0070059), protein phosphorylation (GO:0006468), apoptotic process (GO:0006915)

GO Molecular Function (12): transcription corepressor activity (GO:0003714), protein kinase inhibitor activity (GO:0004860), ATP binding (GO:0005524), protein kinase binding (GO:0019901), protein serine/threonine kinase inhibitor activity (GO:0030291), mitogen-activated protein kinase kinase binding (GO:0031434), ubiquitin protein ligase binding (GO:0031625), ubiquitin-protein transferase regulator activity (GO:0055106), ubiquitin ligase activator activity (GO:1990757), protein kinase activity (GO:0004672), protein binding (GO:0005515), enzyme binding (GO:0019899)

GO Cellular Component (4): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829), plasma membrane (GO:0005886)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Intracellular signaling by second messengers	1
PI3K Cascade	1
Regulation of lipid metabolism by PPARalpha	1
PIP3 activates AKT signaling	1
Co-stimulation by CD28	1
VEGFA-VEGFR2 Pathway	1
Cellular response to starvation	1
Cellular responses to stress	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
negative regulation of DNA-templated transcription	2
cellular anatomical structure	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
autophagy	1
regulation of catabolic process	1
regulation of transmembrane transport	1
D-glucose transmembrane transport	1
protein ubiquitination	1
regulation of protein ubiquitination	1
positive regulation of protein modification by small protein conjugation or removal	1
regulation of proteasomal ubiquitin-dependent protein catabolic process	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
positive regulation of proteasomal protein catabolic process	1
positive regulation of ubiquitin-dependent protein catabolic process	1
response to insulin	1
cellular response to peptide hormone stimulus	1
cellular response to stress	1
MAP kinase activity	1
regulation of protein serine/threonine kinase activity	1
MAPK cascade	1
regulation of MAPK cascade	1
negative regulation of intracellular signal transduction	1
fat cell differentiation	1
negative regulation of cell differentiation	1
regulation of fat cell differentiation	1
fatty acid biosynthetic process	1
regulation of fatty acid biosynthetic process	1
negative regulation of fatty acid metabolic process	1
negative regulation of lipid biosynthetic process	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
insulin receptor signaling pathway	1
negative regulation of signal transduction	1
regulation of insulin receptor signaling pathway	1
negative regulation of cellular response to insulin stimulus	1
response to endoplasmic reticulum stress	1
intrinsic apoptotic signaling pathway	1
phosphorylation	1

Protein interactions and networks

STRING

2587 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TRIB3	AKT1	P31749	966
TRIB3	RIBC2	Q9H4K1	920
TRIB3	ATF4	P18848	856
TRIB3	ASNS	P08184	836
TRIB3	CHAC1	Q9BUX1	789
TRIB3	PRND	Q9UKY0	769
TRIB3	DDIT3	P35638	751
TRIB3	CEBPB	P17676	749
TRIB3	XBP1	P17861	713
TRIB3	MAP2K1	Q02750	708
TRIB3	ATF3	P18847	704
TRIB3	CTNNB1	P35222	700
TRIB3	HSPA5	P11021	689
TRIB3	SMAD3	P84022	689
TRIB3	SLC7A5	Q01650	685

IntAct

266 interactions, top by confidence:

