@article{55e1c8c6cf074773800bc80238ce81ba,
title = "Cancer mutations and targeted drugs can disrupt dynamic signal encoding by the Ras-Erk pathway",
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.",
author = "Bugaj, {L. J.} and Sabnis, {A. J.} and A. Mitchell and Garbarino, {J. E.} and Toettcher, {J. E.} and Bivona, {T. G.} and Lim, {W. A.}",
note = "Funding Information: We thank G. Bollag and Plexxikon for providing PLX8394 and N. Frankel and G. Bollag for critical reading and comments on the manuscript. We also thank N. Repina (University of California, Berkeley) for helpful discussions on optogenetic device design, E. Chow for discussions on device construction, A. Meyer-Franke for technical help with high-content microscopy, and A. Basu (Wayne State University) for providing an alternative device for multiwell optogenetic experiments. This work was funded by the Arnold O. Beckman Postdoctoral Fellowship (L.J.B.); the European Molecular Biology Organization ALTF 419-2010 (A.M.); the UCSF Program for Breakthrough Biomedical Research Postdoctoral Research Award (A.M.); NIH DP2EB024247 (J.E.T.); St. Baldrick{\textquoteright}s Foundation and a Damon Runyon-Sohn Foundation fellowship 6P-13 (A.S.); NIH DP2 CA174497, R01CA169338, R01CA204302, and R01CA211052 (T.G.B); the Pew and Stewart Foundations (T.G.B.); the Howard Hughes Medical Institute (W.A.L); and NIH P50GM081879 and R01GM55040 (W.A.L.). Publisher Copyright: 2017 {\textcopyright} The Authors.",
year = "2018",
month = aug,
day = "31",
doi = "10.1126/science.aao3048",
language = "English (US)",
volume = "361",
journal = "Science",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science",
number = "6405",
}