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

被引：23

作者：

Dessauges, Coralie ^{[1
]}

Mikelson, Jan ^{[2
]}

Dobrzynski, Maciej ^{[1
]}

Jacques, Marc-Antoine ^{[1
]}

Frismantiene, Agne ^{[1
]}

Gagliardi, Paolo Armando ^{[1
]}

Khammash, Mustafa ^{[2
]}

Pertz, Olivier ^{[1
]}

机构：

[1] Univ Bern, Inst Cell Biol, Bern, Switzerland

[2] Swiss Fed Inst Technol, Dept Biosyst Sci & Engn, Basel, Switzerland

来源：

MOLECULAR SYSTEMS BIOLOGY | 2022年 / 18卷 / 06期

基金：

欧盟地平线“2020”; 瑞士国家科学基金会;

关键词：

ERK dynamics; MAPK network; optogenetics; signaling robustness; single-cell biology; NEGATIVE FEEDBACK-REGULATION; SPATIOTEMPORAL CONTROL; ERBB NETWORK; RAS; EXPRESSION; PHOSPHORYLATION; OSCILLATIONS; PHOSPHATASE; ACTIVATION; INHIBITOR;

D O I：

10.15252/msb.202110670

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页数：22

共 71 条

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