1932

Abstract

Notch signaling is a conserved system of communication between adjacent cells, influencing numerous cell fate decisions in the development of multicellular organisms. Aberrant signaling is also implicated in many human pathologies. At its core, Notch has a mechanotransduction module that decodes receptor–ligand engagement at the cell surface under force to permit proteolytic cleavage of the receptor, leading to the release of the Notch intracellular domain (NICD). NICD enters the nucleus and acts as a transcriptional effector to regulate expression of Notch-responsive genes. In this article, we review and integrate current understanding of the detailed molecular basis for Notch signal transduction, highlighting quantitative, structural, and dynamic features of this developmentally central signaling mechanism. We discuss the implications of this mechanistic understanding for the functionality of the signaling pathway in different molecular and cellular contexts.

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2021-05-06
2024-04-18
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Literature Cited

  1. 1. 
    Acar M, Jafar-Nejad H, Takeuchi H, Rajan A, Ibrani D et al. 2008. Rumi is a CAP10 domain glycosyltransferase that modifies Notch and is required for Notch signaling. Cell 132:247–58
    [Google Scholar]
  2. 2. 
    Agnusdei V, Minuzzo S, Frasson C, Grassi A, Axelrod F et al. 2014. Therapeutic antibody targeting of Notch1 in T-acute lymphoblastic leukemia xenografts. Leukemia 28:278–88
    [Google Scholar]
  3. 3. 
    Ahimou F, Mok LP, Bardot B, Wesley C. 2004. The adhesion force of Notch with Delta and the rate of Notch signaling. J. Cell Biol. 167:1217–29
    [Google Scholar]
  4. 4. 
    Andrawes MB, Xu X, Liu H, Ficarro SB, Marto JA et al. 2013. Intrinsic selectivity of Notch 1 for Delta-like 4 over Delta-like 1. J. Biol. Chem. 288:25477–89
    [Google Scholar]
  5. 5. 
    Artavanis-Tsakonas S, Rand MD, Lake RJ. 1999. Notch signaling: cell fate control and signal integration in development. Science 284:770–76
    [Google Scholar]
  6. 6. 
    Aste-Amezaga M, Zhang N, Lineberger JE, Arnold BA, Toner TJ et al. 2010. Characterization of Notch1 antibodies that inhibit signaling of both normal and mutated Notch1 receptors. PLOS ONE 5:e9094
    [Google Scholar]
  7. 7. 
    Aster JC, Blacklow SC. 2012. Targeting the Notch pathway: twists and turns on the road to rational therapeutics. J. Clin. Oncol. 30:2418–20
    [Google Scholar]
  8. 8. 
    Aster JC, Pear WS, Blacklow SC. 2017. The varied roles of Notch in cancer. Annu. Rev. Pathol. 12:245–75
    [Google Scholar]
  9. 9. 
    Aster JC, Xu L, Karnell FG, Patriub V, Pui JC, Pear WS. 2000. Essential roles for ankyrin repeat and transactivation domains in induction of T-cell leukemia by notch1. Mol. Cell. Biol. 20:7505–15
    [Google Scholar]
  10. 10. 
    Baek C, Freem L, Goiame R, Sang H, Morin X, Tozer S. 2018. Mib1 prevents Notch Cis-inhibition to defer differentiation and preserve neuroepithelial integrity during neural delamination. PLOS Biol 16:e2004162
    [Google Scholar]
  11. 11. 
    Bailey AM, Posakony JW. 1995. Suppressor of hairless directly activates transcription of enhancer of split complex genes in response to Notch receptor activity. Genes Dev 9:2609–22
    [Google Scholar]
  12. 12. 
    Bernasconi-Elias P, Hu T, Jenkins D, Firestone B, Gans S et al. 2016. Characterization of activating mutations of NOTCH3 in T-cell acute lymphoblastic leukemia and anti-leukemic activity of NOTCH3 inhibitory antibodies. Oncogene 35:6077–86
    [Google Scholar]
  13. 13. 
    Berndt N, Seib E, Kim S, Troost T, Lyga M et al. 2017. Ubiquitylation-independent activation of Notch signalling by Delta. eLife 6:e27346
    [Google Scholar]
  14. 14. 
    Blacklow SC. 2017. Signal transduction: Notch catches a Jagged edge. Nat. Chem. Biol. 13:570–71
    [Google Scholar]
  15. 15. 
    Bray SJ. 2016. Notch signalling in context. Nat. Rev. Mol. Cell Biol. 17:722–35
    [Google Scholar]
  16. 16. 
    Brennan K, Tateson R, Lewis K, Arias AM. 1997. A functional analysis of Notch mutations in Drosophila. Genetics 147:177–88
    [Google Scholar]
  17. 17. 
    Brou C, Logeat F, Gupta N, Bessia C, LeBail O et al. 2000. A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE. Mol. Cell 5:207–16
    [Google Scholar]
  18. 18. 
    Brown MS, Ye J, Rawson RB, Goldstein JL. 2000. Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans. Cell 100:391–98
    [Google Scholar]
  19. 19. 
    Bruckner K, Perez L, Clausen H, Cohen S. 2000. Glycosyltransferase activity of Fringe modulates Notch-Delta interactions. Nature 406:411–15
    [Google Scholar]
  20. 20. 
