Tribbles pseudokinase 3 (TRIB3)

Tribbles pseudokinase 3 (TRIB3) is a member of the Tribbles family of pseudokinases. While it contains a kinase-like domain structurally similar to serine/threonine kinases, it is catalytically inactive due to the absence of key amino acid residues[3]. TRIB3 acts primarily as a scaffold or adaptor protein, interacting with various signaling molecules to regulate multiple pathways, such as PI3K/AKT and MAPK, and influencing cell cycle control, apoptosis, metabolic adaptation, and endoplasmic reticulum (ER) stress[1][2][3]. Its biological effects are context-dependent: in some cancers, TRIB3 acts as a tumor suppressor by inhibiting pro-survival pathways (notably AKT), whereas in others, especially where overexpressed, it can function as an oncogene by supporting tumor growth, survival, and metabolic reprogramming[1][2][3]. Additionally, it has emerging roles in metabolic disease and as a stress regulator linking metabolic, cardiovascular, and oncogenic processes[5]. No current clinical therapies directly target TRIB3, but its gene or protein expression is under exploration as a prognostic biomarker and a potential therapeutic target in cancer and metabolic disease[3][5].

Other names

Tribbles homolog 3TRIB3C20orf97NIPKSKIP3TRB3TRB-3dJ1103G7.3SINKNeuronal cell death-inducible putative kinasep65-interacting inhibitor of NF-kappa-Bneuronal cell death inducible putative kinasep65-interacting inhibitor of NF-κB

Negative regulation of AKT phosphorylation and activity (PI3K/AKT pathway modulation)[1][3]. - Modulation of MAP kinase pathways (ERK, JNK) and TGF-beta signaling[3]. - Scaffold function for protein complexes regulating cell survival, metabolism, and stress response[3]. - Regulation of ubiquitin-mediated protein degradation (e.g., stabilization of PLIN2 by disrupting TEB4-mediated ubiquitination in renal cell carcinoma)[2]. - Modulation of gene transcription through protein-protein interactions with transcription factors such as ATF4, CHOP, C/EBPβ, p65/RelA, SMAD3[3].