The Self-Limiting Dynamics of TGF-β Signaling In Silico and In Vitro, with Negative Feedback through PPM1A Upregulation
The TGF-β/Smad signaling system decreases its activity through strong negative regulation. Several molecular mechanisms of negative regulation have been published, but the relative impact of each mechanism on the overall system is unknown. In this work, we used computational and experimental methods...
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| Format: | Article |
| Language: | en_US |
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Public Library of Science
2014
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| Online Access: | http://hdl.handle.net/1721.1/88102 https://orcid.org/0000-0002-0339-3685 https://orcid.org/0000-0003-1080-4005 |
| _version_ | 1826208363088707584 |
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| author | Wang, Junjie Tucker-Kellogg, Lisa Ng, Inn Chuan Jia, Ruirui Thiagarajan, P. S. White, Jacob K. Yu, Hanry |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Wang, Junjie Tucker-Kellogg, Lisa Ng, Inn Chuan Jia, Ruirui Thiagarajan, P. S. White, Jacob K. Yu, Hanry |
| author_sort | Wang, Junjie |
| collection | MIT |
| description | The TGF-β/Smad signaling system decreases its activity through strong negative regulation. Several molecular mechanisms of negative regulation have been published, but the relative impact of each mechanism on the overall system is unknown. In this work, we used computational and experimental methods to assess multiple negative regulatory effects on Smad signaling in HaCaT cells. Previously reported negative regulatory effects were classified by time-scale: degradation of phosphorylated R-Smad and I-Smad-induced receptor degradation were slow-mode effects, and dephosphorylation of R-Smad was a fast-mode effect. We modeled combinations of these effects, but found no combination capable of explaining the observed dynamics of TGF-β/Smad signaling. We then proposed a negative feedback loop with upregulation of the phosphatase PPM1A. The resulting model was able to explain the dynamics of Smad signaling, under both short and long exposures to TGF-β. Consistent with this model, immuno-blots showed PPM1A levels to be significantly increased within 30 min after TGF-β stimulation. Lastly, our model was able to resolve an apparent contradiction in the published literature, concerning the dynamics of phosphorylated R-Smad degradation. We conclude that the dynamics of Smad negative regulation cannot be explained by the negative regulatory effects that had previously been modeled, and we provide evidence for a new negative feedback loop through PPM1A upregulation. This work shows that tight coupling of computational and experiments approaches can yield improved understanding of complex pathways. |
| first_indexed | 2024-09-23T14:04:36Z |
| format | Article |
| id | mit-1721.1/88102 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T14:04:36Z |
| publishDate | 2014 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | mit-1721.1/881022022-09-28T18:11:46Z The Self-Limiting Dynamics of TGF-β Signaling In Silico and In Vitro, with Negative Feedback through PPM1A Upregulation Wang, Junjie Tucker-Kellogg, Lisa Ng, Inn Chuan Jia, Ruirui Thiagarajan, P. S. White, Jacob K. Yu, Hanry Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science White, Jacob K. Yu, Hanry The TGF-β/Smad signaling system decreases its activity through strong negative regulation. Several molecular mechanisms of negative regulation have been published, but the relative impact of each mechanism on the overall system is unknown. In this work, we used computational and experimental methods to assess multiple negative regulatory effects on Smad signaling in HaCaT cells. Previously reported negative regulatory effects were classified by time-scale: degradation of phosphorylated R-Smad and I-Smad-induced receptor degradation were slow-mode effects, and dephosphorylation of R-Smad was a fast-mode effect. We modeled combinations of these effects, but found no combination capable of explaining the observed dynamics of TGF-β/Smad signaling. We then proposed a negative feedback loop with upregulation of the phosphatase PPM1A. The resulting model was able to explain the dynamics of Smad signaling, under both short and long exposures to TGF-β. Consistent with this model, immuno-blots showed PPM1A levels to be significantly increased within 30 min after TGF-β stimulation. Lastly, our model was able to resolve an apparent contradiction in the published literature, concerning the dynamics of phosphorylated R-Smad degradation. We conclude that the dynamics of Smad negative regulation cannot be explained by the negative regulatory effects that had previously been modeled, and we provide evidence for a new negative feedback loop through PPM1A upregulation. This work shows that tight coupling of computational and experiments approaches can yield improved understanding of complex pathways. Singapore-MIT Alliance Mechanobiology Institute, Singapore Institute of Bioengineering and Nanotechnology (Singapore) National University of Singapore (NUS Graduate School for Integrative Sciences and Engineering scholar) Singapore-MIT Alliance for Research and Technology 2014-06-24T20:47:46Z 2014-06-24T20:47:46Z 2014-06 Article http://purl.org/eprint/type/JournalArticle 1553-7358 http://hdl.handle.net/1721.1/88102 Wang, Junjie, Lisa Tucker-Kellogg, Inn Chuan Ng, Ruirui Jia, P. S. Thiagarajan, Jacob K. White, and Hanry Yu. “The Self-Limiting Dynamics of TGF-β Signaling In Silico and In Vitro, with Negative Feedback through PPM1A Upregulation.” Edited by Christos A. Ouzounis. PLoS Comput Biol 10, no. 6 (June 5, 2014): e1003573. https://orcid.org/0000-0002-0339-3685 https://orcid.org/0000-0003-1080-4005 en_US http://dx.doi.org/10.1371/journal.pcbi.1003573 PLoS Computational Biology Creative Commons Attribution http://creativecommons.org/licenses/by/4.0/ application/pdf Public Library of Science Public Library of Science |
| spellingShingle | Wang, Junjie Tucker-Kellogg, Lisa Ng, Inn Chuan Jia, Ruirui Thiagarajan, P. S. White, Jacob K. Yu, Hanry The Self-Limiting Dynamics of TGF-β Signaling In Silico and In Vitro, with Negative Feedback through PPM1A Upregulation |
| title | The Self-Limiting Dynamics of TGF-β Signaling In Silico and In Vitro, with Negative Feedback through PPM1A Upregulation |
| title_full | The Self-Limiting Dynamics of TGF-β Signaling In Silico and In Vitro, with Negative Feedback through PPM1A Upregulation |
| title_fullStr | The Self-Limiting Dynamics of TGF-β Signaling In Silico and In Vitro, with Negative Feedback through PPM1A Upregulation |
| title_full_unstemmed | The Self-Limiting Dynamics of TGF-β Signaling In Silico and In Vitro, with Negative Feedback through PPM1A Upregulation |
| title_short | The Self-Limiting Dynamics of TGF-β Signaling In Silico and In Vitro, with Negative Feedback through PPM1A Upregulation |
| title_sort | self limiting dynamics of tgf β signaling in silico and in vitro with negative feedback through ppm1a upregulation |
| url | http://hdl.handle.net/1721.1/88102 https://orcid.org/0000-0002-0339-3685 https://orcid.org/0000-0003-1080-4005 |
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