    Carrieri FA, Murray PJ, Ditsova D, Ferris MA, Davies P, Dale JK. 2019. CDK1 and CDK2 regulate NICD1 turnover and the periodicity of the segmentation clock. EMBO Rep 20:e46436
    [Google Scholar]
  21. 21. 
    Castel D, Mourikis P, Bartels SJ, Brinkman AB, Tajbakhsh S, Stunnenberg HG. 2013. Dynamic binding of RBPJ is determined by Notch signaling status. Genes Dev 27:1059–71
    [Google Scholar]
  22. 22. 
    Chapman G, Sparrow DB, Kremmer E, Dunwoodie SL. 2011. Notch inhibition by the ligand DELTA-LIKE 3 defines the mechanism of abnormal vertebral segmentation in spondylocostal dysostosis. Hum. Mol. Genet. 20:905–16
    [Google Scholar]
  23. 23. 
    Chiang MY, Xu ML, Histen G, Shestova O, Roy M et al. 2006. Identification of a conserved negative regulatory sequence that influences the leukemogenic activity of NOTCH1. Mol. Cell. Biol. 26:6261–71
    [Google Scholar]
  24. 24. 
    Chillakuri CR, Sheppard D, Ilagan MX, Holt LR, Abbott F et al. 2013. Structural analysis uncovers lipid-binding properties of Notch ligands. Cell Rep 5:861–67
    [Google Scholar]
  25. 25. 
    Chowdhury F, Li IT, Ngo TT, Leslie BJ, Kim BC et al. 2016. Defining single molecular forces required for Notch activation using nano yoyo. Nano Lett 16:3892–97
    [Google Scholar]
  26. 26. 
    Collins KJ, Yuan Z, Kovall RA. 2014. Structure and function of the CSL-KyoT2 corepressor complex: a negative regulator of Notch signaling. Structure 22:70–81
    [Google Scholar]
  27. 27. 
    Cordle J, Johnson S, Tay JZ, Roversi P, Wilkin MB et al. 2008. A conserved face of the Jagged/Serrate DSL domain is involved in Notch trans-activation and cis-inhibition. Nat. Struct. Mol. Biol. 15:849–57
    [Google Scholar]
  28. 28. 
    Cordle J, Redfieldz C, Stacey M, van der Merwe PA, Willis AC et al. 2008. Localization of the delta-like-1-binding site in human Notch-1 and its modulation by calcium affinity. J. Biol. Chem. 283:11785–93
    [Google Scholar]
  29. 29. 
    Couturier L, Vodovar N, Schweisguth F. 2012. Endocytosis by Numb breaks Notch symmetry at cytokinesis. Nat. Cell Biol. 14:131–39
    [Google Scholar]
  30. 30. 
    de Celis JF, Bray S. 1997. Feed-back mechanisms affecting Notch activation at the dorsoventral boundary in the Drosophila wing. Development 124:3241–51
    [Google Scholar]
  31. 31. 
    De Strooper B, Annaert W, Cupers P, Saftig P, Craessaerts K et al. 1999. A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature 398:518–22
    [Google Scholar]
  32. 32. 
    Deblandre GA, Lai EC, Kintner C. 2001. Xenopus neuralized is a ubiquitin ligase that interacts with XDelta1 and regulates Notch signaling. Dev. Cell 1:795–806
    [Google Scholar]
  33. 33. 
    Del Bianco C, Aster JC, Blacklow SC. 2008. Mutational and energetic studies of Notch 1 transcription complexes. J. Mol. Biol. 376:131–40
    [Google Scholar]
  34. 34. 
    Del Bianco C, Vedenko A, Choi SH, Berger MF, Shokri L et al. 2010. Notch and MAML-1 complexation do not detectably alter the DNA binding specificity of the transcription factor CSL. PLOS ONE 5:e15034
    [Google Scholar]
  35. 35. 
    Falo-Sanjuan J, Lammers NC, Garcia HG, Bray SJ. 2019. Enhancer priming enables fast and sustained transcriptional responses to Notch signaling. Dev. Cell 50:411–25.e8
    [Google Scholar]
  36. 36. 
    Fehon RG, Kooh PJ, Rebay I, Regan CL, Xu T et al. 1990. Molecular interactions between the protein products of the neurogenic loci Notch and Delta, two EGF-homologous genes in Drosophila. Cell 61:523–34
    [Google Scholar]
  37. 37. 
    Fleming RJ, Gu Y, Hukriede NA. 1997. Serrate-mediated activation of Notch is specifically blocked by the product of the gene fringe in the dorsal compartment of the Drosophila wing imaginal disc. Development 124:2973–81
    [Google Scholar]
  38. 38. 
    Fryer CJ, Lamar E, Turbachova I, Kintner C, Jones KA. 2002. Mastermind mediates chromatin-specific transcription and turnover of the Notch enhancer complex. Genes Dev 16:1397–411
    [Google Scholar]
  39. 39. 
    Fryer CJ, White JB, Jones KA. 2004. Mastermind recruits CycC:CDK8 to phosphorylate the Notch ICD and coordinate activation with turnover. Mol. Cell 16:509–20
    [Google Scholar]
  40. 40. 
    Glittenberg M, Pitsouli C, Garvey C, Delidakis C, Bray S. 2006. Role of conserved intracellular motifs in Serrate signalling, cis-inhibition and endocytosis. EMBO J 25:4697–706
    [Google Scholar]
  41. 41. 
