Proteolytic cleavage of Notch: "HIT and RUN"

Current Molecular Medicine

Volumn 11, Issue 4, 2011, Pages 255-269

  van Tetering, G ^a   Vooijs, M ^a,b  

^a UNIVERSITY MEDICAL CENTER UTRECHT   (Netherlands)

^b MAASTRICHT UNIVERSITY   (Netherlands)

Author keywords

ADAM metalloprotease; Cancer; Furin; GSI ( secretase inhibitor); Notch cleavage; Presenilin; secretase

Indexed keywords

ADAM PROTEIN; ADAM10 ENDOPEPTIDASE; AMYLOID BETA PRECURSOR PROTEIN; AMYLOID BETA PROTEIN; FURIN; GAMMA SECRETASE; IMATINIB; LIGAND; NOTCH RECEPTOR; NOTCH1 RECEPTOR; NOTCH2 RECEPTOR; NOTCH3 RECEPTOR; NOTCH4 RECEPTOR; PRESENILIN 1; PRESENILIN 2; SULINDAC; TUMOR NECROSIS FACTOR ALPHA CONVERTING ENZYME; UNCLASSIFIED DRUG;

ACUTE LEUKEMIA; ALZHEIMER DISEASE; CARCINOGENESIS; CELL COMMUNICATION; DIMERIZATION; EMBRYONAL TISSUE; ENDOCYTOSIS; ENZYME ACTIVITY; EUKARYOTE; GENE DELETION; GENE MUTATION; HOMEOSTASIS; HUMAN; LIGAND BINDING; MORPHOGENESIS; NONHUMAN; NUCLEAR LOCALIZATION SIGNAL; PROTEIN CLEAVAGE; PROTEIN CONFORMATION; PROTEIN DEGRADATION; PROTEIN DOMAIN; PROTEIN EXPRESSION; PROTEIN FOLDING; PROTEIN FUNCTION; PROTEIN LOCALIZATION; PROTEIN STRUCTURE; RECEPTOR BINDING; RECEPTOR LIGAND BINDING; REVIEW; SIGNAL TRANSDUCTION; T CELL LEUKEMIA; TRANSCRIPTION INITIATION;

EUKARYOTA;

EID: 79958141469     PISSN: 15665240     EISSN: 18755666     Source Type: Journal    
DOI: 10.2174/156652411795677972     Document Type: Review

References (158)

1. Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch signaling: cell fate control and signal integration in development. Science 1999; 284: 770-6.
2. Gazave E, Lapebie P, Richards GS, et al. Origin and evolution of the Notch signalling pathway: an overview from eukaryotic genomes. BMC Evol Biol 2009; 9: 249.
3. Wilson A, Radtke F. Multiple functions of Notch signaling in self-renewing organs and cancer. FEBS Lett 2006; 580: 2860-8.
4. Radtke F, Raj K. The role of Notch in tumorigenesis: oncogene or tumour suppressor? Nat Rev Cancer 2003; 3: 756-67.
5. van Es JH, van Gijn ME, Riccio O, et al. Notch/gammasecretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 2005; 435: 959-63.
6. Vooijs M, Ong CT, Hadland B, et al. Mapping the consequence of Notch1 proteolysis in vivo with NIP-CRE. Development 2007; 134: 535-44.
7. Kimble J, Simpson P. The LIN-12/Notch signaling pathway and its regulation. Annu Rev Cell Dev Biol 1997; 13: 333-61.
8. Kopan R, Ilagan MX. The canonical Notch signaling pathway: unfolding the activation mechanism. Cell 2009; 137: 216-33.
9. Moloney DJ, Panin VM, Johnston SH, et al. Fringe is a glycosyltransferase that modifies Notch. Nature 2000; 406: 369-75.
10. Okajima T, Irvine KD. Regulation of notch signaling by olinked fucose. Cell 2002; 111: 893-904.
11. Panin VM, Papayannopoulos V, Wilson R, Irvine KD. Fringe modulates Notch-ligand interactions. Nature 1997; 387: 908-12.
12. Haines N, Irvine KD. Glycosylation regulates Notch signalling. Nat Rev Mol Cell Biol 2003; 4: 786-97.
13. Christensen S, Kodoyianni V, Bosenberg M, Friedman L, Kimble J. lag-1, a gene required for lin-12 and glp-1 signaling in Caenorhabditis elegans, is homologous to human CBF1 and Drosophila Su(H). Development 1996; 122: 1373-83.
14. Fortini ME, Artavanis-Tsakonas S. The suppressor of hairless protein participates in notch receptor signaling. Cell 1994; 79: 273-82.
15. Fryer CJ, Lamar E, Turbachova I, Kintner C, Jones KA. Mastermind mediates chromatin-specific transcription and turnover of the Notch enhancer complex. Genes Dev 2002; 16: 1397-411.
16. Schroeter EH, Kisslinger JA, Kopan R. Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain. Nature 1998; 393: 382-6.
17. Stifani S, Blaumueller CM, Redhead NJ, Hill RE, Artavanis-Tsakonas S. Human homologs of a Drosophila Enhancer of split gene product define a novel family of nuclear proteins. Nat Genet 1992; 2: 343.
18. Gordon WR, Vardar-Ulu D, Histen G, et al. Structural basis for autoinhibition of Notch. Nat Struct Mol Biol 2007; 14: 295-300.
19. van Tetering G, van Diest P, Verlaan I, et al. Metalloprotease ADAM10 is required for Notch1 site 2 cleavage. J Biol Chem 2009; 284: 31018-27.
20. Weng AP, Ferrando AA, Lee W, et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 2004; 306: 269-71.
21. Blaumueller CM, Qi H, Zagouras P, Artavanis-Tsakonas S. Intracellular cleavage of Notch leads to a heterodimeric receptor on the plasma membrane. Cell 1997; 90: 281-91.
22. Kopan R, Schroeter EH, Weintraub H, Nye JS. Signal transduction by activated mNotch: importance of proteolytic processing and its regulation by the extracellular domain. Proc Natl Acad Sci USA 1996; 93: 1683-8.
23. Logeat F, Bessia C, Brou C, et al. The Notch1 receptor is cleaved constitutively by a furin-like convertase. Proc Natl Acad Sci USA 1998; 95: 8108-12.
24. Aster J, Pear W, Hasserjian R, et al. Functional analysis of the TAN-1 gene, a human homolog of Drosophila notch. Cold Spring Harb Symp Quant Biol 1994; 59: 125-36.
25. Crittenden SL, Troemel ER, Evans TC, Kimble J. GLP-1 is localized to the mitotic region of the C. elegans germ line. Development 1994; 120: 2901-11.
26. Bush G, diSibio G, Miyamoto A, et al. Ligand-induced signaling in the absence of furin processing of Notch1. Dev Biol 2001; 229: 494-502.
27. Kidd S, Lieber T. Furin cleavage is not a requirement for Drosophila Notch function. Mech Dev 2002; 115: 41-51.
28. Lake RJ, Grimm LM, Veraksa A, Banos A, Artavanis-Tsakonas S. In vivo analysis of the Notch receptor S1 cleavage. PLoS One 2009; 4: e6728.
