Long Signaling Cascades Tend to Attenuate Retroactivity
Signaling pathways consisting of phosphorylation/dephosphorylation cycles with no explicit feedback allow signals to propagate not only from upstream to downstream but also from downstream to upstream due to retroactivity at the interconnection between phosphorylation/dephosphorylation cycles. Howev...
| Main Authors: | , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | en_US |
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Elsevier
2014
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| Online Access: | http://hdl.handle.net/1721.1/86371 https://orcid.org/0000-0001-6472-8576 |
| _version_ | 1811072007304904704 |
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| author | Ossareh, Hamid R. Ventura, Alejandra C. Merajver, Sofia D. Del Vecchio, Domitilla |
| author2 | Massachusetts Institute of Technology. Department of Mechanical Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Mechanical Engineering Ossareh, Hamid R. Ventura, Alejandra C. Merajver, Sofia D. Del Vecchio, Domitilla |
| author_sort | Ossareh, Hamid R. |
| collection | MIT |
| description | Signaling pathways consisting of phosphorylation/dephosphorylation cycles with no explicit feedback allow signals to propagate not only from upstream to downstream but also from downstream to upstream due to retroactivity at the interconnection between phosphorylation/dephosphorylation cycles. However, the extent to which a downstream perturbation can propagate upstream in a signaling cascade and the parameters that affect this propagation are presently unknown. Here, we determine the downstream-to-upstream steady-state gain at each stage of the signaling cascade as a function of the cascade parameters. This gain can be made smaller than 1 (attenuation) by sufficiently fast kinase rates compared to the phosphatase rates and/or by sufficiently large Michaelis-Menten constants and sufficiently low amounts of total stage protein. Numerical studies performed on sets of biologically relevant parameters indicated that ~50% of these parameters could give rise to amplification of the downstream perturbation at some stage in a three-stage cascade. In an n-stage cascade, the percentage of parameters that lead to an overall attenuation from the last stage to the first stage monotonically increases with the cascade length n and reaches 100% for cascades of length at least 6. |
| first_indexed | 2024-09-23T08:59:25Z |
| format | Article |
| id | mit-1721.1/86371 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T08:59:25Z |
| publishDate | 2014 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/863712022-09-26T09:37:32Z Long Signaling Cascades Tend to Attenuate Retroactivity Ossareh, Hamid R. Ventura, Alejandra C. Merajver, Sofia D. Del Vecchio, Domitilla Massachusetts Institute of Technology. Department of Mechanical Engineering Del Vecchio, Domitilla Signaling pathways consisting of phosphorylation/dephosphorylation cycles with no explicit feedback allow signals to propagate not only from upstream to downstream but also from downstream to upstream due to retroactivity at the interconnection between phosphorylation/dephosphorylation cycles. However, the extent to which a downstream perturbation can propagate upstream in a signaling cascade and the parameters that affect this propagation are presently unknown. Here, we determine the downstream-to-upstream steady-state gain at each stage of the signaling cascade as a function of the cascade parameters. This gain can be made smaller than 1 (attenuation) by sufficiently fast kinase rates compared to the phosphatase rates and/or by sufficiently large Michaelis-Menten constants and sufficiently low amounts of total stage protein. Numerical studies performed on sets of biologically relevant parameters indicated that ~50% of these parameters could give rise to amplification of the downstream perturbation at some stage in a three-stage cascade. In an n-stage cascade, the percentage of parameters that lead to an overall attenuation from the last stage to the first stage monotonically increases with the cascade length n and reaches 100% for cascades of length at least 6. United States. Air Force Office of Scientific Research (Grant FA9550-09-1-0211) 2014-05-02T16:40:01Z 2014-05-02T16:40:01Z 2011-04 2010-11 Article http://purl.org/eprint/type/JournalArticle 00063495 1542-0086 http://hdl.handle.net/1721.1/86371 Ossareh, Hamid R., Alejandra C. Ventura, Sofia D. Merajver, and Domitilla Del Vecchio. “Long Signaling Cascades Tend to Attenuate Retroactivity.” Biophysical Journal 100, no. 7 (April 2011): 1617–1626. © 2011 Biophysical Society https://orcid.org/0000-0001-6472-8576 en_US http://dx.doi.org/10.1016/j.bpj.2011.02.014 Biophysical Journal Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Elsevier Elsevier Open Archive |
| spellingShingle | Ossareh, Hamid R. Ventura, Alejandra C. Merajver, Sofia D. Del Vecchio, Domitilla Long Signaling Cascades Tend to Attenuate Retroactivity |
| title | Long Signaling Cascades Tend to Attenuate Retroactivity |
| title_full | Long Signaling Cascades Tend to Attenuate Retroactivity |
| title_fullStr | Long Signaling Cascades Tend to Attenuate Retroactivity |
| title_full_unstemmed | Long Signaling Cascades Tend to Attenuate Retroactivity |
| title_short | Long Signaling Cascades Tend to Attenuate Retroactivity |
| title_sort | long signaling cascades tend to attenuate retroactivity |
| url | http://hdl.handle.net/1721.1/86371 https://orcid.org/0000-0001-6472-8576 |
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