    Gomez-Lamarca MJ, Falo-Sanjuan J, Stojnic R, Abdul Rehman S, Muresan L et al. 2018. Activation of the Notch signaling pathway in vivo elicits changes in CSL nuclear dynamics. Dev. Cell 44:611–23.e7
    [Google Scholar]
  42. 42. 
    Gordon WR, Roy M, Vardar-Ulu D, Garfinkel M, Mansour MR et al. 2009. Structure of the Notch1-negative regulatory region: implications for normal activation and pathogenic signaling in T-ALL. Blood 113:4381–90
    [Google Scholar]
  43. 43. 
    Gordon WR, Vardar-Ulu D, Histen G, Sanchez-Irizarry C, Aster JC, Blacklow SC. 2007. Structural basis for autoinhibition of Notch. Nat. Struct. Mol. Biol. 14:295–300
    [Google Scholar]
  44. 44. 
    Gordon WR, Zimmerman B, He L, Miles LJ, Huang J et al. 2015. Mechanical allostery: evidence for a force requirement in the proteolytic activation of Notch. Dev. Cell 33:729–36
    [Google Scholar]
  45. 45. 
    Greenwald I, Seydoux G. 1990. Analysis of gain-of-function mutations of the lin-12 gene of Caenorhabditis elegans. Nature 346:197–99
    [Google Scholar]
  46. 46. 
    Hambleton S, Valeyev NV, Muranyi A, Knott V, Werner JM et al. 2004. Structural and functional properties of the human notch-1 ligand binding region. Structure 12:2173–83
    [Google Scholar]
  47. 47. 
    Harvey BM, Haltiwanger RS. 2018. Regulation of Notch function by O-glycosylation. Adv. Exp. Med. Biol. 1066:59–78
    [Google Scholar]
  48. 48. 
    Hass MR, Liow HH, Chen X, Sharma A, Inoue YU et al. 2015. SpDamID: marking DNA bound by protein complexes identifies Notch-dimer responsive enhancers. Mol. Cell 59:685–97
    [Google Scholar]
  49. 49. 
    Hayward AN, Aird EJ, Gordon WR. 2019. A toolkit for studying cell surface shedding of diverse transmembrane receptors. eLife 8:e46983
    [Google Scholar]
  50. 50. 
    Heuss SF, Ndiaye-Lobry D, Six EM, Israel A, Logeat F 2008. The intracellular region of Notch ligands Dll1 and Dll3 regulates their trafficking and signaling activity. PNAS 105:11212–17
    [Google Scholar]
  51. 51. 
    Hubbard EJ, Wu G, Kitajewski J, Greenwald I. 1997. sel-10, a negative regulator of lin-12 activity in Caenorhabditis elegans, encodes a member of the CDC4 family of proteins. Genes Dev 11:3182–93
    [Google Scholar]
  52. 52. 
    Ilagan MX, Lim S, Fulbright M, Piwnica-Worms D, Kopan R. 2011. Real-time imaging of notch activation with a luciferase complementation-based reporter. Sci. Signal. 4:rs7
    [Google Scholar]
  53. 53. 
    Itoh M, Kim CH, Palardy G, Oda T, Jiang YJ et al. 2003. Mind bomb is a ubiquitin ligase that is essential for efficient activation of Notch signaling by Delta. Dev. Cell 4:67–82
    [Google Scholar]
  54. 54. 
    Jarrett SM, Seegar TCM, Andrews M, Adelmant G, Marto JA et al. 2019. Extension of the Notch intracellular domain ankyrin repeat stack by NRARP promotes feedback inhibition of Notch signaling. Sci. Signal. 12:eaay2369
    [Google Scholar]
  55. 55. 
    Kakuda S, Haltiwanger RS. 2017. Deciphering the fringe-mediated Notch code: identification of activating and inhibiting sites allowing discrimination between ligands. Dev. Cell 40:193–201
    [Google Scholar]
  56. 56. 
    Kakuda S, LoPilato RK, Ito A, Haltiwanger RS. 2020. Canonical Notch ligands and Fringes have distinct effects on NOTCH1 and NOTCH2. J. Biol. Chem. 295:1471022
    [Google Scholar]
  57. 57. 
    Kershaw NJ, Church NL, Griffin MD, Luo CS, Adams TE, Burgess AW. 2015. Notch ligand delta-like1: X-ray crystal structure and binding affinity. Biochem. J. 468:159–66
    [Google Scholar]
  58. 58. 
    Khait I, Orsher Y, Golan O, Binshtok U, Gordon-Bar N et al. 2016. Quantitative analysis of delta-like 1 membrane dynamics elucidates the role of contact geometry on Notch signaling. Cell Rep 14:225–33
    [Google Scholar]
  59. 59. 
    Klein T, Arias AM. 1998. Interactions among Delta, Serrate and Fringe modulate Notch activity during Drosophila wing development. Development 125:2951–62
    [Google Scholar]
  60. 60. 
    Klein T, Brennan K, Arias AM. 1997. An intrinsic dominant negative activity of serrate that is modulated during wing development in Drosophila. Dev. Biol. 189:123–34
    [Google Scholar]
  61. 61. 
    Kobia FM, Preusse K, Dai Q, Weaver N, Hass MR et al. 2020. Notch dimerization and gene dosage are important for normal heart development, intestinal stem cell maintenance, and splenic marginal zone B-cell homeostasis during mite infestation. PLOS Biol. 18:e3000850
    [Google Scholar]
  62. 62. 
