title: Endocytosis and intracellular trafficking of Notch and its ligands.
abstract: Notch signaling occurs through direct interaction between Notch, the receptor, and its ligands, presented on the surface of neighboring cells. Endocytosis has been shown to be essential for Notch signal activation in both signal-sending and signal-receiving cells, and numerous genes involved in vesicle trafficking have recently been shown to act as key regulators of the pathway. Defects in vesicle trafficking can lead to gain- or loss-of-function defects in a context-dependent manner. Here, we discuss how endocytosis and vesicle trafficking regulate Notch signaling in both signal-sending and signal-receiving cells. We will introduce the key players in different trafficking steps, and further illustrate how they impact the signal outcome. Some of these players act as general factors and modulate Notch signaling in all contexts, whereas others modulate signaling in a context-specific fashion. We also discuss Notch signaling during mechanosensory organ development in the fly to exemplify how endocytosis and vesicle trafficking are effectively used to determine correct cell fates. In summary, endocytosis plays an essential role in Notch signaling, whereas intracellular vesicle trafficking often plays a context-dependent or regulatory role, leading to divergent outcomes in different developmental contexts.
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Shinya
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Wu-Lin
authors.initials: WL
authors.lastname: Charng
authors.forename: Hugo J
authors.initials: HJ
authors.lastname: Bellen
mesh_terms: D000818:Animals; D002465:Cell Movement; D004705:Endocytosis / Q000502:physiology*; D006801:Humans; D008024:Ligands; D021381:Protein Transport; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D008024:Ligands; D051880:Receptors, Notch
references.citation: Dev Cell. 2005 Sep;9(3):351-63
references.pmid: 16137928
references.citation: Curr Biol. 2003 May 13;13(10):854-60
references.pmid: 12747835
references.citation: Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11925-32
references.pmid: 8876239
references.citation: Development. 1997 Oct;124(20):4039-51
references.pmid: 9374401
references.citation: Nat Rev Neurosci. 2001 Nov;2(11):772-9
references.pmid: 11715054
references.citation: Development. 2008 Mar;135(6):1089-95
references.pmid: 18256200
references.citation: Genetics. 1999 Feb;151(2):675-84
references.pmid: 9927460
references.citation: Dev Biol. 1996 Jun 15;176(2):264-83
references.pmid: 8660866
references.citation: BMC Dev Biol. 2008 May 08;8:50
references.pmid: 18466624
references.citation: Dev Cell. 2002 Aug;3(2):221-31
references.pmid: 12194853
references.citation: Development. 1998 Aug;125(15):2893-900
references.pmid: 9655811
references.citation: Development. 1993 Feb;117(2):493-507
references.pmid: 8330521
references.citation: Nat Cell Biol. 2005 Dec;7(12):1191-201
references.pmid: 16284625
references.citation: EMBO Rep. 2003 Dec;4(12):1163-8
references.pmid: 14608370
references.citation: Curr Biol. 2001 Nov 13;11(22):1729-38
references.pmid: 11719214
references.citation: PLoS Biol. 2009 Sep;7(9):e1000192
references.pmid: 19809570
references.citation: Wilehm Roux Arch Dev Biol. 1981 Jul;190(4):226-229
references.pmid: 28305572
