ERK1/2-MAPK signaling: Metabolic, organellar, and cytoskeletal interactions.

Numerous stimuli activate the extracellular signal-regulated kinases ERK1/2, which phosphorylate a diverse range of substrates, regulating multiple cellular processes. The broad variety of functions controlled by these enzymes is enabled by complex intracellular organization, which requires precise spatiotemporal regulation. Scaffold proteins and the formation of molecular condensates by liquid-liquid phase separation (LLPS) are key in ERK1/2 signal modulation and output. This review provides an overview of ERK1/2 multifaceted actions, with a focus on the cytoskeleton, mitochondria, and metabolism, as well as ERK1/2 regulation by scaffolds and molecular condensates. We highlight recent findings that shed light on ERK1/2 regulation and discuss the implications for cellular functions, disease mechanisms, and therapeutic development.