    Koo BK, Lim HS, Song R, Yoon MJ, Yoon KJ et al. 2005. Mind bomb 1 is essential for generating functional Notch ligands to activate Notch. Development 132:3459–70
    [Google Scholar]
  63. 63. 
    Koo BK, Yoon MJ, Yoon KJ, Im SK, Kim YY et al. 2007. An obligatory role of mind bomb-1 in notch signaling of mammalian development. PLOS ONE 2:e1221
    [Google Scholar]
  64. 64. 
    Kopan R, Schroeter EH, Weintraub H, Nye JS 1996. Signal transduction by activated mNotch: importance of proteolytic processing and its regulation by the extracellular domain. PNAS 93:1683–88
    [Google Scholar]
  65. 65. 
    Kovall RA, Hendrickson WA. 2004. Crystal structure of the nuclear effector of Notch signaling, CSL, bound to DNA. EMBO J 23:3441–51
    [Google Scholar]
  66. 66. 
    Krejci A, Bernard F, Housden BE, Collins S, Bray SJ. 2009. Direct response to Notch activation: signaling crosstalk and incoherent logic. Sci. Signal. 2:ra1
    [Google Scholar]
  67. 67. 
    Kuang Y, Golan O, Preusse K, Cain B, Christensen CJ et al. 2020. Enhancer architecture sensitizes cell specific responses to Notch gene dose via a bind and discard mechanism. eLife 9:e53659
    [Google Scholar]
  68. 68. 
    Kuroda K, Han H, Tani S, Tanigaki K, Tun T et al. 2003. Regulation of marginal zone B cell development by MINT, a suppressor of Notch/RBP-J signaling pathway. Immunity 18:301–12
    [Google Scholar]
  69. 69. 
    Kurth P, Preiss A, Kovall RA, Maier D. 2011. Molecular analysis of the notch repressor-complex in Drosophila: characterization of potential hairless binding sites on suppressor of hairless. PLOS ONE 6:e27986
    [Google Scholar]
  70. 70. 
    Lacy MM, Ma R, Ravindra NG, Berro J. 2018. Molecular mechanisms of force production in clathrin-mediated endocytosis. FEBS Lett 592:3586–605
    [Google Scholar]
  71. 71. 
    Ladi E, Nichols JT, Ge W, Miyamoto A, Yao C et al. 2005. The divergent DSL ligand Dll3 does not activate Notch signaling but cell autonomously attenuates signaling induced by other DSL ligands. J. Cell Biol. 170:983–92
    [Google Scholar]
  72. 72. 
    Lai EC, Deblandre GA, Kintner C, Rubin GM. 2001. Drosophila neuralized is a ubiquitin ligase that promotes the internalization and degradation of delta. Dev. Cell 1:783–94
    [Google Scholar]
  73. 73. 
    Langridge PD, Struhl G. 2017. Epsin-dependent ligand endocytosis activates Notch by force. Cell 171:1383–96.e12
    [Google Scholar]
  74. 74. 
    Le Borgne R, Remaud S, Hamel S, Schweisguth F 2005. Two distinct E3 ubiquitin ligases have complementary functions in the regulation of delta and serrate signaling in Drosophila. PLOS Biol 3:e96
    [Google Scholar]
  75. 75. 
    LeBon L, Lee TV, Sprinzak D, Jafar-Nejad H, Elowitz MB 2014. Fringe proteins modulate Notch-ligand cis and trans interactions to specify signaling states. eLife 3:e02950
    [Google Scholar]
  76. 76. 
    Lee C, Shin H, Kimble J. 2019. Dynamics of Notch-dependent transcriptional bursting in its native context. Dev. Cell 50:426–35.e4
    [Google Scholar]
  77. 77. 
    Lee TV, Sethi MK, Leonardi J, Rana NA, Buettner FF et al. 2013. Negative regulation of Notch signaling by xylose. PLOS Genet 9:e1003547
    [Google Scholar]
  78. 78. 
    Li K, Li Y, Wu W, Gordon WR, Chang DW et al. 2008. Modulation of Notch signaling by antibodies specific for the extracellular negative regulatory region of NOTCH3. J. Biol. Chem. 283:8046–54
    [Google Scholar]
  79. 79. 
    Liu H, Chi AW, Arnett KL, Chiang MY, Xu L et al. 2010. Notch dimerization is required for leukemogenesis and T-cell development. Genes Dev 24:2395–407
    [Google Scholar]
  80. 80. 
    Liu Z, Brunskill E, Varnum-Finney B, Zhang C, Zhang A et al. 2015. The intracellular domains of Notch1 and Notch2 are functionally equivalent during development and carcinogenesis. Development 142:2452–63
    [Google Scholar]
  81. 81. 
    Liu Z, Chen S, Boyle S, Zhu Y, Zhang A et al. 2013. The extracellular domain of Notch2 increases its cell-surface abundance and ligand responsiveness during kidney development. Dev. Cell 25:585–98
    [Google Scholar]
  82. 82. 
    Logeat F, Bessia C, Brou C, LeBail O, Jarriault S et al. 1998. The Notch1 receptor is cleaved constitutively by a furin-like convertase. PNAS 95:8108–12
    [Google Scholar]
  83. 83. 
    Luca VC, Jude KM, Pierce NW, Nachury MV, Fischer S, Garcia KC 2015. Structural biology: structural basis for Notch1 engagement of Delta-like 4. Science 347:847–53
    [Google Scholar]
  84. 84. 
