Journal
CELL
Volume 164, Issue 4, Pages 780-791Publisher
CELL PRESS
DOI: 10.1016/j.cell.2016.01.012
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Funding
- Jane Coffin Childs Memorial Fund Postdoctoral Fellowship [A121505]
- Human Frontiers of Science Program (HFSP)
- European Molecular Biology Organization (EMBO) Postdoctoral Fellowship
- NIH grants [K99 1K99EB021030, PN2 EY016546, P50GM081879, R01 GM055040, R01 CA196277]
- Howard Hughes Medical Institute
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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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