Frick, Christopher L. and Yarka, Clare and Nunns, Harry and Goentoro, Lea (2017) Sensing relative signal in the Tgf-β/Smad pathway. Proceedings of the National Academy of Sciences of the United States of America . ISSN 0027-8424. (In Press) http://resolver.caltech.edu/CaltechAUTHORS:20170320-153408239
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How signaling pathways function reliably despite cellular variation remains a question in many systems. In the transforming growth factor-β (Tgf-β) pathway, exposure to ligand stimulates nuclear localization of Smad proteins, which then regulate target gene expression. Examining Smad3 dynamics in live reporter cells, we found evidence for fold-change detection. Although the level of nuclear Smad3 varied across cells, the fold change in the level of nuclear Smad3 was a more precise outcome of ligand stimulation. The precision of the fold-change response was observed throughout the signaling duration and across Tgf-β doses, and significantly increased the information transduction capacity of the pathway. Using single-molecule FISH, we further observed that expression of Smad3 target genes (ctgf, snai1, and wnt9a) correlated more strongly with the fold change, rather than the level, of nuclear Smad3. These findings suggest that some target genes sense Smad3 level relative to background, as a strategy for coping with cellular noise.
|Additional Information:||© 2017 National Academy of Sciences. Edited by Arup K. Chakraborty, Massachusetts Institute of Technology, Cambridge, MA, and approved February 3, 2017 (received for review July 12, 2016). Published ahead of print March 20, 2017. We thank Michael Abrams, Zakary Singer, and Kibeom Kim for insightful comments on the manuscript. We also thank Xun Wang for sharing plasmid constructs, Yaron Antebi for help in developing cell tracking and segmentation scripts, and especially, Zakary Singer, Eric Lubeck, and Long Cai for help with smFISH. We thank Diana Perez and Rochelle Diamond (Caltech Flow Cytometry and Cell Sorting Facility) for expert cell sorting. We thank Eric Batchelor and Michael Elowitz for discussions on the study. This work was supported by NIH Training Grants 2T32GM007616-36 (to C.L.F.) and 5T32GM007616-37 (to H.N.), NIH New Innovator Award DP2OD008471, the James S. McDonnell Scholar Award in Complex Systems (Grant 220020365), and National Science Foundation Career Award NSF.1453863 (to L.G.). Author contributions: C.L.F. and L.G. designed research; C.L.F. and C.Y. performed research; H.N. contributed new reagents/analytic tools; C.L.F. and C.Y. analyzed data; and C.L.F. and L.G. wrote the paper. The authors declare no conflict of interest. This article is a PNAS Direct Submission. This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1611428114/-/DCSupplemental. Freely available online through the PNAS open access option.|
|Subject Keywords:||signal transduction; fold-change detection; Tgf-β; Smad; information|
|Official Citation:||Christopher L. Frick, Clare Yarka, Harry Nunns, and Lea Goentoro Sensing relative signal in the Tgf-β/Smad pathway PNAS 2017 ; published ahead of print March 20, 2017, doi:10.1073/pnas.1611428114|
|Usage Policy:||No commercial reproduction, distribution, display or performance rights in this work are provided.|
|Deposited By:||Tony Diaz|
|Deposited On:||20 Mar 2017 22:44|
|Last Modified:||20 Mar 2017 22:44|
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