    Luca VC, Kim BC, Ge C, Kakuda S, Wu D et al. 2017. Notch-Jagged complex structure implicates a catch bond in tuning ligand sensitivity. Science 355:1320–24
    [Google Scholar]
  85. 85. 
    Lyman D, Young MW 1993. Further evidence for function of the Drosophila Notch protein as a transmembrane receptor. PNAS 90:10395–99
    [Google Scholar]
  86. 86. 
    Maier D, Kurth P, Schulz A, Russell A, Yuan Z et al. 2011. Structural and functional analysis of the repressor complex in the Notch signaling pathway of Drosophila melanogaster. Mol. Biol. Cell 22:3242–52
    [Google Scholar]
  87. 87. 
    Malecki MJ, Sanchez-Irizarry C, Mitchell JL, Histen G, Xu ML et al. 2006. Leukemia-associated mutations within the NOTCH1 heterodimerization domain fall into at least two distinct mechanistic classes. Mol. Cell. Biol. 26:4642–51
    [Google Scholar]
  88. 88. 
    McMillan BJ, Schnute B, Ohlenhard N, Zimmerman B, Miles L et al. 2015. A tail of two sites: a bipartite mechanism for recognition of Notch ligands by mind bomb E3 ligases. Mol. Cell 57:912–24
    [Google Scholar]
  89. 89. 
    Meloty-Kapella L, Shergill B, Kuon J, Botvinick E, Weinmaster G. 2012. Notch ligand endocytosis generates mechanical pulling force dependent on dynamin, epsins, and actin. Dev. Cell 22:1299–312
    [Google Scholar]
  90. 90. 
    Mohtashami M, Shah DK, Nakase H, Kianizad K, Petrie HT, Zuniga-Pflucker JC. 2010. Direct comparison of Dll1- and Dll4-mediated Notch activation levels shows differential lymphomyeloid lineage commitment outcomes. J. Immunol. 185:867–76
    [Google Scholar]
  91. 91. 
    Moloney DJ, Panin VM, Johnston SH, Chen J, Shao L et al. 2000. Fringe is a glycosyltransferase that modifies Notch. Nature 406:369–75
    [Google Scholar]
  92. 92. 
    Morel V, Lecourtois M, Massiani O, Maier D, Preiss A, Schweisguth F. 2001. Transcriptional repression by suppressor of hairless involves the binding of a hairless-dCtBP complex in Drosophila. Curr. Biol. 11:789–92
    [Google Scholar]
  93. 93. 
    Morsut L, Roybal KT, Xiong X, Gordley RM, Coyle SM et al. 2016. Engineering customized cell sensing and response behaviors using synthetic Notch receptors. Cell 164:780–91
    [Google Scholar]
  94. 94. 
    Mumm JS, Schroeter EH, Saxena MT, Griesemer A, Tian X et al. 2000. A ligand-induced extracellular cleavage regulates gamma-secretase-like proteolytic activation of Notch1. Mol. Cell 5:197–206
    [Google Scholar]
  95. 95. 
    Nam Y, Sliz P, Pear WS, Aster JC, Blacklow SC 2007. Cooperative assembly of higher-order Notch complexes functions as a switch to induce transcription. PNAS 104:2103–8
    [Google Scholar]
  96. 96. 
    Nam Y, Sliz P, Song L, Aster JC, Blacklow SC. 2006. Structural basis for cooperativity in recruitment of MAML coactivators to Notch transcription complexes. Cell 124:973–83
    [Google Scholar]
  97. 97. 
    Nandagopal N, Santat LA, Elowitz MB. 2019. Cis-activation in the Notch signaling pathway. eLife 8:e37880
    [Google Scholar]
  98. 98. 
    Nandagopal N, Santat LA, LeBon L, Sprinzak D, Bronner ME, Elowitz MB. 2018. Dynamic ligand discrimination in the Notch signaling pathway. Cell 172:869–80.e19
    [Google Scholar]
  99. 99. 
    Nichols JT, Miyamoto A, Olsen SL, D'Souza B, Yao C, Weinmaster G 2007. DSL ligand endocytosis physically dissociates Notch1 heterodimers before activating proteolysis can occur. J. Cell Biol. 176:445–58
    [Google Scholar]
  100. 100. 
    Okajima T, Irvine KD. 2002. Regulation of notch signaling by o-linked fucose. Cell 111:893–904
    [Google Scholar]
  101. 101. 
    O'Neil J, Grim J, Strack P, Rao S, Tibbitts D et al. 2007. FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors. J. Exp. Med. 204:1813–24
    [Google Scholar]
  102. 102. 
    Oswald F, Kostezka U, Astrahantseff K, Bourteele S, Dillinger K et al. 2002. SHARP is a novel component of the Notch/RBP-Jkappa signalling pathway. EMBO J 21:5417–26
    [Google Scholar]
  103. 103. 
    Pandey A, Niknejad N, Jafar-Nejad H. 2021. Multifaceted regulation of Notch signaling by glycosylation. Glycobiology 31:828
    [Google Scholar]
  104. 104. 
    Panin VM, Papayannopoulos V, Wilson R, Irvine KD. 1997. Fringe modulates Notch-ligand interactions. Nature 387:908–12
    [Google Scholar]
  105. 105. 
    Parks AL, Klueg KM, Stout JR, Muskavitch MA. 2000. Ligand endocytosis drives receptor dissociation and activation in the Notch pathway. Development 127:1373–85
    [Google Scholar]
  106. 106. 