references.citation: J Biol Chem. 2003 Jun 20;278(25):23196-203
references.pmid: 12682059
references.citation: Biochem Soc Trans. 2009 Feb;37(Pt 1):204-7
references.pmid: 19143632
references.citation: Mol Genet Genomics. 2006 Mar;275(3):251-63
references.pmid: 16395579
references.citation: Dev Biol. 1990 Mar;138(1):147-58
references.pmid: 2106460
references.citation: Mol Cell Biol. 2008 Jan;28(1):165-76
references.pmid: 17967888
references.citation: Dev Biol. 2009 Sep 15;333(2):373-85
references.pmid: 19580805
references.citation: J Biol Chem. 2000 Nov 17;275(46):35734-7
references.pmid: 10940313
references.citation: Genetics. 1998 Dec;150(4):1477-85
references.pmid: 9832525
references.citation: EMBO Rep. 2005 Sep;6(9):836-42
references.pmid: 16113648
references.citation: Dev Biol. 1990 Apr;138(2):464-72
references.pmid: 2108067
references.citation: Annu Rev Cell Dev Biol. 2003;19:141-72
references.pmid: 14570567
references.citation: Cell. 1994 Feb 11;76(3):477-91
references.pmid: 8313469
references.citation: PLoS One. 2008 Jul 16;3(7):e2735
references.pmid: 18628966
references.citation: Biochemistry. 2001 Apr 24;40(16):5049-55
references.pmid: 11305921
references.citation: Bioessays. 2002 May;24(5):405-10
references.pmid: 12001263
references.citation: Nat Rev Mol Cell Biol. 2006 Oct;7(10):713-26
references.pmid: 16990851
references.citation: J Biol Chem. 1994 Jul 1;269(26):17386-9
references.pmid: 8021238
references.citation: J Cell Sci. 2008 Oct 1;121(Pt 19):3109-19
references.pmid: 18799787
references.citation: Nat Rev Mol Cell Biol. 2009 Sep;10(9):597-608
references.pmid: 19696797
references.citation: Development. 2005 Jun;132(12):2883-94
references.pmid: 15930117
references.citation: Annu Rev Biochem. 2009;78:857-902
references.pmid: 19317650
references.citation: Mol Biol Cell. 2005 Aug;16(8):3480-7
references.pmid: 15901829
references.citation: Curr Biol. 2010 Mar 23;20(6):538-43
references.pmid: 20226669
references.citation: Cell. 2008 May 30;133(5):852-63
references.pmid: 18510929
references.citation: Development. 1997 Sep;124(17):3439-48
references.pmid: 9310338
references.citation: Nature. 1998 Aug 20;394(6695):793-7
references.pmid: 9723620
references.citation: Mol Cell Biol. 1998 Apr;18(4):2230-9
references.pmid: 9528794
references.citation: Traffic. 2005 Jun;6(6):429-41
references.pmid: 15882441
references.citation: Genetics. 2006 Dec;174(4):1947-61
references.pmid: 17028337
references.citation: Proc Natl Acad Sci U S A. 1937 Mar;23(3):133-7
references.pmid: 16588136
references.citation: Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):8108-12
references.pmid: 9653148
references.citation: Genetics. 1990 Nov;126(3):665-77
references.pmid: 2123462
references.citation: Dev Cell. 2007 Dec;13(6):783-95
references.pmid: 18061562
references.citation: Dev Biol. 1973 Jun;32(2):373-86
references.pmid: 4208027
references.citation: Dev Cell. 2003 Jan;4(1):67-82
references.pmid: 12530964
references.citation: Mech Dev. 2002 Jul;115(1-2):41-51
references.pmid: 12049766
references.citation: Traffic. 2009 Jul;10(7):792-802
references.pmid: 19416471
references.citation: Proc Natl Acad Sci U S A. 2005 Feb 22;102(8):2760-5
references.pmid: 15701692
references.citation: Genetics. 1999 Jun;152(2):567-76
references.pmid: 10353900
references.citation: Nature. 1995 Aug 31;376(6543):775-8
