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Engineering Customized Cell Sensing and Response Behaviors Using Synthetic Notch Receptors

Morsut, Leonardo and Roybal, Kole T. and Xiong, Xin and Gordley, Russell M. and Coyle, Scott M. and Thomson, Matthew and Lim, Wendell A. (2016) Engineering Customized Cell Sensing and Response Behaviors Using Synthetic Notch Receptors. Cell, 164 (4). pp. 780-791. ISSN 0092-8674. PMCID PMC4752866. doi:10.1016/j.cell.2016.01.012.

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The Notch protein is one of the most mechanistically direct transmembrane receptors—the intracellular domain contains a transcriptional regulator that is released from the membrane when engagement of the cognate extracellular ligand induces intramembrane proteolysis. We find that chimeric forms of Notch, in which both the extracellular sensor module and the intracellular transcriptional module are replaced with heterologous protein domains, can serve as a general platform for generating novel cell-cell contact signaling pathways. Synthetic Notch (synNotch) pathways can drive user-defined functional responses in diverse mammalian cell types. Because individual synNotch pathways do not share common signaling intermediates, the pathways are functionally orthogonal. Thus, multiple synNotch receptors can be used in the same cell to achieve combinatorial integration of environmental cues, including Boolean response programs, multi-cellular signaling cascades, and self-organized cellular patterns. SynNotch receptors provide extraordinary flexibility in engineering cells with customized sensing/response behaviors to user-specified extracellular cues.

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Additional Information:© 2016 Elsevier Inc. Received: November 27, 2015. Revised: January 4, 2016. Accepted: January 8, 2016. Published: January 28, 2016. We would like to thank members of the Lim lab for helpful discussions and comments on the manuscript. We thank K. McNally and Joan Garbarino for technical assistance and R. Nicoll for neurons. This work was supported by a Jane Coffin Childs Memorial Fund Postdoctoral Fellowship A121505 (K.T.R.), a Human Frontiers of Science Program (HFSP), a European Molecular Biology Organization (EMBO) Postdoctoral Fellowship (L.M.), NIH grants K99 1K99EB021030 (L.M.), PN2 EY016546, P50GM081879, R01 GM055040, and R01 CA196277, and the Howard Hughes Medical Institute (W.A.L.).
Funding AgencyGrant Number
Jane Coffin Childs Memorial FundA121505
Human Frontiers Science ProgramUNSPECIFIED
European Molecular Biology Organization (EMBO)UNSPECIFIED
NIHK99 1K99EB021030
NIHPN2 EY016546
NIHR01 GM055040
NIHR01 CA196277
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Issue or Number:4
PubMed Central ID:PMC4752866
Record Number:CaltechAUTHORS:20170217-155108197
Persistent URL:
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:74412
Deposited By: Donna Wrublewski
Deposited On:18 Feb 2017 03:49
Last Modified:11 Nov 2021 05:27

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