29. Gordon WR, Vardar-Ulu D, L'Heureux S, et al. Effects of S1 cleavage on the structure, surface export, and signaling activity of human Notch1 and Notch2. PLoS One 2009; 4: e6613.
30. Watanabe K, Nagaoka T, Lee JM, et al. Enhancement of Notch receptor maturation and signaling sensitivity by Cripto-1. J Cell Biol 2009; 187: 343-53.
31. Brou C, Logeat F, Gupta N, et al. A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE. Mol Cell 2000; 5: 207-16.
32. Mumm JS, Schroeter EH, Saxena MT, et al. A ligandinduced extracellular cleavage regulates gamma-secretaselike proteolytic activation of Notch1. Mol Cell 2000; 5: 197-206.
33. Parks AL, Klueg KM, Stout JR, Muskavitch MA. Ligand endocytosis drives receptor dissociation and activation in the Notch pathway. Development 2000; 127: 1373-85.
34. Georgiadis D, Yiotakis A. Specific targeting of metzincin family members with small-molecule inhibitors: progress toward a multifarious challenge. Bioorg Med Chem 2008; 16: 8781-94.
35. Gomez-del Arco P, Kashiwagi M, Jackson AF, et al. Alternative promoter usage at the Notch1 locus supports ligand-independent signaling in T cell development and leukemogenesis. Immunity 2010; 33: 685-98.
36. Pan D, Rubin GM. Kuzbanian controls proteolytic processing of Notch and mediates lateral inhibition during Drosophila and vertebrate neurogenesis. Cell 1997; 90: 271-80.
37. Sotillos S, Roch F, Campuzano S. The metalloproteasedisintegrin Kuzbanian participates in Notch activation during growth and patterning of Drosophila imaginal discs. Development 1997; 124: 4769-79.
38. Wen C, Metzstein MM, Greenwald I. SUP-17, a Caenorhabditis elegans ADAM protein related to Drosophila KUZBANIAN, and its role in LIN-12/NOTCH signalling. Development 1997; 124: 4759-67.
39. Rooke J, Pan D, Xu T, Rubin GM. KUZ, a conserved metalloprotease-disintegrin protein with two roles in Drosophila neurogenesis. Science 1996; 273: 1227-31.
40. Fambrough D, Pan D, Rubin GM, Goodman CS. The cell surface metalloprotease/disintegrin Kuzbanian is required for axonal extension in Drosophila. Proc Natl Acad Sci USA 1996; 93: 13233-8.
41. Hattori M, Osterfield M, Flanagan JG. Regulated cleavage of a contact-mediated axon repellent. Science 2000; 289: 1360-5.
42. Jarriault S, Greenwald I. Evidence for functional redundancy between C. elegans ADAM proteins SUP-17/Kuzbanian and ADM-4/TACE. Dev Biol 2005; 287: 1-10.
43. Qi H, Rand MD, Wu X, et al. Processing of the notch ligand delta by the metalloprotease Kuzbanian. Science 1999; 283: 91-4.
44. Varnum-Finney B, Wu L, Yu M, et al. Immobilization of Notch ligand, Delta-1, is required for induction of notch signaling. J Cell Sci 2000; 113 Pt 23: 4313-8.
45. Mishra-Gorur K, Rand MD, Perez-Villamil B, Artavanis-Tsakonas S. Down-regulation of Delta by proteolytic processing. J Cell Biol 2002; 159: 313-24.
46. LaVoie MJ, Selkoe DJ. The Notch ligands, Jagged and Delta, are sequentially processed by alpha-secretase and presenilin/gamma-secretase and release signaling fragments. J Biol Chem 2003; 278: 34427-37.
47. Six E, Ndiaye D, Laabi Y, et al. The Notch ligand Delta1 is sequentially cleaved by an ADAM protease and gammasecretase. Proc Natl Acad Sci USA 2003; 100: 7638-43.
48. Fiuza UM, Klein T, Martinez Arias A, Hayward P. Mechanisms of ligand-mediated inhibition in Notch signaling activity in Drosophila. Dev Dyn 2010; 239: 798-805.
49. Sapir A, Assa-Kunik E, Tsruya R, Schejter E, Shilo BZ. Unidirectional Notch signaling depends on continuous cleavage of Delta. Development 2005; 132: 123-32.
50. Vooijs M, Schroeter EH, Pan Y, Blandford M, Kopan R. Ectodomain shedding and intramembrane cleavage of mammalian Notch proteins is not regulated through oligomerization. J Biol Chem 2004; 279: 50864-73.
51. Lieber T, Kidd S, Young MW. kuzbanian-mediated cleavage of Drosophila Notch. Genes Dev 2002; 16: 209-21.
52. Conlon RA, Reaume AG, Rossant J. Notch1 is required for the coordinate segmentation of somites. Development 1995; 121: 1533-45.