references.pmid: 7651536
references.citation: Nature. 1999 Apr 8;398(6727):518-22
references.pmid: 10206645
references.citation: Dev Cell. 2008 Nov;15(5):762-72
references.pmid: 19000840
references.citation: EMBO J. 1991 Oct;10(10):2975-83
references.pmid: 1717258
references.citation: J Biol Chem. 2002 Mar 8;277(10):8033-40
references.pmid: 11777909
references.citation: PLoS One. 2009 Aug 24;4(8):e6728
references.pmid: 19701455
references.citation: Nature. 1991 May 30;351(6325):411-4
references.pmid: 1674590
references.citation: J Neuropathol Exp Neurol. 2002 Feb;61(2):125-31
references.pmid: 11855381
references.citation: FASEB J. 2000 Dec;14(15):2383-6
references.pmid: 11024004
references.citation: Cell. 1990 May 4;61(3):523-34
references.pmid: 2185893
references.citation: EMBO Rep. 2006 Nov;7(11):1147-53
references.pmid: 17028573
references.citation: Mol Biol Cell. 1997 Sep;8(9):1751-62
references.pmid: 9307971
references.citation: J Cell Sci. 1999 Oct;112 ( Pt 19):3289-97
references.pmid: 10504334
references.citation: Development. 1995 Aug;121(8):2633-44
references.pmid: 7671825
references.citation: Dev Biol. 1997 Dec 15;192(2):585-98
references.pmid: 9441691
references.citation: Development. 1997 Sep;124(17):3427-37
references.pmid: 9310337
references.citation: Cell. 1998 Dec 11;95(6):779-91
references.pmid: 9865696
references.citation: J Cell Biol. 2000 Dec 11;151(6):1345-52
references.pmid: 11121447
references.citation: Curr Biol. 2005 May 24;15(10):955-62
references.pmid: 15916953
references.citation: Blood. 2009 Apr 30;113(18):4381-90
references.pmid: 19075186
references.citation: Development. 2005 Sep;132(18):4041-50
references.pmid: 16093323
references.citation: Dev Cell. 2005 Nov;9(5):687-98
references.pmid: 16256743
references.citation: Curr Biol. 2004 Dec 29;14(24):2237-44
references.pmid: 15620650
references.citation: Development. 2004 Nov;131(21):5355-66
references.pmid: 15469967
references.citation: PLoS Biol. 2005 Apr;3(4):e96
references.pmid: 15760269
references.citation: Nat Struct Mol Biol. 2007 Apr;14(4):295-300
references.pmid: 17401372
references.citation: Development. 1989 Oct;107(2):389-405
references.pmid: 2517255
references.citation: Development. 2006 May;133(10):1871-80
references.pmid: 16611691
references.citation: Cell. 2005 Sep 9;122(5):763-73
references.pmid: 16137758
references.citation: Cell. 2009 Apr 17;137(2):216-33
references.pmid: 19379690
references.citation: Dev Cell. 2001 Dec;1(6):807-16
references.pmid: 11740942
references.citation: Nature. 2009 Apr 23;458(7241):1051-5
references.pmid: 19295516
references.citation: J Cell Sci. 2009 Jul 15;122(Pt 14):2413-23
references.pmid: 19571114
references.citation: Dev Cell. 2006 Nov;11(5):655-69
references.pmid: 17084358
references.citation: Genes Dev. 1998 Apr 15;12(8):1086-91
references.pmid: 9553038
references.citation: Dev Cell. 2005 Nov;9(5):711-20
references.pmid: 16256745
references.citation: Curr Biol. 2006 Apr 4;16(7):702-9
references.pmid: 16581517
references.citation: J Cell Biol. 2004 Dec 20;167(6):1217-29
references.pmid: 15611340
references.citation: J Biol Chem. 2005 Feb 11;280(6):4383-92
references.pmid: 15569674
references.citation: Dev Cell. 2002 Jan;2(1):79-89
references.pmid: 11782316
references.citation: EMBO J. 2006 Oct 18;25(20):4697-706
