Open AccessOptogenetic actuator – ERK biosensor circuits identify MAPK network nodes that shape ERK dynamics
Author(s) -
Dessauges Coralie,
Mikelson Jan,
Dobrzyński Maciej,
Jacques MarcAntoine,
Frismantiene Agne,
Gagliardi Paolo Armando,
Khammash Mustafa,
Pertz Olivier
Publication year - 2022
Publication title -
molecular systems biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 8.523
H-Index - 148
ISSN - 1744-4292
DOI - 10.15252/msb.202110670
Subject(s) - optogenetics , mapk/erk pathway , biology , neuroscience , network dynamics , microbiology and biotechnology , computational biology , signal transduction , mathematics , discrete mathematics
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.