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Science-Signaling-Breakthrough.Pdf ` 2013: Signaling Breakthroughs of the Year Jason D. Berndt and Nancy R. Gough (7 January 2014) Science Signaling 7 (307), eg1. [DOI: 10.1126/scisignal.2005013] The following resources related to this article are available online at http://stke.sciencemag.org. This information is current as of 1 February 2014. Article Tools Visit the online version of this article to access the personalization and article tools: http://stke.sciencemag.org/cgi/content/full/sigtrans;7/307/eg1 References This article cites 37 articles, 14 of which can be accessed for free: http://stke.sciencemag.org/cgi/content/full/sigtrans;7/307/eg1#otherarticles Glossary Look up definitions for abbreviations and terms found in this article: http://stke.sciencemag.org/glossary/ Permissions Obtain information about reproducing this article: Downloaded from http://www.sciencemag.org/about/permissions.dtl stke.sciencemag.org on February 1, 2014 Science Signaling (ISSN 1937-9145) is published weekly, except the last week in December, by the American Association for the Advancement of Science, 1200 New York Avenue, NW, Washington, DC 20005. Copyright 2008 by the American Association for the Advancement of Science; all rights reserved. EDITORIAL GUIDE CELL BIOLOGY not only provides a molecular mechanism by which stress hormone signaling, and thus 2013: Signaling Breakthroughs of the Year mood and disease resistance, changes with the circadian cycle, it also is one of only a Jason D. Berndt1* and Nancy R. Gough2* few examples of neurotransmitter switching in adult neurons. The editorial staff and distinguished scientists in the fi eld of cell signaling nominat- It is well known that cells in the nervous ed diverse research as advances for 2013. Breakthroughs in understanding how system respond differently depending on the spatial and temporal signals control cellular behavior ranged from fi ltering high- precise spatial and temporal combinations of frequency stimuli to interpreting circadian inputs. This year’s nominations also inputs. Temporal information can be encoded highlight the importance of understanding cell signaling in the context of physiol- by biochemical events that take place across ogy and disease, such as links between the nervous system and cancer. Further- multiple systems or pathways. Chrousos rec- more, the application of new techniques to study cell signaling—such as optoge- ommended a study in which a cell receiving netics, DNA editing with CRISPR-Cas9, and sequencing untranslated regions of an initial signal responds by altering its abil- transcripts—continues to expand the realm and impact of signaling research. ity to respond to another signal through reg- ulation of alternative splicing. This work by After polling our Board of Reviewing Edi- Timing is everything in cells and in sig- Lal et al. (3) illustrates “cross-talk between tors and other prominent researchers to naling networks. Complex molecular cas- … two receptor systems that allows seamless Downloaded from bring you this 12th edition of “Signaling cades, feedback mechanisms, and crosstalk integration of extracellular and intracellular Breakthroughs of the Year,” we received are coordinated to enable cells to translate signaling pathways and genomic effects to several nominations with important implica- signals into physiological responses. We fi ne-tune biological responses.” The authors tions for human disease and focus on four begin our list of breakthroughs at the cellu- found that estrogen-mediated transcription main areas: (i) the increasing recognition lar level, focusing on the nervous system in regulates the splicing machinery, which ul- of the importance of temporal dynamics in cancer and mood disorders. Magnon et al. timately affects the function of G protein– signaling pathways; (ii) new understand- noted that neurons are commonly present in coupled receptors (GPCRs) that respond to stke.sciencemag.org ing of the mTOR pathway; (iii) previously tumors, leading the authors to ask whether other hormonal signals. Although chronic unknown roles for lipids, metabolites, and nervous system activation could play a role stress increases the risk of disease, and stress posttranslational modifi cations; and (iv) sev- in tumor progression (1). Using orthotopic hormones can contribute to disease pathol- eral techniques that provide unprecedented xenografts of human prostate cancer cells ogy, stress hormones are also essential in the insights into signaling biology. in mice, they found that tumors were infi l- response to injury and infl ammation and can We had an outstanding list of contribu- trated with both sympathetic and parasym- inhibit disease progression. CRH is a stress tors, including George P. Chrousos (Uni- pathetic nerve fi bers. Severing sympathetic