references.pmid: 17006545
references.citation: Dev Cell. 2001 Dec;1(6):783-94
references.pmid: 11740940
references.citation: Dev Cell. 2003 Oct;5(4):559-70
references.pmid: 14536058
references.citation: Nat Cell Biol. 2009 Jul;11(7):815-24
references.pmid: 19543274
references.citation: Dev Cell. 2006 Feb;10(2):245-55
references.pmid: 16459303
references.citation: Science. 1995 Aug 18;269(5226):973-7
references.pmid: 7638622
references.citation: Dev Cell. 2009 Sep;17(3):387-402
references.pmid: 19758563
references.citation: Curr Biol. 2004 Dec 29;14(24):2228-36
references.pmid: 15620649
references.citation: Proc Natl Acad Sci U S A. 2008 Aug 12;105(32):11212-7
references.pmid: 18676613
references.citation: Curr Biol. 2001 Oct 30;11(21):1675-9
references.pmid: 11696324
references.citation: Proc Natl Acad Sci U S A. 1991 Jan 15;88(2):632-6
references.pmid: 1899143
references.citation: Curr Opin Cell Biol. 2008 Aug;20(4):415-26
references.pmid: 18511251
references.citation: Dev Cell. 2006 Feb;10(2):257-64
references.pmid: 16459304
references.citation: Development. 1994 Mar;120(3):473-81
references.pmid: 8162848
references.citation: Development. 2005 May;132(10):2319-32
references.pmid: 15829515
references.citation: Neuron. 1996 Jul;17(1):27-41
references.pmid: 8755476
references.citation: Dev Cell. 2003 Jul;5(1):139-48
references.pmid: 12852858
references.citation: Science. 2006 Nov 17;314(5802):1135-9
references.pmid: 17110576
references.citation: J Cell Biol. 2001 Jan 8;152(1):1-13
references.pmid: 11149916
references.citation: Nature. 2009 Mar 26;458(7237):445-52
references.pmid: 19325624
references.citation: Mol Biol Cell. 1998 Jul;9(7):1709-23
references.pmid: 9658166
references.citation: Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):13838-43
references.pmid: 19666558
references.citation: Dev Cell. 2003 Aug;5(2):231-43
references.pmid: 12919675
references.citation: Curr Opin Cell Biol. 2009 Aug;21(4):552-9
references.pmid: 19497727
references.citation: Nature. 2006 Oct 12;443(7112):651-7
references.pmid: 17035995
references.citation: Neuron. 2005 Apr 21;46(2):219-32
references.pmid: 15848801
references.citation: Dev Cell. 2005 Nov;9(5):699-710
references.pmid: 16256744
references.citation: Neuron. 2006 Oct 5;52(1):15-31
references.pmid: 17015224
references.citation: Mech Dev. 1995 Apr;50(2-3):201-16
references.pmid: 7619731
references.citation: J Biol Chem. 2008 Feb 15;283(7):3846-53
references.pmid: 18077452
references.citation: Traffic. 2007 Jun;8(6):640-6
references.pmid: 17488288
references.citation: Dev Dyn. 2006 Apr;235(4):886-94
references.pmid: 16425217
references.citation: Dev Cell. 2009 May;16(5):633-47
references.pmid: 19460341
references.citation: Exp Cell Res. 2009 May 15;315(9):1610-8
references.pmid: 19007773
references.citation: J Cell Biol. 2006 May 8;173(3):443-52
references.pmid: 16682530
references.citation: J Cell Biol. 2007 Feb 12;176(4):445-58
references.pmid: 17296795
references.citation: J Cell Biol. 2008 Feb 25;180(4):755-62
references.pmid: 18299346
references.citation: J Biol Chem. 2009 Sep 25;284(39):26427-38
references.pmid: 19567869
references.citation: Cell. 2002 Jan 25;108(2):261-9
references.pmid: 11832215
references.citation: Development. 2004 Dec;131(23):5807-15
references.pmid: 15539484
references.citation: J Neurosci. 2002 Apr 1;22(7):2530-40
