title: Engineering Customized Cell Sensing and Response Behaviors Using Synthetic Notch Receptors.
abstract: 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.
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Center for Systems and Synthetic Biology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Morsut
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Center for Systems and Synthetic Biology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute.
authors.forename: Kole T
authors.initials: KT
authors.lastname: Roybal
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Center for Systems and Synthetic Biology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute.
authors.forename: Xin
authors.initials: X
authors.lastname: Xiong
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Center for Systems and Synthetic Biology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute.
authors.forename: Russell M
authors.initials: RM
authors.lastname: Gordley
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Center for Systems and Synthetic Biology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Coyle
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Center for Systems and Synthetic Biology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Thomson
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Center for Systems and Synthetic Biology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute. Electronic address: wendell.lim@ucsf.edu.
authors.forename: Wendell A
authors.initials: WA
authors.lastname: Lim
mesh_terms: D000818:Animals; D060846:Cell Engineering; D002460:Cell Line; D004285:Dogs; D006801:Humans; D051379:Mice; D009474:Neurons / Q000378:metabolism; D051880:Receptors, Notch / Q000737:chemistry* / Q000378:metabolism; D015398:Signal Transduction; D058615:Synthetic Biology / Q000379:methods*; D014158:Transcription, Genetic
chemical_list: D051880:Receptors, Notch
references.citation: Development. 2015 Sep 15;142(18):3113-25
references.pmid: 26395140
references.citation: Nature. 2010 May 6;465(7294):86-90
references.pmid: 20418862
references.citation: Nat Cell Biol. 2000 Feb;2(2):76-83
references.pmid: 10655586
references.citation: Nature. 2001 May 17;411(6835):355-65
references.pmid: 11357143
references.citation: J Cell Sci. 2002 Mar 15;115(Pt 6):1095-7
references.pmid: 11884509
references.citation: Nat Methods. 2014 Dec;11(12):1253-60
references.pmid: 25362362
references.citation: Proc Natl Acad Sci U S A. 2015 Nov 24;112(47):14429-35
references.pmid: 26598662
references.citation: BMC Evol Biol. 2009;9:249
references.pmid: 19825158
references.citation: Nat Rev Mol Cell Biol. 2009 Jun;10(6):410-22
references.pmid: 19461664
references.citation: N Engl J Med. 2013 Apr 18;368(16):1509-18
references.pmid: 23527958
references.citation: Sci Transl Med. 2013 Apr 3;5(179):179ps7
references.pmid: 23552369
references.citation: Nature. 2013 Jan 17;493(7432):318-26
references.pmid: 23325214
references.citation: Cell. 2012 Jun 22;149(7):1447-60
references.pmid: 22704655
references.citation: Sci Signal. 2012 Apr 17;5(220):ra31
references.pmid: 22510469
references.citation: Acta Histochem. 2011 May;113(3):248-55
references.pmid: 20122714
references.citation: Curr Top Dev Biol. 2010;92:165-200
references.pmid: 20816395
references.citation: Curr Top Dev Biol. 2010;92:31-71
references.pmid: 20816392
references.citation: Cell. 2015 Jan 15;160(1-2):339-50
references.pmid: 25533786
references.citation: ACS Synth Biol. 2014 Dec 19;3(12):892-902
references.pmid: 24611683
references.citation: Cell. 1987 Dec 24;51(6):987-1000
references.pmid: 3690668
references.citation: Nat Rev Mol Cell Biol. 2014 Feb;15(2):95-107
references.pmid: 24434884
references.citation: Development. 1997 Apr;124(8):1485-95
references.pmid: 9108365
references.citation: Proc Natl Acad Sci U S A. 1998 Jan 20;95(2):669-74
references.pmid: 9435250
references.citation: Cell. 1998 May 15;93(4):649-60
references.pmid: 9604939
references.citation: Curr Biol. 1998 Jun 18;8(13):771-4
references.pmid: 9651681
references.citation: Science. 1999 Apr 30;284(5415):770-6
references.pmid: 10221902
references.citation: Neuron. 2006 Nov 9;52(3):425-36
references.pmid: 17088209
references.citation: Nat Struct Mol Biol. 2007 Apr;14(4):295-300
references.pmid: 17401372
references.citation: Proc Natl Acad Sci U S A. 2008 Jan 8;105(1):64-9
references.pmid: 18165312
references.citation: Ann Biomed Eng. 2015 Mar;43(3):641-56
references.pmid: 25201605
references.citation: Cancer Cell. 2015 Apr 13;27(4):439-49
references.pmid: 25858803
references.citation: Dev Cell. 2015 Jun 22;33(6):729-36
references.pmid: 26051539
references.citation: Nature. 2008 Feb 14;451(7180):783-8
references.pmid: 18273011
references.citation: Cell. 2009 Apr 17;137(2):216-33
references.pmid: 19379690