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Evidence that fold-change, and not absolute level, of β-catenin dictates Wnt signaling

Goentoro, Lea and Kirschner, Marc W. (2009) Evidence that fold-change, and not absolute level, of β-catenin dictates Wnt signaling. Molecular Cell, 36 (5). pp. 872-84. ISSN 1097-2765. PMCID PMC2921914. doi:10.1016/j.molcel.2009.11.017. https://resolver.caltech.edu/CaltechAUTHORS:20150616-090524378

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Abstract

In response to Wnt stimulation, β-catenin accumulates and activates target genes. Using modeling and experimental analysis, we found that the level of β-catenin is sensitive to perturbations in the pathway, such that cellular variation would be expected to alter the signaling outcome. One unusual parameter was robust: the fold-change in β-catenin level (post-Wnt/pre-Wnt). In Xenopus, dorsal-anterior development and target gene expression are robust to perturbations that alter the final level but leave the fold-change intact. These suggest, first, that despite cellular noise, the cell responds reliably to Wnt stimulation by maintaining a robust fold-change in β-catenin. Second, the transcriptional machinery downstream of the Wnt pathway does not simply read the β-catenin level after Wnt stimulation but computes fold-changes in β-catenin. Analogous to Weber's Law in sensory physiology, some gene transcription networks must respond to fold-changes in signals, rather than absolute levels, which may buffer stochastic, genetic, and environmental variation.


Item Type:Article
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URLURL TypeDescription
http://dx.doi.org/10.1016/j.molcel.2009.11.017DOIArticle
http://www.sciencedirect.com/science/article/pii/S1097276509008582PublisherArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2921914/PubMed CentralArticle
http://www.sciencedirect.com/science/MiamiMultiMediaURL/1-s2.0-S1097276509008582/1-s2.0-S1097276509008582-mmc1.pdf/272198/html/S1097276509008582/4d4694757513457a2d07a90d8e34eeea/mmc1.pdfPublisherSupplemental Data
http://dx.doi.org/10.1016/j.molcel.2009.11.032Featured InMolecular Cell: Previews
http://www.signaling-gateway.org/update/updates/201002/nrg2743.htmlFeatured InNature Reviews Genetics: the signaling gateway
http://dx.doi.org/10.1126/scisignal.2101ec397Featured InScience Signaling: Editors' Choice
ORCID:
AuthorORCID
Goentoro, Lea0000-0002-3904-0195
Additional Information: © 2009 Elsevier. Received 20 August 2009, Revised 13 November 2009, Accepted 18 November 2009, Available online 10 December 2009. Published: December 10, 2009. We wish to dedicate this paper to Reinhart Heinrich (1946–2006), who opened for us the study of quantitative features of signal transduction and who, in his influential work, extracted many general biological truths by mathematical analysis. He is sorely missed. The authors thank Uri Alon for insights on the study. For helpful suggestions and critical reading of the manuscript, the authors thank Hao Yuan Kueh, Pedro Bordalo, Roy Kishony, Johan Paulsson, Martin Feinberg, Eric Batchelor, Natalie Andrew, Ran Kafri, Sophie Dumont, Ana Hernandez, Andres Lebehnson, Richard Deibler, Allon Klein, Leon Peshkin, Jean-Baptise Michel, Ethan Lee, and Adrian Salic. For technical help, the authors thank Michael Gage, Robert Freeman, Martin Wuehr, Paul Jorgensen, and Jennifer Gallop. Lentiviral-transduced cells were generous gifts from Ana Hernandez. RKO-pBAR/Renilla cells were generous gifts from Ben Major and Randall Moon. L.G. is a Robert Black Fellow of the Damon Runyon Foundation (DRG-1958-07). This work was supported by R01 HD037277 (M.W.K.) and the Novartis-Harvard-Hebrew University program.
Funders:
Funding AgencyGrant Number
Damon Runyon Cancer Research FoundationDRG-1958-07
NIHR01 HD037277
Novartis-Harvard-Hebrew University programUNSPECIFIED
Issue or Number:5
PubMed Central ID:PMC2921914
DOI:10.1016/j.molcel.2009.11.017
Record Number:CaltechAUTHORS:20150616-090524378
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20150616-090524378
Official Citation:Lea Goentoro, Marc W. Kirschner, Evidence that Fold-Change, and Not Absolute Level, of β-Catenin Dictates Wnt Signaling, Molecular Cell, Volume 36, Issue 5, 11 December 2009, Pages 872-884, ISSN 1097-2765, http://dx.doi.org/10.1016/j.molcel.2009.11.017. (http://www.sciencedirect.com/science/article/pii/S1097276509008582)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:58276
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:16 Jun 2015 17:41
Last Modified:10 Nov 2021 22:02

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