hormone that can either increase the prolif- versity of Athens Medical School, Greece; nerves that normally innervate the prostate eration and invasion of breast cancer cells or on February 1, 2014 Georgetown University and National In- inhibited the growth of established tumors, inhibit estrogen-mediated cell proliferation stitute of Child Health and Development, as did inhibition of adrenergic or muscarinic in breast cancer. Estrogen inhibited the ex- USA); Henrik Dohlman (University of acetylcholine receptors. Analysis of pros- pression of the mRNA encoding serine- and North Carolina Chapel Hill, USA); James tate cancer samples from patients revealed arginine-rich splicing factor 55, ultimately Ferrell Jr. (Stanford University, USA); that the density of sympathetic and para- stimulating the expression of the gene en- Anne-Claude Gavin (European Molecular sympathetic nerve innervation correlated coding the CRH type-2 receptor and altering Biology Laboratory Heidelberg, Germany); with poor prognosis. the splicing of another gene encoding the Toby Gibson (European Molecular Biology The nervous system also contributes to CRH type-1 receptor. These changes were Laboratory Heidelberg, Germany); Tony circadian rhythm, a biological process in associated with decreased invasion of cul- Hunter (Salk Institute, USA); Stephen P. which cells respond to daily fl uctuations in tured breast cancer cells and with estrogen Jackson (Gurdon Institute University of light. Disruptions in circadian rhythm have receptor status in patients with breast cancer, Cambridge, UK); Norbert Perrimon (Har- profound effects on animal behavior and suggesting that this switch may contribute to vard Medical School, USA); Steve J. Smer- mood, as exemplifi ed by seasonal affective tumor progression. These results exemplify don (Medical Research Council National disorder, which is related to the decrease in a potentially new paradigm in the regulation Institute for Medical Research, UK); Solo- light during winter. Dulcis et al. found that of GPCRs through alternative splicing and mon Snyder (Johns Hopkins University, rodents exposed to periods of light mimick- show how the cell’s “history” and “previous USA); Arthur Weiss (University of Califor- ing long summer days and then switched experiences” set the responsiveness to sub- nia San Francisco, USA); and Michael B. to short periods of light mimicking winter sequent signals. Similar to CRH, transform- Yaffe (David H. Koch Institute for Integra- days exhibited a reversible switch in neu- ing growth factor–β (TGF-β) is both a tumor tive Cancer Research, The Broad Institute, rotransmitters in the hypothalamic neurons suppressor and tumor promoter. The study and Massachusetts Institute of Technology, that control the release of corticotropin- by Vizán et al. (4) revealed how differences USA). releasing hormone (CRH) (2). This study in the dynamics of the traffi cking of subunits of the TGF-β receptor altered the cellular re- 1 Associate Editor of Science Signaling, American Association for the Advancement of Science, 1200 sponse to subsequent exposure to TGF-β. New York Avenue, N.W., Washington, DC 20005, USA. 2Editor of Science Signaling, American Asso- ciation for the Advancement of Science, 1200 New York Avenue, N.W., Washington, DC 20005, USA. As with CRH, the effect of TGF-β on tumor *Corresponding author. E-mail: [email protected] (J.D.B.); [email protected] (N.R.G.) cells may depend on the cell’s history. www.SCIENCESIGNALING.org 7 January 2014 Vol 7 Issue 307 eg1 1 EDITORIAL GUIDE In addition to crosstalk between pathways, to those with proteins involved in terminating Temporal encoding in molecular signal- temporal information encoded in the signal the mitogenic signal and promoting cytoskel- ing is not limited to receptor tyrosine kinases itself can infl uence cellular responses (Fig. etal rearrangement, cell migration, and inva- and ERK. In fact, the sequential biochemical 1). Toettcher et al. showed that this principle sion. Thus, a single scaffolding protein can events that occur during the cell cycle have exists in signaling networks at the molecular serve as a both a network hub protein and a long been known to require exquisite tim- level by analyzing phosphorylation cascades central processing node to manage the tim- ing. Gibson and Ferrell recommended two downstream of receptor tyrosine kinases ing of diverse functional outputs. Weiss noted studies that refi ne our understanding of how through the use of optogenetic techniques that this study, “opened our eyes to more early multisite phosphorylation can direct this pro- to directly stimulate Ras in cells with light temporal regulation and feedback than we cess, and Gibson suggested that “signaling (5). High-frequency, short-duration bursts of previously
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