53. Huppert SS, Le A, Schroeter EH, et al. Embryonic lethality in mice homozygous for a processing-deficient allele of Notch1. Nature 2000; 405: 966-70.
54. Swiatek PJ, Lindsell CE, del Amo FF, Weinmaster G, Gridley T. Notch1 is essential for postimplantation development in mice. Genes Dev 1994; 8: 707-19.
55. Radtke F, Wilson A, Stark G, et al. Deficient T cell fate specification in mice with an induced inactivation of Notch1. Immunity 1999; 10: 547-58.
56. Peschon JJ, Slack JL, Reddy P, et al. An essential role for ectodomain shedding in mammalian development. Science 1998; 282: 1281-4.
57. Hartmann D, de Strooper B, Serneels L, et al. The disintegrin/metalloprotease ADAM 10 is essential for Notch signalling but not for alpha-secretase activity in fibroblasts. Hum Mol Genet 2002; 11: 2615-24.
58. Manilay JO, Anderson AC, Kang C, Robey EA. Impairment of thymocyte development by dominant-negative Kuzbanian (ADAM-10) is rescued by the Notch ligand, delta-1. J Immunol 2005; 174: 6732-41.
59. Tian L, Wu X, Chi C, et al. ADAM10 is essential for proteolytic activation of Notch during thymocyte development. Int Immunol 2008; 20: 1181-7.
60. Gibb DR, El Shikh M, Kang DJ, et al. ADAM10 is essential for Notch2-dependent marginal zone B cell development and CD23 cleavage in vivo. J Exp Med 2010; 207: 623-35.
61. Jorissen E, Prox J, Bernreuther C, et al. The disintegrin/metalloproteinase ADAM10 is essential for the establishment of the brain cortex. J Neurosci 2010; 30: 4833-44.
62. Borrell-Pages M, Rojo F, Albanell J, Baselga J, Arribas J. TACE is required for the activation of the EGFR by TGFalpha in tumors. EMBO J 2003; 22: 1114-24.
63. Delwig A, Rand MD. Kuz and TACE can activate Notch independent of ligand. Cell Mol Life Sci 2008; 65: 2232-43.
64. Tousseyn T, Thathiah A, Jorissen E, et al. ADAM10, the ratelimiting protease of regulated intramembrane proteolysis of Notch and other proteins, is processed by ADAMS-9, ADAMS-15, and the gamma-secretase. J Biol Chem 2009; 284: 11738-47.
65. Nichols JT, Miyamoto A, Olsen SL, et al. DSL ligand endocytosis physically dissociates Notch1 heterodimers before activating proteolysis can occur. J Cell Biol 2007; 176: 445-58.
66. Struhl G, Adachi A. Requirements for presenilin-dependent cleavage of notch and other transmembrane proteins. Mol Cell 2000; 6: 625-36.
67. Seugnet L, Simpson P, Haenlin M. Requirement for dynamin during Notch signaling in Drosophila neurogenesis. Dev Biol 1997; 192: 585-98.
68. Greenwald I. Structure/function studies of lin-12/Notch proteins. Curr Opin Genet Dev 1994; 4: 556-62.
69. Lieber T, Kidd S, Alcamo E, Corbin V, Young MW. Antineurogenic phenotypes induced by truncated Notch proteins indicate a role in signal transduction and may point to a novel function for Notch in nuclei. Genes Dev 1993; 7: 1949-65.
70. Sanchez-Irizarry C, Carpenter AC, Weng AP, et al. Notch subunit heterodimerization and prevention of ligandindependent proteolytic activation depend, respectively, on a novel domain and the LNR repeats. Mol Cell Biol 2004; 24: 9265-73.
71. Malecki MJ, Sanchez-Irizarry C, Mitchell JL, et al. Leukemiaassociated mutations within the NOTCH1 heterodimerization domain fall into at least two distinct mechanistic classes. Mol Cell Biol 2006; 26: 4642-51.
72. Sulis ML, Williams O, Palomero T, et al. NOTCH1 extracellular juxtamembrane expansion mutations in T-ALL. Blood 2008; 112: 733-40.
73. Bozkulak EC, Weinmaster G. Selective use of ADAM10 and ADAM17 in activation of Notch1 signaling. Mol Cell Biol 2009; 29: 5679-95.
74. Asai M, Hattori C, Szabo B, et al. Putative function of ADAM9, ADAM10, and ADAM17 as APP alpha-secretase. Biochem Biophys Res Commun 2003; 301: 231-5.
75. Dyczynska E, Sun D, Yi H, et al. Proteolytic processing of delta-like 1 by ADAM proteases. J Biol Chem 2007; 282: 436-44.
76. Sawey ET, Johnson JA, Crawford HC. Matrix metalloproteinase 7 controls pancreatic acinar cell transdifferentiation by activating the Notch signaling pathway. Proc Natl Acad Sci USA 2007; 104: 19327-32.
77. Saxena MT, Schroeter EH, Mumm JS, Kopan R. Murine notch homologs (N1-4) undergo presenilin-dependent proteolysis. J Biol Chem 2001; 276: 40268-73.
