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Science. 2018 Aug 31;361(6405). pii: eaao3048. doi: 10.1126/science.aao3048.

Cancer mutations and targeted drugs can disrupt dynamic signal encoding by the Ras-Erk pathway.

Author information

1
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
2
Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94158, USA.
3
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
4
Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
5
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA. wendell.lim@ucsf.edu toettcher@princeton.edu trever.bivona@ucsf.edu.
6
Division of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94158, USA.
7
Center for Systems and Synthetic Biology, University of California, San Francisco, San Francisco, CA 94158, USA.

Abstract

The Ras-Erk (extracellular signal-regulated kinase) pathway encodes information in its dynamics; the duration and frequency of Erk activity can specify distinct cell fates. To enable dynamic encoding, temporal information must be accurately transmitted from the plasma membrane to the nucleus. We used optogenetic profiling to show that both oncogenic B-Raf mutations and B-Raf inhibitors can cause corruption of this transmission, so that short pulses of input Ras activity are distorted into abnormally long Erk outputs. These changes can reshape downstream transcription and cell fates, resulting in improper decisions to proliferate. These findings illustrate how altered dynamic signal transmission properties, and not just constitutively increased signaling, can contribute to cell proliferation and perhaps cancer, and how optogenetic profiling can dissect mechanisms of signaling dysfunction in disease.

Comment in

PMID:
30166458
PMCID:
PMC6430110
DOI:
10.1126/science.aao3048
[Indexed for MEDLINE]
Free PMC Article

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