A	B	Type	Score
ATF4	TRIB3	psi-mi:“MI:0915”(physical association)	0.900
TRIB3	ATF4	psi-mi:“MI:0915”(physical association)	0.900
TRIB3	APOBEC3C	psi-mi:“MI:0915”(physical association)	0.670
BCL6	TRIB3	psi-mi:“MI:0915”(physical association)	0.670
TRIB3	STK40	psi-mi:“MI:0914”(association)	0.640
RPGRIP1	TRIB3	psi-mi:“MI:0915”(physical association)	0.560
TRIB3	RPGRIP1	psi-mi:“MI:0915”(physical association)	0.560
TRIB3	MDFI	psi-mi:“MI:0915”(physical association)	0.560
HOXC8	TRIB3	psi-mi:“MI:0915”(physical association)	0.560
GRB2	TRIB3	psi-mi:“MI:0915”(physical association)	0.560
ARMC7	TRIB3	psi-mi:“MI:0915”(physical association)	0.560
FAM161A	TRIB3	psi-mi:“MI:0915”(physical association)	0.560
TEKT4	TRIB3	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (241): TRIB3 (Affinity Capture-Western), TRIB3 (Reconstituted Complex), TRIB3 (Two-hybrid), TRIB3 (Two-hybrid), STK40 (Affinity Capture-MS), PDDC1 (Affinity Capture-MS), RFWD2 (Affinity Capture-MS), TRIB3 (Affinity Capture-Western), SQSTM1 (Affinity Capture-Western), TRIB3 (Reconstituted Complex), SQSTM1 (Reconstituted Complex), TRIB3 (Protein-peptide), ATF4 (Two-hybrid), MDFI (Two-hybrid), RPGRIP1 (Two-hybrid)

ESM2 similar proteins: A0A061IR73, A0A1B0GUU1, A6H687, A8MYJ7, B1WC39, D3ZVB0, E1BD59, G3MY25, G3MZC5, O75064, P07199, P27790, P29597, P48988, P52333, P52824, Q08DF2, Q0VCE3, Q13608, Q1JPD6, Q2VPB7, Q3TAP4, Q3U1Y4, Q3ZBE0, Q499M4, Q53EQ6, Q5JZY3, Q62137, Q63272, Q6B0B8, Q6DI92, Q6ZPS2, Q6ZS72, Q7TM95, Q80VI1, Q86UT6, Q8BYG9, Q8N9M5, Q8R5G7, Q8TE96

Diamond homologs: A2XFF4, A3B529, B3NE99, B4IAQ8, B4PDM5, B4QK53, B8BBT7, D3ZML2, F1QGZ6, O13945, O22932, O22971, O65554, O80902, O94168, P07334, P34244, P92937, P92958, Q02723, Q0D4B2, Q0JI49, Q0VCE3, Q10LQ2, Q12263, Q17QV9, Q19469, Q28283, Q28GW8, Q2QMI0, Q2QY53, Q2RAX3, Q38997, Q53P85, Q54DF2, Q54SJ5, Q59W62, Q5GLH2, Q5JLQ9, Q5JLS2

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
TRIB3	“down-regulates activity”	AKT	binding
TRIB3	“down-regulates activity”	AKT1	binding
DDIT3	“up-regulates quantity by expression”	TRIB3	“transcriptional regulation”
TRIB3	“down-regulates quantity by destabilization”	ACACA	binding
TRIB3	“down-regulates quantity by destabilization”	ACACB	binding
TRIB3	“up-regulates activity”	COP1	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

87 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	72
Likely benign	9
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

674 predictions. Top by Δscore:

Variant	Effect	Δscore
20:388298:CAAGG:C	donor_loss	1.0000
20:388299:AAGG:A	donor_loss	1.0000
20:388300:AGGTA:A	donor_loss	1.0000
20:388302:G:C	donor_loss	1.0000
20:388303:T:A	donor_loss	1.0000
20:391284:CA:C	acceptor_loss	1.0000
20:391285:A:AT	acceptor_loss	1.0000
20:391286:GGT:G	acceptor_gain	1.0000
20:391286:GGTGT:G	acceptor_gain	1.0000
20:391575:GAGAG:G	donor_gain	1.0000
20:391577:GAG:G	donor_gain	1.0000
20:391578:AGG:A	donor_loss	1.0000
20:391579:GGTG:G	donor_loss	1.0000
20:391580:G:GG	donor_gain	1.0000
20:391581:T:A	donor_loss	1.0000
20:396189:A:AG	acceptor_gain	1.0000
20:396189:AT:A	acceptor_gain	1.0000
20:396190:T:A	acceptor_gain	1.0000
20:396190:T:G	acceptor_gain	1.0000
20:396196:A:AG	acceptor_gain	1.0000
20:396196:AG:A	acceptor_gain	1.0000
20:396197:G:GT	acceptor_gain	1.0000
20:396197:GG:G	acceptor_gain	1.0000
20:396197:GGA:G	acceptor_gain	1.0000
20:396197:GGAA:G	acceptor_gain	1.0000
20:388007:C:G	acceptor_gain	0.9900
20:388008:CAG:C	acceptor_loss	0.9900
20:388009:A:AG	acceptor_gain	0.9900
20:388009:AGAT:A	acceptor_gain	0.9900
20:388010:G:GT	acceptor_gain	0.9900

