PA2G4 in health and disease: An underestimated multifunctional regulator.

backgroundProliferation-associated protein 2G4 (PA2G4), also known as ErbB3-binding protein 1 (EBP1), is an evolutionarily conserved, ubiquitously expressed, multifunctional factor in health and disease. In recent decades, its role as a sophisticated regulator in a broad range of biological processes has drawn widespread attention from researchers. AIM OF REVIEW: We introduce the molecular structure, functional modules, and post-translational modifications of PA2G4. We further elaborate on its role and function in immune microenvironment modulation, cell growth, neural homeostasis and embryonic development. In particular, we summarize its relevance to tumorigenesis and cancer progression and describe its molecular mechanisms in regulating the hallmarks of cancers. This review aims to provide a comprehensive blueprint of PA2G4 functions and to inspire further basic and translational studies. KEY SCIENTIFIC CONCEPTS OF REVIEW: Owing to its versatile domains and motifs, PA2G4 regulates a variety of molecular processes, including transcription, translation, proteostasis and epigenetic modulation, suggesting its critical roles in maintaining homeostasis. There are two isoforms of the PA2G4 protein: PA2G4-p42 and PA2G4-p48. While both isoforms regulate cellular activities, they often exert distinct or even contradictory effects. Dysfunction and aberrant expression of PA2G4 isoforms lead to the occurrence and progression of various diseases, indicating their role as predictive markers or therapeutic targets.