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Diversity in Notch Ligand-Receptor Signaling Interactions


Kuintzle, Rachael Christine (2023) Diversity in Notch Ligand-Receptor Signaling Interactions. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/w8gj-jb92.


The ability to understand and predict signaling between different cell types is a major challenge in biology. The Notch pathway enables direct signaling through membrane-bound ligands and receptors, and is used in diverse contexts. While its canonical molecular signaling mechanism is well characterized, its many-to-many interacting pathway components, the complexity of their expression patterns, and the presence of same-cell (cis) as well as inter-cellular (trans) receptor-ligand interactions, have made it difficult to predict how a given cell will signal to others. Here, we use a cell-based approach, with Chinese hamster ovary (CHO-K1) cells and C2C12 mouse myoblasts, to systematically characterize trans-activation, cis-inhibition, and cis-activation efficiencies for the essential receptors (Notch1 and Notch2) and activating ligands (Dll1, Dll4, Jag1, and Jag2), in the presence of Lunatic Fringe (Lfng) or the enzymatically dead Lfng D289E mutant. All ligands trans-activate Notch1 and Notch2, except for Jag1, which competitively inhibits Notch1 signaling, and whose Notch1 binding strength is potentiated by Lfng. For Notch1, cis-activation is generally weaker than trans-activation, but for Notch2, cis-activation by Delta ligands is much stronger than trans-activation, and Notch2 cis-activation by Jag1 is similar in strength to trans-activation. Cis-inhibition is associated with weak cis-activation, as Dll1 and Dll4 do not cis-inhibit Notch2. Lfng expression potentiates trans-activation of both Notch1 and Notch2 by the Delta ligands and weakens trans-activation of both receptors by the Jagged ligands. The map of receptor-ligand-Fringe interaction outcomes revealed here should help guide rational perturbation and control of the Notch pathway.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:Notch signaling
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Biochemistry and Molecular Biophysics
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Elowitz, Michael B.
Thesis Committee:
  • Pachter, Lior S. (chair)
  • Thomson, Matthew
  • Bronner, Marianne E.
  • Hay, Bruce A.
  • Elowitz, Michael B.
Defense Date:2 May 2023
Funding AgencyGrant Number
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)F31 HD100185
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)R01 HD7335C
Record Number:CaltechTHESIS:05302023-215054202
Persistent URL:
Kuintzle, Rachael Christine0000-0002-1035-4983
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:15235
Deposited By: Rachael Kuintzle
Deposited On:01 Jun 2023 16:33
Last Modified:09 Feb 2024 20:50

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