TRIB3: Pseudokinase Tribbles Homolog 3 – A Key Regulator of Stress Responses and Metabolic Signaling
Comprehensive genomic and functional overview of TRIB3, a pseudokinase implicated in insulin resistance, cancer, and cellular stress adaptation.
Gene Information Card
| Symbol | TRIB3 |
|---|---|
| Full Name | tribbles pseudokinase 3 |
| Gene Type | protein-coding |
| Chromosomal Location | 20p13 |
| NCBI Gene ID | 57761 ncbi.nlm.nih.gov/gene/57761 |
| Ensembl ID | ENSG00000101255 |
| UniProt ID | Q96RU7 |
| OMIM ID | 607898 |
| HGNC ID | 16228 |
| Aliases | SINK, SKIP3, TRB3, C20orf97 |
Description
TRIB3 (tribbles pseudokinase 3) encodes a member of the tribbles family of pseudokinases that lack catalytic activity but function as adaptor or scaffold proteins. TRIB3 modulates multiple signaling pathways including insulin signaling, NF-kappaB activation, and the unfolded protein response (UPR). It is induced by cellular stress and plays roles in apoptosis, cell proliferation, and metabolism. Dysregulation of TRIB3 is associated with insulin resistance, type 2 diabetes, and various cancers.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Type 2 diabetes / Insulin resistance | TRIB3 overexpression inhibits Akt phosphorylation and impairs insulin signaling | PMID: 12882977, 14645221 |
| Breast cancer | TRIB3 promotes tumor growth and chemoresistance via NF-kappaB and ATF4 pathways | PMID: 22198277, 25645940 |
| Colorectal cancer | TRIB3 enhances cell survival under ER stress and correlates with poor prognosis | PMID: 23208501 |
| Hepatocellular carcinoma | TRIB3 overexpression linked to metastasis and poor survival through TGF-beta signaling | PMID: 28341829 |
| Cardiovascular disease | TRIB3 contributes to endothelial dysfunction and atherosclerosis via oxidative stress | PMID: 20628016 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Liver | 12.5 | Medium |
| Pancreas | 8.3 | Low |
| Adipose tissue | 15.1 | Medium |
| Skeletal muscle | 6.7 | Low |
| Kidney | 10.2 | Medium |
| Heart | 5.4 | Low |
| Brain | 3.8 | Low |
| Lung | 9.9 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HepG2 (liver cancer) | 18.2 | High expression; induced by ER stress |
| MCF7 (breast cancer) | 14.5 | Moderate; upregulated by ATF4 |
| HeLa (cervical cancer) | 11.3 | Moderate; responsive to hypoxia |
| A549 (lung cancer) | 8.7 | Low to moderate |
| K562 (leukemia) | 6.1 | Low |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.199A>G (p.Ile67Val) | missense | 0.02% (gnomAD) | Unknown functional impact |
| c.404C>T (p.Pro135Leu) | missense | <0.01% | Reported in COSMIC; potential loss of function |
| c.511G>A (p.Gly171Ser) | missense | <0.01% | COSMIC; uncertain significance |
| c.1A>G (p.Met1?) | start loss | Rare | Likely loss of function |
Mutation functional classification
Loss of Function (LOF)
Rare missense and start-loss variants (e.g., p.Met1?) are predicted to reduce or abolish TRIB3 protein expression or function.
Gain of Function (GOF)
No well-characterized gain-of-function mutations have been reported in TRIB3.
Dominant Negative (DN)
No dominant-negative mutations have been described for TRIB3.
View complete mutation data：
Gene Ontology (GO)
| • GO:0004672 – protein kinase activity (pseudokinase) | • GO:0005515 – protein binding |
| • GO:0005829 – cytosol | • GO:0005737 – cytoplasm |
| • GO:0005634 – nucleus | • GO:0043066 – negative regulation of apoptotic process |
| • GO:0046323 – glucose import | • GO:0032869 – cellular response to insulin stimulus |
| • GO:0030968 – endoplasmic reticulum unfolded protein response | • GO:0007250 – activation of NF-kappaB-inducing kinase activity |
Pathways
• Insulin signaling pathway (Reactome: R-HSA-74752)
• Unfolded Protein Response (UPR) (Reactome: R-HSA-381119)
• ATF4-mediated stress response (Reactome: R-HSA-381038)
• NF-kappaB signaling (Reactome: R-HSA-975138)
• Apoptosis modulation (Reactome: R-HSA-109581)
Protein Summary
TRIB3 is a 358-amino acid pseudokinase that lacks catalytic activity but acts as a scaffold and adaptor. It contains a central kinase-like domain and a C-terminal COP1-binding motif. TRIB3 interacts with Akt, ATF4, CHOP, and NF-kappaB pathway components. It is induced by ER stress and nutrient deprivation, and it modulates insulin signaling, apoptosis, and cell proliferation. The protein is predominantly cytoplasmic but can translocate to the nucleus under stress.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| TRIB3 Knockout HEK293 Cell Line | EDJ-KQ3515 | Human | 57761 | Details Get a Quote |
| TRIB3 Knockout A-549 Cell Line | EDJ-KQ25337 | Human | 57761 | Details Get a Quote |
| TRIB3 Knockout HCT 116 Cell Line | EDJ-KQ25338 | Human | 57761 | Details Get a Quote |
| TRIB3 Knockout HeLa Cell Line | EDJ-KQ25339 | Human | 57761 | Details Get a Quote |
| TRIB3 Knockout U-87MG ATCC Cell Line | EDJ-KZ62 | Human | 57761 | Details Get a Quote |
| TRIB3 Knockout HAP1 Cell Line | EDC07915 | Human | 57761 | Details Get a Quote |
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