    Pavlopoulos E, Pitsouli C, Klueg KM, Muskavitch MA, Moschonas NK, Delidakis C. 2001. Neuralized encodes a peripheral membrane protein involved in delta signaling and endocytosis. Dev. Cell 1:807–16
    [Google Scholar]
  107. 107. 
    Pei Z, Baker NE. 2008. Competition between Delta and the Abruptex domain of Notch. BMC Dev. Biol. 8:4
    [Google Scholar]
  108. 108. 
    Petcherski AG, Kimble J. 2000. LAG-3 is a putative transcriptional activator in the C. elegans Notch pathway. Nature 405:364–68
    [Google Scholar]
  109. 109. 
    Petcherski AG, Kimble J. 2000. Mastermind is a putative activator for Notch. Curr. Biol. 10:R471–73
    [Google Scholar]
  110. 110. 
    Preusse K, Tveriakhina L, Schuster-Gossler K, Gaspar C, Rosa AI et al. 2015. Context-dependent functional divergence of the Notch ligands DLL1 and DLL4 in vivo. PLOS Genet 11:e1005328
    [Google Scholar]
  111. 111. 
    Rand MD, Grimm LM, Artavanis-Tsakonas S, Patriub V, Blacklow SC et al. 2000. Calcium depletion dissociates and activates heterodimeric notch receptors. Mol. Cell. Biol. 20:1825–35
    [Google Scholar]
  112. 112. 
    Rawson RB, Zelenski NG, Nijhawan D, Ye J, Sakai J et al. 1997. Complementation cloning of S2P, a gene encoding a putative metalloprotease required for intramembrane cleavage of SREBPs. Mol. Cell 1:47–57
    [Google Scholar]
  113. 113. 
    Rebay I, Fleming RJ, Fehon RG, Cherbas L, Cherbas P, Artavanis-Tsakonas S. 1991. Specific EGF repeats of Notch mediate interactions with Delta and Serrate: implications for Notch as a multifunctional receptor. Cell 67:687–99
    [Google Scholar]
  114. 114. 
    Roybal KT, Rupp LJ, Morsut L, Walker WJ, McNally KA et al. 2016. Precision tumor recognition by T cells with combinatorial antigen-sensing circuits. Cell 164:770–79
    [Google Scholar]
  115. 115. 
    Roybal KT, Williams JZ, Morsut L, Rupp LJ, Kolinko I et al. 2016. Engineering T cells with customized therapeutic response programs using synthetic Notch receptors. Cell 167:419–32.e16
    [Google Scholar]
  116. 116. 
    Sakai J, Rawson RB, Espenshade PJ, Cheng D, Seegmiller AC et al. 1998. Molecular identification of the sterol-regulated luminal protease that cleaves SREBPs and controls lipid composition of animal cells. Mol. Cell 2:505–14
    [Google Scholar]
  117. 117. 
    Sanchez-Irizarry C, Carpenter AC, Weng AP, Pear WS, Aster JC, Blacklow SC. 2004. Notch subunit heterodimerization and prevention of ligand-independent proteolytic activation depend, respectively, on a novel domain and the LNR repeats. Mol. Cell. Biol. 24:9265–73
    [Google Scholar]
  118. 118. 
    Seegar TCM, Killingsworth LB, Saha N, Meyer PA, Patra D et al. 2017. Structural basis for regulated proteolysis by the alpha-secretase ADAM10. Cell 171:1638–48.e7
    [Google Scholar]
  119. 119. 
    Seo D, Southard KM, Kim JW, Lee HJ, Farlow J et al. 2016. A mechanogenetic toolkit for interrogating cell signaling in space and time. Cell 165:1507–18
    [Google Scholar]
  120. 120. 
    Serth K, Schuster-Gossler K, Kremmer E, Hansen B, Marohn-Kohn B, Gossler A. 2015. O-fucosylation of DLL3 is required for its function during somitogenesis. PLOS ONE 10:e0123776
    [Google Scholar]
  121. 121. 
    Sethi MK, Buettner FF, Ashikov A, Krylov VB, Takeuchi H et al. 2012. Molecular cloning of a xylosyltransferase that transfers the second xylose to O-glucosylated epidermal growth factor repeats of Notch. J. Biol. Chem. 287:2739–48
    [Google Scholar]
  122. 122. 
    Sethi MK, Buettner FF, Krylov VB, Takeuchi H, Nifantiev NE et al. 2010. Identification of glycosyltransferase 8 family members as xylosyltransferases acting on O-glucosylated Notch epidermal growth factor repeats. J. Biol. Chem. 285:1582–86
    [Google Scholar]
  123. 123. 
    Seugnet L, Simpson P, Haenlin M. 1997. Requirement for dynamin during Notch signaling in Drosophila neurogenesis. Dev. Biol. 192:585–98
    [Google Scholar]
  124. 124. 
    Severson E, Arnett KL, Wang H, Zang C, Taing L et al. 2017. Genome-wide identification and characterization of Notch transcription complex-binding sequence-paired sites in leukemia cells. Sci. Signal. 10:eaag1598
    [Google Scholar]
  125. 125. 
    Shaya O, Binshtok U, Hersch M, Rivkin D, Weinreb S et al. 2017. Cell-cell contact area affects Notch signaling and Notch-dependent patterning. Dev. Cell 40:505–11.e6
    [Google Scholar]
  126. 126. 