AlphaMissense

2249 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:396394:T:C	F261L	0.993
20:396396:C:A	F261L	0.993
20:396396:C:G	F261L	0.993
20:396346:T:A	W245R	0.983
20:396346:T:C	W245R	0.983
20:391557:T:C	F188L	0.976
20:391559:T:A	F188L	0.976
20:391559:T:G	F188L	0.976
20:396367:T:C	F252L	0.976
20:396369:C:A	F252L	0.976
20:396369:C:G	F252L	0.976
20:396348:G:C	W245C	0.975
20:396348:G:T	W245C	0.975
20:396431:T:C	I273T	0.971
20:391563:T:C	F190L	0.966
20:391565:C:A	F190L	0.966
20:391565:C:G	F190L	0.966
20:396394:T:A	F261I	0.966
20:396395:T:C	F261S	0.966
20:396395:T:G	F261C	0.966
20:396349:A:C	S246R	0.963
20:396351:C:A	S246R	0.963
20:396351:C:G	S246R	0.963
20:396356:G:A	G248D	0.962
20:396392:C:A	P260H	0.961
20:396299:A:T	E229V	0.955
20:396421:T:C	F270L	0.955
20:396423:C:A	F270L	0.955
20:396423:C:G	F270L	0.955
20:396488:T:A	V292D	0.955

dbSNP variants (sampled 300 via entrez): RS1000068301 (20:398006 T>C), RS1000232773 (20:382878 T>C), RS1000307157 (20:387840 G>A,T), RS1000310121 (20:396080 G>A,T), RS1000325578 (20:382569 G>A), RS1000342203 (20:386078 G>A), RS1000568586 (20:384425 G>A), RS1000640902 (20:390630 T>A,G), RS1000665128 (20:384164 G>A), RS1001072914 (20:394820 C>T), RS1001087751 (20:395084 A>G), RS1001178207 (20:389433 C>T), RS1001255165 (20:384709 G>C), RS1001465085 (20:379791 C>T), RS1001728584 (20:394401 A>G)

Disease associations

OMIM: gene MIM:607898 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
cardiomyopathy	Limited	Autosomal dominant

Mondo (1): cardiomyopathy (MONDO:0004994)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST000905_10	Information processing speed	2.000000e-07
GCST007010_4	Logical memory (delayed recall)	6.000000e-07
GCST007011_4	Logical memory (immediate recall)	3.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004363	information processing speed
EFO:0004874	memory performance

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D009202	Cardiomyopathies	C14.280.238

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs2295490	Efficacy	3	methylphenidate	Attention Deficit Disorder with Hyperactivity

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2295490	TRIB3	3	0.00	1	methylphenidate

