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Dessauges, Coralie; Mikelson, Jan; Dobrzyński, Maciej; Jacques, Marc‐Antoine; Frismantiene, Agne; Gagliardi, Paolo Armando; Khammash, Mustafa; Pertz, Olivier
Molecular systems biology, June 2022, Letnik: 18, Številka: 6Journal Article
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. Synopsis MAPK signaling involves a complex network of interacting nodes, whose role in shaping ERK dynamics remains largely unknown. Optogenetic actuator‐ERK biosensor circuits combined with RNAi perturbations highlight specific nodes that regulate ERK dynamics. Genetic circuits consisting of optogenetic actuators and an ERK biosensor enable large‐scale interrogation of single‐cell ERK dynamics. RNAi perturbations of 50 MAPK nodes provide new insight into MAPK network circuitry. Two negative feedbacks within the MAPK network act simultaneously in the regulation of ERK dynamics. Perturbation of one of the negative feedbacks further potentiates RAF/MEK/ERK node inhibition leading to homogeneous suppression of ERK dynamics within a cell population. MAPK signaling involves a complex network of interacting nodes, whose role in shaping ERK dynamics remains largely unknown. Optogenetic actuator‐ERK biosensor circuits combined with RNAi perturbations highlight specific nodes that regulate ERK dynamics.
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