    Shergill B, Meloty-Kapella L, Musse AA, Weinmaster G, Botvinick E. 2012. Optical tweezers studies on Notch: single-molecule interaction strength is independent of ligand endocytosis. Dev. Cell 22:1313–20
    [Google Scholar]
  127. 127. 
    Shimizu K, Chiba S, Kumano K, Hosoya N, Takahashi T et al. 1999. Mouse jagged1 physically interacts with notch2 and other notch receptors: assessment by quantitative methods. J. Biol. Chem. 274:32961–69
    [Google Scholar]
  128. 128. 
    Sprinzak D, Lakhanpal A, LeBon L, Garcia-Ojalvo J, Elowitz MB. 2011. Mutual inactivation of Notch receptors and ligands facilitates developmental patterning. PLOS Comput. Biol. 7:e1002069
    [Google Scholar]
  129. 129. 
    Sprinzak D, Lakhanpal A, LeBon L, Santat LA, Fontes ME et al. 2010. Cis-interactions between Notch and Delta generate mutually exclusive signalling states. Nature 465:86–90
    [Google Scholar]
  130. 130. 
    Stephenson NL, Avis JM 2012. Direct observation of proteolytic cleavage at the S2 site upon forced unfolding of the Notch negative regulatory region. PNAS 109:E2757–65
    [Google Scholar]
  131. 131. 
    Struhl G, Adachi A. 1998. Nuclear access and action of notch in vivo. Cell 93:649–60
    [Google Scholar]
  132. 132. 
    Struhl G, Greenwald I. 1999. Presenilin is required for activity and nuclear access of Notch in Drosophila. Nature 398:522–25
    [Google Scholar]
  133. 133. 
    Suckling RJ, Korona B, Whiteman P, Chillakuri C, Holt L et al. 2017. Structural and functional dissection of the interplay between lipid and Notch binding by human Notch ligands. EMBO J 36:2204–15
    [Google Scholar]
  134. 134. 
    Sun X, Artavanis-Tsakonas S. 1996. The intracellular deletions of Delta and Serrate define dominant negative forms of the Drosophila Notch ligands. Development 122:2465–74
    [Google Scholar]
  135. 135. 
    Sun X, Artavanis-Tsakonas S. 1997. Secreted forms of DELTA and SERRATE define antagonists of Notch signaling in Drosophila. Development 124:3439–48
    [Google Scholar]
  136. 136. 
    Tabaja N, Yuan Z, Oswald F, Kovall RA. 2017. Structure-function analysis of RBP-J-interacting and tubulin-associated (RITA) reveals regions critical for repression of Notch target genes. J. Biol. Chem. 292:10549–63
    [Google Scholar]
  137. 137. 
    Takeuchi H, Fernandez-Valdivia RC, Caswell DS, Nita-Lazar A, Rana NA et al. 2011. Rumi functions as both a protein O-glucosyltransferase and a protein O-xylosyltransferase. PNAS 108:16600–5
    [Google Scholar]
  138. 138. 
    Taniguchi Y, Furukawa T, Tun T, Han H, Honjo T. 1998. LIM protein KyoT2 negatively regulates transcription by association with the RBP-J DNA-binding protein. Mol. Cell. Biol. 18:644–54
    [Google Scholar]
  139. 139. 
    Taylor P, Takeuchi H, Sheppard D, Chillakuri C, Lea SM et al. 2014. Fringe-mediated extension of O-linked fucose in the ligand-binding region of Notch1 increases binding to mammalian Notch ligands. PNAS 111:7290–95
    [Google Scholar]
  140. 140. 
    Thompson BJ, Buonamici S, Sulis ML, Palomero T, Vilimas T et al. 2007. The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia. J. Exp. Med. 204:1825–35
    [Google Scholar]
  141. 141. 
    Tiyanont K, Wales TE, Aste-Amezaga M, Aster JC, Engen JR, Blacklow SC. 2011. Evidence for increased exposure of the Notch1 metalloprotease cleavage site upon conversion to an activated conformation. Structure 19:546–54
    [Google Scholar]
  142. 142. 
    Tiyanont K, Wales TE, Siebel CW, Engen JR, Blacklow SC. 2013. Insights into Notch3 activation and inhibition mediated by antibodies directed against its negative regulatory region. J. Mol. Biol. 425:3192–204
    [Google Scholar]
  143. 143. 
    Toda S, Blauch LR, Tang SKY, Morsut L, Lim WA. 2018. Programming self-organizing multicellular structures with synthetic cell-cell signaling. Science 361:156–62
    [Google Scholar]
  144. 144. 
    Tsunematsu R, Nakayama K, Oike Y, Nishiyama M, Ishida N et al. 2004. Mouse Fbw7/Sel-10/Cdc4 is required for notch degradation during vascular development. J. Biol. Chem. 279:9417–23
    [Google Scholar]
  145. 145. 
    Tveriakhina L, Schuster-Gossler K, Jarrett SM, Andrawes MB, Rohrbach M et al. 2018. The ectodomains determine ligand function in vivo and selectivity of DLL1 and DLL4 toward NOTCH1 and NOTCH2 in vitro. eLife 7:e40045
    [Google Scholar]
  146. 146. 
    Viswanathan R, Necakov A, Trylinski M, Harish RK, Krueger D et al. 2019. Optogenetic inhibition of Delta reveals digital Notch signalling output during tissue differentiation. EMBO Rep 20:e47999
    [Google Scholar]
  147. 147. 