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Trbl family

CTD chemical–gene interactions

202 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	10
Valproic Acid	affects cotreatment, increases expression, affects expression	9
Cyclosporine	increases expression	9
Benzo(a)pyrene	increases methylation, decreases expression	7
bisphenol A	affects expression, increases expression	6
Tunicamycin	increases expression	6
Dronabinol	increases reaction, affects cotreatment, decreases expression, decreases phosphorylation, decreases reaction (+3 more)	5
Arsenic Trioxide	increases expression, decreases reaction, affects cotreatment	4
Acetaminophen	increases expression	4
Cisplatin	affects expression, increases expression, affects response to substance	4
(+)-JQ1 compound	affects cotreatment, affects expression, decreases expression	3
Silver	increases expression	3
Tetrachlorodibenzodioxin	decreases expression	3
Tretinoin	increases expression, decreases expression, increases reaction, increases secretion, affects cotreatment	3
Cadmium Chloride	decreases expression, increases abundance, increases expression	3
perfluorooctanoic acid	increases expression	2
ochratoxin A	decreases acetylation, decreases expression	2
didecyldimethylammonium	increases expression	2
cupric chloride	increases expression	2
S-(1,2-dichlorovinyl)cysteine	increases expression	2
perfluorooctane sulfonic acid	increases expression	2
entinostat	increases expression, affects cotreatment	2
azaspiracid	increases expression	2
Bortezomib	affects cotreatment, decreases reaction, increases expression, increases response to substance, increases reaction	2
Troglitazone	decreases expression, increases expression	2
Amiodarone	increases expression	2
Ascorbic Acid	decreases expression, affects cotreatment, increases expression	2
Cadmium	increases abundance, increases expression	2
Cannabidiol	increases expression, affects cotreatment	2
Copper	affects binding, increases expression	2

