세미나

G-protein-coupled receptors (GPCRs), the largest family of signaling receptors, as well as important drug targets, are known to activate extracellular-signal-regulated kinase (ERK)—a master regulator of cell proliferation and survival. However, the precise mechanisms that underlie GPCR-mediated ERK activation are not clearly understood. Here we investigated how spatially organized GPCR signaling controls ERK activity by utilizing subcellularly targeted ERK activity biosensors. First, we demonstrated that β2-adrenergic receptor (β2AR)-mediated ERK activity is spatially compartmentalized based on the observation that we found the ERK activity at endosomes, but not at the plasma membrane. This pool of ERK activity depends on active, endosome-localized Gαs and requires ligand-stimulated β2AR endocytosis. We further identified an endosomally localized non-canonical signaling complex comprising Gαs, RAF and MEK, resulting in endosomal ERK activity that propagates into the nucleus. Selective inhibition of endosomal β2AR and Gαs signaling blunted nuclear ERK activity, cMYC gene expression and cell proliferation. Furthermore, we investigated spatial organization of β1AR signaling, since β1AR localizes not only on the plasma membrane, but also on the Golgi at the basal status unlike β2AR. We found that Golgi localized β1AR independently controls ERK by using different transducer protein for regulating spatial compartmentation from the plasma membrane localized β1AR. This Golgi-localized β1AR-mediated Golgi ERK activity specifically controls Golgi fragmentation, controlling cell cycle progression. These results reveal non-canonical mechanisms for the spatial regulation of ERK through GPCR signaling and identify functionally important endo-membrane localized GPCR signaling pathways.