    Vooijs M, Ong CT, Hadland B, Huppert S, Liu Z et al. 2007. Mapping the consequence of Notch1 proteolysis in vivo with NIP-CRE. Development 134:535–44
    [Google Scholar]
  148. 148. 
    Wang H, Zou J, Zhao B, Johannsen E, Ashworth T et al. 2011. Genome-wide analysis reveals conserved and divergent features of Notch1/RBPJ binding in human and murine T-lymphoblastic leukemia cells. PNAS 108:14908–13
    [Google Scholar]
  149. 149. 
    Wang W, Struhl G. 2004. Drosophila Epsin mediates a select endocytic pathway that DSL ligands must enter to activate Notch. Development 131:5367–80
    [Google Scholar]
  150. 150. 
    Wang W, Struhl G. 2005. Distinct roles for Mind bomb, Neuralized and Epsin in mediating DSL endocytosis and signaling in Drosophila. Development 132:2883–94
    [Google Scholar]
  151. 151. 
    Wang X, Ha T. 2013. Defining single molecular forces required to activate integrin and notch signaling. Science 340:991–94
    [Google Scholar]
  152. 152. 
    Wang Y, Shao L, Shi S, Harris RJ, Spellman MW et al. 2001. Modification of epidermal growth factor-like repeats with O-fucose: molecular cloning and expression of a novel GDP-fucose protein O-fucosyltransferase. J. Biol. Chem. 276:40338–45
    [Google Scholar]
  153. 153. 
    Wang Z, Wang F, Zhong J, Zhu T, Zheng Y et al. 2020. Using apelin-based synthetic Notch receptors to detect angiogenesis and treat solid tumors. Nat. Commun. 11:2163
    [Google Scholar]
  154. 154. 
    Weng AP, Ferrando AA, Lee W, Morris JP 4th, Silverman LB et al. 2004. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 306:269–71
    [Google Scholar]
  155. 155. 
    Wilson JJ, Kovall RA. 2006. Crystal structure of the CSL-Notch-Mastermind ternary complex bound to DNA. Cell 124:985–96
    [Google Scholar]
  156. 156. 
    Wu L, Aster JC, Blacklow SC, Lake R, Artavanis-Tsakonas S, Griffin JD. 2000. MAML1, a human homologue of Drosophila mastermind, is a transcriptional co-activator for NOTCH receptors. Nat. Genet. 26:484–89
    [Google Scholar]
  157. 157. 
    Wu Y, Cain-Hom C, Choy L, Hagenbeek TJ, de Leon GP et al. 2010. Therapeutic antibody targeting of individual Notch receptors. Nature 464:1052–57
    [Google Scholar]
  158. 158. 
    Xu A, Lei L, Irvine KD. 2005. Regions of Drosophila Notch that contribute to ligand binding and the modulatory influence of Fringe. J. Biol. Chem. 280:30158–65
    [Google Scholar]
  159. 159. 
    Xu T, Park SS, Giaimo BD, Hall D, Ferrante F et al. 2017. RBPJ/CBF1 interacts with L3MBTL3/MBT1 to promote repression of Notch signaling via histone demethylase KDM1A/LSD1. EMBO J 36:3232–49
    [Google Scholar]
  160. 160. 
    Xu X, Choi SH, Hu T, Tiyanont K, Habets R et al. 2015. Insights into autoregulation of Notch3 from structural and functional studies of its negative regulatory region. Structure 23:1227–35
    [Google Scholar]
  161. 161. 
    Yamamoto S, Charng WL, Rana NA, Kakuda S, Jaiswal M et al. 2012. A mutation in EGF repeat-8 of Notch discriminates between Serrate/Jagged and Delta family ligands. Science 338:1229–32
    [Google Scholar]
  162. 162. 
    Yang G, Zhou R, Zhou Q, Guo X, Yan C et al. 2019. Structural basis of Notch recognition by human gamma-secretase. Nature 565:192–97
    [Google Scholar]
  163. 163. 
    Ye Y, Lukinova N, Fortini ME. 1999. Neurogenic phenotypes and altered Notch processing in Drosophila Presenilin mutants. Nature 398:525–29
    [Google Scholar]
  164. 164. 
    Yeh E, Dermer M, Commisso C, Zhou L, McGlade CJ, Boulianne GL. 2001. Neuralized functions as an E3 ubiquitin ligase during Drosophila development. Curr. Biol. 11:1675–79
    [Google Scholar]
  165. 165. 
    Yen WC, Fischer MM, Axelrod F, Bond C, Cain J et al. 2015. Targeting Notch signaling with a Notch2/Notch3 antagonist (tarextumab) inhibits tumor growth and decreases tumor-initiating cell frequency. Clin. Cancer Res. 21:2084–95
    [Google Scholar]
  166. 166. 
    Yuan Z, Praxenthaler H, Tabaja N, Torella R, Preiss A et al. 2016. Structure and function of the Su(H)-Hairless repressor complex, the major antagonist of Notch signaling in Drosophila melanogaster. PLOS Biol 14:e1002509
    [Google Scholar]
  167. 167. 
    Yuan Z, VanderWielen BD, Giaimo BD, Pan L, Collins CE et al. 2019. Structural and functional studies of the RBPJ-SHARP complex reveal a conserved corepressor binding site. Cell Rep 26:845–54.e6
    [Google Scholar]
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