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

Dessauges, Coralie; Mikelson, Jan; Dobrzyński, Maciej; Jacques, Marc-Antoine; Frismantiene, Agne; Gagliardi, Paolo Armando; Khammash, Mustafa; Pertz, Olivier (2022). Optogenetic actuator - ERK biosensor circuits identify MAPK network nodes that shape ERK dynamics. Molecular systems biology, 18(6), e10670. EMBO Press 10.15252/msb.202110670

Preview

Text Molecular_Systems_Biology_-_2022_-_Dessauges_-_Optogenetic_actuator_ERK_biosensor_circuits_identify_MAPK_network_nodes.pdf - Published Version Available under License Creative Commons: Attribution (CC-BY). Download (4MB) | Preview

Combining single-cell measurements of ERK activity dynamics with perturbations provides insights into the MAPK network topology. We built circuits consisting of an optogenetic actuator to activate MAPK signaling and an ERK biosensor to measure single-cell ERK dynamics. This allowed us to conduct RNAi screens to investigate the role of 50 MAPK proteins in ERK dynamics. We found that the MAPK network is robust against most node perturbations. We observed that the ERK-RAF and the ERK-RSK2-SOS negative feedback operate simultaneously to regulate ERK dynamics. Bypassing the RSK2-mediated feedback, either by direct optogenetic activation of RAS, or by RSK2 perturbation, sensitized ERK dynamics to further perturbations. Similarly, targeting this feedback in a human ErbB2-dependent oncogenic signaling model increased the efficiency of a MEK inhibitor. The RSK2-mediated feedback is thus important for the ability of the MAPK network to produce consistent ERK outputs, and its perturbation can enhance the efficiency of MAPK inhibitors.

Interest & Impact

Downloads

362 since deposited on 14 Jun 2022
176 in the past 12 months

Citations

5 Citations in Web of Science ®
6 Citations in Scopus

Search

in Google Scholar™

Services

Actions (login required)

Edit item

Actions (login required)

Edit item