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

Autor: Kwon Y; Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA., Mehta S; Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA., Clark M; Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA., Walters G; Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA., Zhong Y; Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA., Lee HN; Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA., Sunahara RK; Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA., Zhang J; Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA. jzhang32@health.ucsd.edu.; Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA. jzhang32@health.ucsd.edu.; Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA. jzhang32@health.ucsd.edu.
Jazyk: angličtina
Zdroj: Nature [Nature] 2022 Nov; Vol. 611 (7934), pp. 173-179. Date of Electronic Publication: 2022 Oct 26.
DOI: 10.1038/s41586-022-05343-3
Abstrakt: 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.)
Databáze: MEDLINE
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