Non-canonical β-adrenergic activation of ERK at endosomes.

G-protein-coupled receptors (GPCRs), the largest family of signalling receptors, as well as important drug targets, are known to activate extracellular-signal-regulated kinase (ERK)-a master regulator of cell proliferation and survival ¹ . However, the precise mechanisms that underlie GPCR-mediated ERK activation are not clearly understood ^2-4 . Here we investigated how spatially organized β ₂ -adrenergic receptor (β ₂ AR) signalling controls ERK. Using subcellularly targeted ERK activity biosensors ⁵ , we show that β ₂ AR signalling induces ERK activity at endosomes, but not at the plasma membrane. This pool of ERK activity depends on active, endosome-localized Gα _s and requires ligand-stimulated β ₂ AR endocytosis. We further identify an endosomally localized non-canonical signalling axis comprising Gα _s , RAF and mitogen-activated protein kinase kinase, resulting in endosomal ERK activity that propagates into the nucleus. Selective inhibition of endosomal β ₂ AR and Gα _s signalling blunted nuclear ERK activity, MYC gene expression and cell proliferation. These results reveal a non-canonical mechanism for the spatial regulation of ERK through GPCR signalling and identify a functionally important endosomal signalling axis.
(© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)