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Cis-activation in the Notch signaling pathway

The Notch signaling pathway consists of transmembrane ligands and receptors that can interact both within the same cell (cis) and across cell boundaries (trans). Previous work has shown that cis-interactions act to inhibit productive signaling. Here, by analyzing Notch activation in single cells whi...

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Autores principales: Nandagopal, Nagarajan, Santat, Leah A, Elowitz, Michael B
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6345567/
https://www.ncbi.nlm.nih.gov/pubmed/30628888
http://dx.doi.org/10.7554/eLife.37880
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author Nandagopal, Nagarajan
Santat, Leah A
Elowitz, Michael B
author_facet Nandagopal, Nagarajan
Santat, Leah A
Elowitz, Michael B
author_sort Nandagopal, Nagarajan
collection PubMed
description The Notch signaling pathway consists of transmembrane ligands and receptors that can interact both within the same cell (cis) and across cell boundaries (trans). Previous work has shown that cis-interactions act to inhibit productive signaling. Here, by analyzing Notch activation in single cells while controlling cell density and ligand expression level, we show that cis-ligands can also activate Notch receptors. This cis-activation process resembles trans-activation in its ligand level dependence, susceptibility to cis-inhibition, and sensitivity to Fringe modification. Cis-activation occurred for multiple ligand-receptor pairs, in diverse cell types, and affected survival in neural stem cells. Finally, mathematical modeling shows how cis-activation could potentially expand the capabilities of Notch signaling, for example enabling ‘negative’ (repressive) signaling. These results establish cis-activation as an additional mode of signaling in the Notch pathway, and should contribute to a more complete understanding of how Notch signaling functions in developmental, physiological, and biomedical contexts.
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spelling pubmed-63455672019-01-28 Cis-activation in the Notch signaling pathway Nandagopal, Nagarajan Santat, Leah A Elowitz, Michael B eLife Computational and Systems Biology The Notch signaling pathway consists of transmembrane ligands and receptors that can interact both within the same cell (cis) and across cell boundaries (trans). Previous work has shown that cis-interactions act to inhibit productive signaling. Here, by analyzing Notch activation in single cells while controlling cell density and ligand expression level, we show that cis-ligands can also activate Notch receptors. This cis-activation process resembles trans-activation in its ligand level dependence, susceptibility to cis-inhibition, and sensitivity to Fringe modification. Cis-activation occurred for multiple ligand-receptor pairs, in diverse cell types, and affected survival in neural stem cells. Finally, mathematical modeling shows how cis-activation could potentially expand the capabilities of Notch signaling, for example enabling ‘negative’ (repressive) signaling. These results establish cis-activation as an additional mode of signaling in the Notch pathway, and should contribute to a more complete understanding of how Notch signaling functions in developmental, physiological, and biomedical contexts. eLife Sciences Publications, Ltd 2019-01-10 /pmc/articles/PMC6345567/ /pubmed/30628888 http://dx.doi.org/10.7554/eLife.37880 Text en © 2019, Nandagopal et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Computational and Systems Biology
Nandagopal, Nagarajan
Santat, Leah A
Elowitz, Michael B
Cis-activation in the Notch signaling pathway
title Cis-activation in the Notch signaling pathway
title_full Cis-activation in the Notch signaling pathway
title_fullStr Cis-activation in the Notch signaling pathway
title_full_unstemmed Cis-activation in the Notch signaling pathway
title_short Cis-activation in the Notch signaling pathway
title_sort cis-activation in the notch signaling pathway
topic Computational and Systems Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6345567/
https://www.ncbi.nlm.nih.gov/pubmed/30628888
http://dx.doi.org/10.7554/eLife.37880
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