Cis-activation in the Notch signaling pathway

  1. Nagarajan Nandagopal
  2. Leah A Santat
  3. Michael B Elowitz  Is a corresponding author
  1. Howard Hughes Medical Institute, California Institute of Technology, United States

Abstract

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.

Data availability

RNA sequencing data have been deposited in GEO under accession codes GSE113937. Source data files have been provided for Figure 5.

The following data sets were generated

Article and author information

Author details

  1. Nagarajan Nandagopal

    Division of Biology and Biological Engineering, Howard Hughes Medical Institute, California Institute of Technology, Pasadena, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Leah A Santat

    Division of Biology and Biological Engineering, Howard Hughes Medical Institute, California Institute of Technology, Pasadena, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Michael B Elowitz

    Division of Biology and Biological Engineering, Howard Hughes Medical Institute, California Institute of Technology, Pasadena, United States
    For correspondence
    melowitz@caltech.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1221-0967

Funding

National Institutes of Health (R01 HD075335)

  • Nagarajan Nandagopal
  • Leah A Santat
  • Michael B Elowitz

Howard Hughes Medical Institute (M.B.E.)

  • Nagarajan Nandagopal
  • Leah A Santat
  • Michael B Elowitz

Defense Sciences Office, DARPA (HR0011-16-0138)

  • Nagarajan Nandagopal
  • Leah A Santat
  • Michael B Elowitz

National Science Foundation (EFRI 1137269)

  • Nagarajan Nandagopal
  • Leah A Santat
  • Michael B Elowitz

Howard Hughes Medical Institute (Graduate Student Fellowship)

  • Nagarajan Nandagopal

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Naama Barkai, Weizmann Institute of Science, Israel

Publication history

  1. Received: April 26, 2018
  2. Accepted: January 9, 2019
  3. Accepted Manuscript published: January 10, 2019 (version 1)
  4. Version of Record published: January 24, 2019 (version 2)

Copyright

© 2019, Nandagopal et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Nagarajan Nandagopal
  2. Leah A Santat
  3. Michael B Elowitz
(2019)
Cis-activation in the Notch signaling pathway
eLife 8:e37880.
https://doi.org/10.7554/eLife.37880

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