TRIB3

Official Full Name

tribbles pseudokinase 3

Organism

Homo sapiens

Gene ID

57761

Background

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. [provided by RefSeq, Jul 2014]

Synonyms

NIPK; SINK; TRB3; SKIP3; C20orf97

Cat.No.	Product Name	Price
CSC-DC016562	Panoply™ Human TRIB3 Knockdown Stable Cell Line	Inquiry
CSC-SC016562	Panoply™ Human TRIB3 Over-expressing Stable Cell Line	Inquiry
CSC-RT0825	Human TRIB3 Knockout Cell Line-HeLa	Inquiry
CLOE-1220	Human TRIB3 Insect Cell Lysate	Inquiry
CLKO-0328	TRIB3 KO Cell Lysate-HeLa	Inquiry
CSC-RO01407	Human TRIB3 Stable Cell Line - U-87 MG	Inquiry

Cat.No.	Product Name	Price
AD16863Z	Human TRIB3 adenoviral particles	Inquiry

Cat.No.	Product Name	Price
SHH434344	shRNA set against Mouse TRIB3 (NM_175093.2)	Inquiry
SHH434348	shRNA set against Rat TRIB3 (NM_144755.2)	Inquiry
SHH434340	shRNA set against Human TRIB3 (NM_021158.3)	Inquiry
SHL092024	shRNA set against Mouse Trib3(NM_175093.2)	Inquiry
SHL093000	shRNA set against Human TRIB3(NM_021158.3)	Inquiry
SHL093036	shRNA set against Rat Trib3(NM_144755.2)	Inquiry
SHW018016	shRNA set against Danio rerio TRIB3 (NM_212869)	Inquiry

Cat.No.	Product Name	Price
CDCR381506	Rat Trib3 ORF Clone(NM_144755.2)	Inquiry
CDFG001619	Human TRIB3 cDNA Clone(NM_021158.3)	Inquiry
CDFR014459	Rat Trib3 cDNA Clone(NM_144755.2)	Inquiry
MiUTR1H-10711	TRIB3 miRNA 3'UTR clone	Inquiry
MiUTR1M-12118	TRIB3 miRNA 3'UTR clone	Inquiry
MiUTR1R-08197	TRIB3 miRNA 3'UTR clone	Inquiry
SKO0192	TRIB3 Validated sgRNA vector	Inquiry
CDCB179491	Danio rerio TRIB3 ORF Clone (NM_212869)	Inquiry
CDCB189587	Rabbit TRIB3 ORF clone (XM_008256176.1)	Inquiry
CDCL186625	Human TRIB3 ORF clone(NM_021158.3)	Inquiry
CDCL186626	Mouse TRIB3 ORF clone(NM_175093.2)	Inquiry
CDCS415302	Human TRIB3 ORF Clone (BC019363)	Inquiry

Detailed Information

The TRIB3 gene encodes Tribbles pseudokinase 3, located on human chromosome 20p13-p12.2. It belongs to the Tribbles family, a highly conserved group of proteins named after the Drosophila Tribbles protein, which plays key roles in regulating cell division and differentiation during embryonic development. Structurally, TRIB3 contains a kinase-like domain highly similar to serine/threonine kinases. However, critical catalytic residues are substituted, rendering it catalytically inactive; hence, it is classified as a pseudokinase. Despite lacking intrinsic kinase activity, the kinase-like domain is essential for protein–protein interactions, allowing TRIB3 to function as a molecular scaffold or decoy that modulates multiple signaling pathways. TRIB3 expression is tightly regulated and can be induced by various cellular stress signals, including endoplasmic reticulum (ER) stress, nutrient deprivation, hypoxia, and inflammatory signals mediated by transcription factors such as ATF4 and CHOP. This makes TRIB3 a central node integrating cellular stress responses.

Biological Significance

TRIB3 exhibits highly context-dependent biological functions, primarily serving as a key signaling integrator and negative feedback regulator. In metabolic regulation, TRIB3 is a potent endogenous inhibitor of the insulin/AKT pathway. It binds directly to AKT1 and AKT2, sterically blocking phosphorylation at Thr308 by PDK1 and thereby inhibiting downstream insulin signaling. Physiologically, this establishes a negative feedback loop preventing overactivation of insulin signaling. Pathologically, sustained TRIB3 overexpression, as seen in obesity or type 2 diabetes, contributes to insulin resistance and metabolic dysregulation.

Figure 1. The mechanisms of TRIB3 in DM and its complications. (Lu G, et al., 2024)

In stress responses, TRIB3 functions as a core regulator of integrated stress response (ISR). Cellular stress such as ER stress induces ATF4 and CHOP expression, which in turn upregulate TRIB3. TRIB3 interacts with ATF4 and CHOP, inhibiting their transcriptional activity and forming a negative feedback loop that limits ISR intensity and duration, preventing excessive apoptosis. TRIB3 also interacts with the NF-κB pathway, binding p65/RELA and suppressing its phosphorylation and transcriptional activity, thereby negatively regulating NF-κB–mediated inflammatory gene expression and survival signals.

In cancer biology, TRIB3's multifaceted regulatory functions can have dual effects. In some contexts, it promotes apoptosis via AKT and NF-κB inhibition, functioning as a tumor suppressor. In other contexts, it helps tumor cells adapt to hypoxia, nutrient deprivation, and other stress conditions, thereby enhancing tumor survival, invasion, and therapy resistance. This functional diversity makes TRIB3 a complex and highly valuable signaling hub.

Clinical Relevance

TRIB3 is clinically significant due to its roles in metabolic diseases and cancer. In metabolism, it is a key molecular and genetic factor in type 2 diabetes and insulin resistance. Polymorphisms in TRIB3 are associated with susceptibility to type 2 diabetes, and its expression is abnormally elevated in muscle and adipose tissues of diabetic patients. Targeting the TRIB3–AKT interaction represents a potential therapeutic strategy to restore insulin sensitivity, although drug development is challenging due to the difficulty of targeting protein–protein interactions.

In oncology, TRIB3 expression correlates with prognosis, invasiveness, and therapy response, depending on cancer type and microenvironment. In solid tumors such as colorectal and pancreatic cancers, high TRIB3 expression is often linked to poor prognosis and chemoresistance, likely due to its role in helping tumor cells survive under stress. Targeting TRIB3 could sensitize tumors to chemotherapy or targeted therapies. Conversely, in certain leukemias or lymphomas, TRIB3 may act as a tumor suppressor, where restoring its function could be therapeutically beneficial. TRIB3 also influences the tumor immune microenvironment, potentially modulating cytokine secretion or immunogenic cell death to indirectly affect anti-tumor immunity. Precise targeting of TRIB3 offers broad therapeutic potential but requires high specificity to avoid disrupting its normal physiological negative feedback roles. Future research must elucidate TRIB3's tissue- and disease-specific mechanisms to guide effective therapeutic development.

References

Qian B, Wang H, Men X, et al. TRIB3 is implicated in glucotoxicity- and endoplasmic reticulum-stress-induced beta-cell apoptosis. J Endocrinol. 2008;199(3):407–416.
Mondal D, Mathur A, Chandra PK. Tripping on TRIB3 at the junction of health, metabolic dysfunction and cancer. Biochimie. 2016 May;124:34-52.
Lu G, Li J, Gao T, Liu Q, et al. Integration of dietary nutrition and TRIB3 action into diabetes mellitus. Nutr Rev. 2024 Feb 12;82(3):361-373.

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