Cancer mutations and targeted drugs can disrupt dynamic signal encoding by the Ras-Erk pathway
Year: 2018
Type: article
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.
Source: Science
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: Howard Hughes Medical Institute, Arnold and Mabel Beckman Foundation, Damon Runyon Cancer Research Foundation, European Molecular Biology Organization, Wayne State University, Plexxikon, National Institutes of Health, University of California, San Francisco, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Biomedical Imaging and Bioengineering
Awards: G1213983933, G1402578135, Harnessing optogenetics to diagnose and therapeutically rewire cancer cell signaling, Exploring Design Principles of Cellular Control Circuits, G2476988533, Rational Combined Inhibition of NF-kB and EGFR to Optimize Lung Cancer Treatment, Discovery of Rational Companion Therapeutic Targets to Optimize Cancer Treatment, G4087236399, Protein Recognition in Signal Transduction, G8878349277, G9000320891, G9000327539, G967570009
OpenAlex ID: W2889007489