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Published January 10, 2019 | Submitted + Published + Supplemental Material
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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 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.

Additional Information

© 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. Received: 26 April 2018; Accepted: 09 January 2019; Published: 10 January 2019. This work was supported by Howard Hughes Medical Institute (M.B.E.), and the Defense Advanced Research Projects Agency under Contract No. HR0011-16-0138, by the National Institutes of Health grant R01 HD075335 and the NSF under grant EFRI 1137269. N.N. was a Howard Hughes Medical Institute International Student Research fellow. We thank Pulin Li, Mark Budde, Heidi Klumpe, Ronghui Zhu, Rachael Kuintzle, Laurent Potvin-Trottier and James Linton for critical feedback on the manuscript. Harry Choi and Colby Calvert, Caltech Flow Cytometry Facility, Caltech Biological Imaging Facility, and the Millard and Muriel Jacobs Genetics and Genomics Laboratory at Caltech provided essential technical assistance. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Author contributions: Nagarajan Nandagopal, Leah A Santat, Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing—original draft, Writing—review and editing; Michael B Elowitz, Conceptualization, Resources, Supervision, Funding acquisition, Investigation, Methodology, Writing—original draft, Project administration, Writing—review and editing. The authors declare that no competing interests exist. Data availability: RNA sequencing data have been deposited in GEO under accession codes GSE113937. Source data files have been provided for Figure 5.

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Published - elife-37880-v2.pdf

Submitted - 313171.full.pdf

Supplemental Material - elife-37880-supp-v1.zip


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August 19, 2023
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