Abstract
Extracellular signal-regulated kinase 5 (ERK5), a unique member of the mitogen-activated protein kinase (MAPK) family, plays a critical role in cell fate determination due to its distinct structure. This review aims to systematically summarize the central role of the ERK5 signaling pathway in cell specification and differentiation. Substantial evidence indicates that, by integrating diverse extracellular signals and regulating key transcription factors, ERK5 precisely controls the fate specification and differentiation of various cell types, including stem cells, neural cells, immune cells, endothelial cells, and osteoblasts. Furthermore, aberrant MEK5/ERK5 signaling is closely linked to the pathogenesis and progression of various diseases, particularly cancer, and is associated with drug resistance. By delineating the signaling mechanisms and functions of ERK5 across different cellular contexts, this review seeks to deepen the understanding of its physiological and pathological activities and to provide new potential targets and insights for regenerative medicine and cancer therapy.