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Non-canonical β-adrenergic activation of ERK at endosomes

Yonghoon Kwon1, Sohum Mehta1, Mary Clark1

  • 1Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA.

Nature
|October 26, 2022
PubMed

Insights

G-protein-coupled receptor (GPCR) signaling activates extracellular-signal-regulated kinase (ERK) from endosomes, not the plasma membrane. This spatial control impacts cell proliferation by regulating nuclear ERK activity.

Area of Science:

  • Cellular signaling
  • Molecular biology
  • Receptor biology

Background:

  • G-protein-coupled receptors (GPCRs) are crucial signaling molecules and drug targets.
  • GPCRs activate extracellular-signal-regulated kinase (ERK), a key regulator of cell proliferation and survival.
  • The exact mechanisms of GPCR-mediated ERK activation remain unclear.

Purpose of the Study:

  • To investigate the spatial organization of beta2-adrenergic receptor (β2AR) signaling in controlling ERK activation.
  • To elucidate the role of endosomal signaling in GPCR-mediated cellular responses.

Main Methods:

  • Utilized subcellularly targeted ERK activity biosensors.
  • Investigated β2AR signaling, endocytosis, and Gαs localization.
  • Employed pharmacological inhibition of endosomal signaling pathways.

Main Results:

  • β2AR signaling induced ERK activity specifically at endosomes, not the plasma membrane.
  • Endosomal ERK activity depends on endosome-localized Gαs and β2AR endocytosis.
  • Identified a non-canonical endosomal Gαs-RAF-MAPK axis controlling nuclear ERK, MYC expression, and cell proliferation.

Conclusions:

  • Revealed a non-canonical mechanism for spatial regulation of ERK via GPCR signaling.
  • Demonstrated a functionally significant endosomal signaling axis controlling cell proliferation.
  • Highlighted the importance of endosomal receptor localization in signal transduction.

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