[초청강연] Illuminating Spatial Organization of GPCR Signaling in the Living Cell:  Non-canonical b-adrenergic activation of ERK at Endosomes

Title:
Illuminating Spatial Organization of GPCR Signaling in the Living Cell:
Non-canonical b-adrenergic activation of ERK at Endosomes

Abstract
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. However, the
precise mechanisms that underlie GPCR-mediated ERK activation are not clearly
understood. Here we investigated how spatially organized β2-adrenergic receptor
(β2AR) signalling controls ERK. Using subcellularly targeted ERK activity biosensors,
we show that β2AR signalling induces 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 identify an
endosomally localized non-canonical signalling axis comprising Gαs, RAF and
mitogen-activated protein kinase kinase, resulting in endosomal ERK activity that
propagates into the nucleus. Selective inhibition of endosomal β2AR and
Gαs 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.