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Mol Cell. 2017 Sep 7;67(5):757-769.e5. doi: 10.1016/j.molcel.2017.07.016. Epub 2017 Aug 17.

Tracing Information Flow from Erk to Target Gene Induction Reveals Mechanisms of Dynamic and Combinatorial Control.

Author information

1
Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
2
Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ 08544, USA.
3
Howard Hughes Medical Institute; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
4
Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA. Electronic address: toettcher@princeton.edu.

Abstract

Cell signaling networks coordinate specific patterns of protein expression in response to external cues, yet the logic by which signaling pathway activity determines the eventual abundance of target proteins is complex and poorly understood. Here, we describe an approach for simultaneously controlling the Ras/Erk pathway and monitoring a target gene's transcription and protein accumulation in single live cells. We apply our approach to dissect how Erk activity is decoded by immediate early genes (IEGs). We find that IEG transcription decodes Erk dynamics through a shared band-pass filtering circuit; repeated Erk pulses transcribe IEGs more efficiently than sustained Erk inputs. However, despite highly similar transcriptional responses, each IEG exhibits dramatically different protein-level accumulation, demonstrating a high degree of post-transcriptional regulation by combinations of multiple pathways. Our results demonstrate that the Ras/Erk pathway is decoded by both dynamic filters and logic gates to shape target gene responses in a context-specific manner.

KEYWORDS:

Erk; MAP kinase; cell signaling; dynamics; immediate early genes; optogenetics; signal processing; transcription regulation

PMID:
28826673
PMCID:
PMC5591080
DOI:
10.1016/j.molcel.2017.07.016
[Indexed for MEDLINE]
Free PMC Article

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