TTC3 (tetratricopeptide repeat domain 3) is an E3 ubiquitin ligase that catalyzes K48-linked polyubiquitin chain formation, primarily functioning in protein quality control and cellular signaling regulation 1. The protein mediates ubiquitination and proteasomal degradation of key signaling molecules, including phosphorylated AKT proteins in the nucleus, establishing a negative feedback mechanism for AKT pathway regulation 1. TTC3 positively regulates TGF-β1-induced epithelial-mesenchymal transition by targeting SMURF2 for ubiquitination and degradation 2. Located within the Down syndrome critical region on chromosome 21, TTC3 overexpression contributes to cognitive impairment through disrupted protein quality control mechanisms 1. The protein exhibits cytotoxic effects when overexpressed, forming nuclear aggregates through proteolytic cleavage, with N-terminal fragments being particularly potent inhibitors of cell proliferation 3. In cancer contexts, TTC3 serves as a diagnostic biomarker, with elevated expression detected in prostate cancer tissues and urine samples from cancer patients 4. The protein's role extends to metabolic regulation and inflammatory responses, as evidenced by its identification as a potential biomarker in gestational diabetes mellitus 5. TTC3's multifaceted functions in ubiquitin-mediated protein degradation make it clinically relevant for neurodegenerative diseases, cancer diagnosis, and metabolic disorders.