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 beta(2)-adrenergic receptor (beta(2)AR) signalling controls ERK. Using subcellularly targeted ERK activity biosensors(5), we show that beta(2)AR signalling induces ERK activity at endosomes, but not at the plasma membrane. This pool of ERK activity depends on active, endosome-localized G alpha(s) and requires ligand-stimulated beta(2)AR endocytosis. We further identify an endosomally localized non-canonical signalling axis comprising G alpha(s), RAF and mitogen-activated protein kinase kinase, resulting in endosomal ERK activity that propagates into the nucleus. Selective inhibition of endosomal beta(2)AR and G alpha(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.

Automated summary

This study reveals a non-canonical mechanism for the spatial regulation of ERK through β(2)AR signaling and identifies a functionally important endosomal signaling axis.