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Optogenetic actuator - ERK biosensor circuits identify MAPK network nodes that shape ERK dynamics.

Coralie Dessauges1, Jan Mikelson2, Maciej Dobrzyński1

  • 1Institute of Cell Biology, University of Bern, Bern, Switzerland.

Molecular Systems Biology
|June 13, 2022
PubMed
Summary

This study reveals how the MAPK network regulates ERK dynamics using optogenetics and RNAi screens. Disrupting RSK2-mediated feedback enhances MAPK inhibitor efficiency in cancer signaling.

Keywords:
ERK dynamicsMAPK networkoptogeneticssignaling robustnesssingle-cell biology

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Area of Science:

  • Cellular signaling pathways
  • Systems biology
  • Molecular network topology

Background:

  • The Mitogen-Activated Protein Kinase (MAPK) pathway is crucial for cellular functions.
  • Understanding MAPK network topology and feedback mechanisms is essential for targeted therapies.

Purpose of the Study:

  • To investigate the role of MAPK proteins in ERK dynamics using single-cell measurements.
  • To identify feedback loops regulating MAPK signaling and their impact on network robustness.
  • To evaluate the therapeutic potential of targeting specific feedback mechanisms in oncogenic signaling.

Main Methods:

  • Development of optogenetic circuits for controlled MAPK activation and ERK biosensing.
  • High-throughput RNA interference (RNAi) screens to perturb 50 MAPK proteins.
  • Analysis of single-cell ERK activity dynamics under various perturbations.

Main Results:

  • The MAPK network exhibits robustness against most node perturbations.
  • Simultaneous operation of ERK-RAF and ERK-RSK2-SOS negative feedback loops regulates ERK dynamics.
  • Bypassing RSK2-mediated feedback sensitizes ERK dynamics and enhances MEK inhibitor efficacy in ErbB2-dependent cancer models.

Conclusions:

  • The RSK2-mediated feedback is critical for maintaining consistent ERK signaling output.
  • Perturbing this feedback loop can improve the effectiveness of MAPK pathway inhibitors.
  • This research provides insights into MAPK network regulation and potential therapeutic strategies for cancer.