Abstract
Cellular processes rely heavily on protein phosphorylation, a mechanism essential for organismal physiology and pathology. The CMGC family comprises a large group of serine/threonine kinases defined by a conserved catalytic core and closely related kinase domains. While several CMGC members have been extensively studied, others, including the RCK and CDKL subfamilies, remain less studied. Here, we synthesize current knowledge of CMGC kinases, emphasizing their structural organization, mechanisms of activation, and roles in infection and disease. CMGC kinases such as CDKs and DYRKs are activated downstream of growth factor signaling to drive proliferative programs. In contrast, other CMGC members respond to cellular stress signals, including stress cytokines, and function during quiescence or adverse conditions to regulate antiproliferative and pro-survival pathways. Through these context-dependent activities, CMGCs govern fundamental cellular processes, including growth, metabolism, transcription, and genome integrity. Although individual CMGC kinases operate within distinct signaling cascades, substantial crosstalk exists among their pathways. Both DNA and RNA viruses exploit host CMGC networks to reprogram the intracellular environment and enhance replication. While CMGC–virus interactions are often proviral, specific CMGC-mediated antiviral responses have been described, notably in SARS-CoV-2 infection. Collectively, CMGC kinases occupy a central position in cellular homeostasis and disease.