G0 or no-G0: phosphatase control of quiescence and cell cycle entry

During each cell cycle, cells must decide whether to continue to proliferate or to exit the cell cycle into a reversible arrest state, known as quiescence, or G0. This decision must be highly regulated to ensure proper tissue homeostasis. Studies on kinase-driven signalling pathways that regulate this decision point have dominated the field, and the role of phosphatases remains comparatively underexplored, yet the role of phosphatases is vitally important in signal transduction. In the present review, we examine how phosphatases contribute to the regulation of quiescence in mammalian cells across three stages: entry into quiescence, maintenance of the quiescent state, and quiescence exit into the cell cycle. We discuss how phosphatases counteract mitogenic signalling pathways, including MAPK/ERK and PI3K-AKT-mTOR, and maintain low cyclin-dependent kinase (CDK) activity through dephosphorylation of key cell cycle regulators, such as the retinoblastoma family proteins and CDK inhibitors. Finally, we highlight emerging evidence that dynamic regulation of phosphatase activity shapes the transition from quiescence back into proliferation. Understanding how phosphatases regulate the reversible nature of cell cycle arrest is important for understanding how tissues maintain homeostasis and how dysregulation of quiescence contributes to disease, including cancer.