Journal Article

Non-canonical β-adrenergic activation of ERK at endosomes

Clark, Mary, Zhang, Jin, Zhong, Yanghao, Mehta, Sohum, Sunahara, Roger K., Walters, Geneva, Kwon, Yonghoon, Lee, Ha Neul

2022

Overview

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. β 2 -adrenergic receptor(β 2 AR) signalling induces ERK activity at endosomes, but not at the plasma membrane, and this activity is dependent on active, endosome-localized Gα s and requires ligand-stimulated β 2 AR endocytosis.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 13/95 / 14 / 14/19 / 14/33 / 631/80/2373 / 631/80/86/2363 / 631/92/275 / 9/10 / 96/109 / Adrenergic Agents - metabolism / Adrenergic Agents - pharmacology / Adrenergic receptors / Cell growth / Cell Proliferation / Endocytosis / Endosomes / Endosomes - drug effects / Endosomes - enzymology / Endosomes - metabolism / Epidermal growth factor / Extracellular signal-regulated kinase / Extracellular Signal-Regulated MAP Kinases - metabolism / G protein-coupled receptors / Gene expression / Genes, myc / GTP-Binding Protein alpha Subunits, Gs - metabolism / Humanities and Social Sciences / Kinases / Ligands / MAP kinase / Mitogen-Activated Protein Kinase Kinases - metabolism / multidisciplinary / Myc protein / Phosphorylation / Phosphorylation - drug effects / Plasma / Protein kinase / Proteins / Raf protein / Receptors (physiology) / Receptors, Adrenergic, beta-2 - metabolism / Science / Science (multidisciplinary) / Signal Transduction - drug effects / Signal Transduction - physiology / Signaling / Therapeutic targets / Whooping cough