TBL2 (transducin beta-like 2) is a WD40 repeat-containing, ER-localized transmembrane protein functioning as a multifunctional scaffold and translational regulator. Primary function: TBL2 regulates translation of specific mRNAs during endoplasmic reticulum (ER) stress 1. The WD40 domain enables direct binding to ATF4 mRNA and association with the 60S ribosomal subunit, facilitating selective ATF4 translation when global protein synthesis is suppressed 12. Mechanism: TBL2 acts as a scaffolding protein promoting protein-protein interactions. It facilitates PRMT5-WDR77 complex formation to enhance AKT phosphorylation 3 and interacts with PERK during ER stress to support ATF4-mediated stress adaptation 1. Additionally, TBL2 interacts with the mitochondrial protein TERE1 to regulate oxidative stress and nuclear receptor signaling 4. Disease relevance: TBL2 is overexpressed in multiple malignancies. In breast cancer, elevated TBL2 correlates with poor survival and promotes proliferation via AKT activation 3. In lung adenocarcinoma, TBL2 acts as a driver gene facilitating ER stress adaptation and tumor growth 5. In glioblastoma, TBL2 suppression inhibits proliferation and migration through AMPK/mTOR-mediated autophagy 6. Beyond cancer, reduced TBL2 methylation associates with hyperlipidemia risk 7, and genetic variants influence lipid metabolism 8. Clinical significance: TBL2 represents a potential therapeutic target across multiple cancer types and metabolic disorders.