references.pmid: 11923418
references.citation: Biochem J. 2009 Mar 1;418(2):233-46
references.pmid: 19196244
references.citation: Development. 2000 Apr;127(7):1373-85
references.pmid: 10704384
references.citation: Development. 2009 Dec;136(24):4089-98
references.pmid: 19906847
references.citation: Curr Biol. 1999 May 6;9(9):460-9
references.pmid: 10322111
references.citation: Curr Opin Cell Biol. 2009 Aug;21(4):575-81
references.pmid: 19442504
references.citation: Nature. 1991 Jun 13;351(6327):583-6
references.pmid: 1828536
references.citation: Mol Biol Cell. 2007 Jan;18(1):1-13
references.pmid: 17065551
references.citation: Nat Rev Mol Cell Biol. 2009 Sep;10(9):609-22
references.pmid: 19696798
references.citation: J Cell Sci. 2009 Jun 1;122(Pt 11):1713-21
references.pmid: 19461071
references.citation: J Cell Biol. 2004 Jul 5;166(1):73-83
references.pmid: 15240571
references.citation: Development. 2004 Nov;131(22):5527-37
references.pmid: 15496440
references.citation: Nature. 2002 Mar 28;416(6879):451-5
references.pmid: 11919637
references.citation: Dev Biol. 2003 Mar 15;255(2):313-33
references.pmid: 12648493
references.citation: Curr Biol. 2004 Aug 24;14(16):R674-85
references.pmid: 15324689
references.citation: Nat Cell Biol. 2005 Dec;7(12):1232-9
references.pmid: 16258546
references.citation: Curr Biol. 2006 Nov 21;16(22):2228-33
references.pmid: 17088062
references.citation: Curr Biol. 2004 Dec 29;14(24):R1043-5
references.pmid: 15620635
references.citation: Mol Cell. 2000 Sep;6(3):625-36
references.pmid: 11030342
references.citation: Development. 2004 Nov;131(21):5367-80
references.pmid: 15469974
references.citation: Genetics. 2009 Aug;182(4):1101-8
references.pmid: 19528324
references.citation: Nature. 1995 Jun 29;375(6534):754-60
references.pmid: 7596406
references.citation: Dev Cell. 2006 Nov;11(5):641-53
references.pmid: 17084357
references.citation: J Cell Biol. 1996 Jun;133(6):1205-15
references.pmid: 8682859
references.citation: FEBS Lett. 2002 Feb 20;513(1):11-8
references.pmid: 11911874
references.citation: Dev Biol. 2002 Mar 15;243(2):260-71
references.pmid: 11884035
references.citation: Dev Cell. 2001 Dec;1(6):795-806
references.pmid: 11740941
references.citation: Curr Opin Neurobiol. 2004 Feb;14(1):6-14
references.pmid: 15018932
references.citation: Cancer Sci. 2008 Jul;99(7):1293-303
references.pmid: 18429951
references.citation: Cell. 2000 May 26;101(5):499-510
references.pmid: 10850492
references.citation: Curr Biol. 2003 Apr 1;13(7):R273-5
references.pmid: 12676105
references.citation: Curr Opin Genet Dev. 2009 Aug;19(4):323-8
references.pmid: 19447603
references.citation: PLoS One. 2009;4(1):e4165
references.pmid: 19132102
references.citation: J Biol Chem. 1999 Nov 12;274(46):32961-9
references.pmid: 10551863
references.citation: J Cell Sci. 2000 Dec;113 Pt 23:4313-8
references.pmid: 11069775
references.citation: J Biol Chem. 2003 Jul 18;278(29):26687-94
references.pmid: 12736250
references.citation: Nat Struct Mol Biol. 2005 Oct;12(10):879-85
references.pmid: 16155582
references.citation: Genetics. 2005 Dec;171(4):1605-15
references.pmid: 16157663
references.citation: Dev Biol. 2003 Mar 15;255(2):363-72
references.pmid: 12648496
references.citation: Trends Cell Biol. 2008 May;18(5):220-7
references.pmid: 18396046