Cellosaurus cell lines

6 cell lines: 6 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B1EA	Abcam HCT 116 TRIB3 KO	Cancer cell line	Male
CVCL_B2JL	Abcam HeLa TRIB3 KO	Cancer cell line	Female
CVCL_E1ES	Ubigene U-87 MG TRIB3 KO	Cancer cell line	Male
CVCL_TT78	HAP1 TRIB3 (-) 1	Cancer cell line	Male
CVCL_TT79	HAP1 TRIB3 (-) 2	Cancer cell line	Male
CVCL_TT80	HAP1 TRIB3 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00348530	PHASE4	UNKNOWN	Carvedilol Versus Verapamil in Chronic Heart Failure Secondary to Non-Ischemic Cardiomyopathy
NCT00371891	PHASE4	COMPLETED	Ontario Multidetector Computed Tomographic (MDCT) Coronary Angiography Study (OMCAS)
NCT00401856	PHASE4	COMPLETED	CMR to Assess Fibrosis in Cardiomyopathy Using Eplerenone
NCT00559338	PHASE4	COMPLETED	Impact of Nesiritide Infusion for Decompensated Heart Failure in the Emergency Department
NCT00606775	PHASE4	UNKNOWN	The Preventive Efficacy of Carvedilol on Cardiac Dysfunction in Duchenne Muscular Dystrophy
NCT00658203	PHASE4	COMPLETED	Clinical Evaluation on Advanced Resynchronization
NCT00701220	PHASE4	COMPLETED	Statin Therapy for Ischemic and Nonischemic Cardiomyopathy
NCT00800761	PHASE4	COMPLETED	Intensive Combined Chelation Therapy for Iron-Induced Cardiac Disease in Patients With Thalassemia Major
NCT00806390	PHASE4	TERMINATED	Prevention of Anthracycline or Trastuzumab Induced Cardiomyopathy by Metoprolol
NCT01006473	PHASE4	COMPLETED	Exercise Training in Chagas Cardiomyopathy
NCT01261065	PHASE4	COMPLETED	Mechanisms of Improvement With Beta-Blocker Treatment in Heart Failure
NCT01345188	PHASE4	COMPLETED	Ranolazine in Ischemic Cardiomyopathy
NCT01868841	PHASE4	COMPLETED	123-I mIBG (AdreView) Heart-to-Mediastinal (H/M) Ratio and SPECT Imaging on a Small Field of View-High Efficiency Cardiac SPECT System
NCT02640846	PHASE4	UNKNOWN	Effects of Levosimendan, Milrinone and Norepinephrine on Left and Right Ventricular Function in Septic Shock
NCT03228823	PHASE4	UNKNOWN	Prospective Assessment of Premature Ventricular Contractions Suppression in Cardiomyopathy(PAPS)
NCT04323852	PHASE4	COMPLETED	Can Vitamin D Reduce Heart Muscle Damage After Bypass Surgery?
NCT05034432	PHASE4	RECRUITING	The PIVATAL Study -Study of Ventricular Arrhythmia (VTA) Ablation in Left Ventricular Assist Device (LVAD) Patients
NCT05718128	PHASE4	RECRUITING	Clinical Study of Endocardial Myocardial Biopsy
NCT06964464	PHASE4	RECRUITING	Comparative Effectiveness of Carvedilol Versus Metoprolol Succinate in Heart Failure Patients With an Implantable Cardioverter Defibrillator
NCT00170183	PHASE3	COMPLETED	Brain Natriuretic Peptide (BNP) to Preserve Renal Function in Hospitalized Patients With Heart Failure
NCT00270387	PHASE3	COMPLETED	A Study of Short-Term Outcomes and Economic Impact For Patients With Worsening Congestive Heart Failure When Natrecor (Nesiritide) is Added to Standard-Care Therapy, Compared to Administration of Placebo With Standard-Care Therapy
NCT00321295	PHASE3	COMPLETED	Biventricular Pacing In Patients With Left Ventricular Dysfunction After Cardiovascular Surgery
NCT00483197	PHASE3	UNKNOWN	VentrAssistTM LVAD as a Bridge to Cardiac Transplantation - Pivotal Trial
NCT00490321	PHASE3	UNKNOWN	VentrAssistTM LVAD for the Treatment of Advanced Heart Failure - Destination Therapy
NCT00626028	PHASE3	COMPLETED	Comparison of Inhaled Nitric Oxide and Oxygen in Participants Reactivity During Acute Pulmonary Vasodilator Testing
NCT01013714	PHASE3	UNKNOWN	Cardiac Sympathetic Denervation for Prevention of Ventricular Tachyarrhythmias
NCT01217827	PHASE3	COMPLETED	Implantable Cardioverter-Defibrillator Use in the VA System
NCT01648634	PHASE3	COMPLETED	Nebivolol for the Prevention of Left Ventricular Systolic Dysfunction in Patients With Duchenne Muscular Dystrophy
NCT02924285	PHASE3	COMPLETED	Catheter Ablation Versus Amiodarone for Therapy of Premature Ventricular Contractions in Patients With Structural Heart Disease
NCT03860935	PHASE3	COMPLETED	Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy
NCT04166331	PHASE3	COMPLETED	Adjunctive DobutAmine in sePtic Cardiomyopathy With Tissue Hypoperfusion
NCT05175066	PHASE3	COMPLETED	Bisoprolol Administration to Prevent Anthracycline-induced Cardiotoxicity
NCT05237323	PHASE3	COMPLETED	Micophenolate Mofetil Versus Azathioprine in Myocarditis
NCT06158698	PHASE3	RECRUITING	CMP-MYTHiC Trial and Registry - CardioMyoPathy With MYocarditis THerapy With Colchicine
NCT06563895	PHASE3	RECRUITING	Acoramidis Transthyretin Amyloidosis Prevention Trial in the Young (ACT-EARLY) Study in Asymptomatic Carriers of a Pathogenic TTR Variant
NCT06846086	PHASE3	RECRUITING	Cardioprotective Effects of Melatonin in Patients With Cardiomyopathy
NCT07116473	PHASE3	NOT_YET_RECRUITING	To Evaluate the Long-term Safety and Tolerability of Acoramidis in Participants With Newly Diagnosed ATTR-CM (ACT-EARLY OLE)
NCT00185250	PHASE2	COMPLETED	Betaferon/ Betaseron (Interferon Beta-1b) in Patients With Chronic Viral Cardiomyopathy
NCT00490347	PHASE2	COMPLETED	VentrAssistTM LVAD as a Bridge to Cardiac Transplantation - Feasibility Trial
NCT00694161	PHASE2	COMPLETED	The Effects Of Fx-1006A On Transthyretin Stabilization And Clinical Outcome Measures In Patients With V122I Or Wild-Type TTR Amyloid Cardiomyopathy