78. Li K, Li Y, Wu W, et al. Modulation of Notch signaling by antibodies specific for the extracellular negative regulatory region of NOTCH3. J Biol Chem 2008; 283: 8046-54.
79. Petcherski AG, Kimble J. Mastermind is a putative activator for Notch. Curr Biol 2000; 10: R471-3.
80. Tamura K, Taniguchi Y, Minoguchi S, et al. Physical interaction between a novel domain of the receptor Notch and the transcription factor RBP-J kappa/Su(H). Curr Biol 1995; 5: 1416-23.
81. Jarriault S, Brou C, Logeat F, et al. Signalling downstream of activated mammalian Notch. Nature 1995; 377: 355-8.
82. Barrick D, Kopan R. The Notch transcription activation complex makes its move. Cell 2006; 124: 883-5.
83. Lubman OY, Korolev SV, Kopan R. Anchoring notch genetics and biochemistry; structural analysis of the ankyrin domain sheds light on existing data. Mol Cell 2004; 13: 619-26.
84. Wilson JJ, Kovall RA. Crystal structure of the CSL-Notch-Mastermind ternary complex bound to DNA. Cell 2006; 124: 985-96.
85. Nam Y, Sliz P, Song L, Aster JC, Blacklow SC. Structural basis for cooperativity in recruitment of MAML coactivators to Notch transcription complexes. Cell 2006; 124: 973-83.
86. Kurooka H, Kuroda K, Honjo T. Roles of the ankyrin repeats and C-terminal region of the mouse notch1 intracellular region. Nucleic Acids Res 1998; 26: 5448-55.
87. Kato H, Taniguchi Y, Kurooka H, et al. Involvement of RBP-J in biological functions of mouse Notch1 and its derivatives. Development 1997; 124: 4133-41.
88. Aster JC, Xu L, Karnell FG, et al. Essential roles for ankyrin repeat and transactivation domains in induction of T-cell leukemia by notch1. Mol Cell Biol 2000; 20: 7505-15.
89. Struhl G, Adachi A. Nuclear access and action of notch in vivo. Cell 1998; 93: 649-60.
90. Sanalkumar R, Dhanesh SB, James J. Non-canonical activation of Notch signaling/target genes in vertebrates. Cell Mol Life Sci 2010; 67: 2957-68.
91. Fortini ME, Rebay I, Caron LA, Artavanis-Tsakonas S. An activated Notch receptor blocks cell-fate commitment in the developing Drosophila eye. Nature 1993; 365: 555-7.
92. Struhl G, Fitzgerald K, Greenwald I. Intrinsic activity of the Lin-12 and Notch intracellular domains in vivo. Cell 1993; 74: 331-45.
93. Kopan R, Nye JS, Weintraub H. The intracellular domain of mouse Notch: a constitutively activated repressor of myogenesis directed at the basic helix-loop-helix region of MyoD. Development 1994; 120: 2385-96.
94. Coffman CR, Skoglund P, Harris WA, Kintner CR. Expression of an extracellular deletion of Xotch diverts cell fate in Xenopus embryos. Cell 1993; 73: 659-71.
95. Rebay I, Fehon RG, Artavanis-Tsakonas S. Specific truncations of Drosophila Notch define dominant activated and dominant negative forms of the receptor. Cell 1993; 74: 319-29.
96. Pear WS, Aster JC, Scott ML, et al. Exclusive development of T cell neoplasms in mice transplanted with bone marrow expressing activated Notch alleles. J Exp Med 1996; 183: 2283-91.
97. Shawber C, Nofziger D, Hsieh JJ, et al. Notch signaling inhibits muscle cell differentiation through a CBF1-independent pathway. Development 1996; 122: 3765-73.
98. Lecourtois M, Schweisguth F. Indirect evidence for Deltadependent intracellular processing of notch in Drosophila embryos. Curr Biol 1998; 8: 771-4.
99. Kidd S, Lieber T, Young MW. Ligand-induced cleavage and regulation of nuclear entry of Notch in Drosophila melanogaster embryos. Genes Dev 1998; 12: 3728-40.
100. Struhl G, Greenwald I. Presenilin is required for activity and nuclear access of Notch in Drosophila. Nature 1999; 398: 522-5.
101. Tokunaga A, Kohyama J, Yoshida T, et al. Mapping spatiotemporal activation of Notch signaling during neurogenesis and gliogenesis in the developing mouse brain. J Neurochem 2004; 90: 142-54.
102. Cheng HT, Kim M, Valerius MT, et al. Notch2, but not Notch1, is required for proximal fate acquisition in the mammalian nephron. Development 2007; 134: 801-11.
103. Pan Y, Lin MH, Tian X, et al. gamma-secretase functions through Notch signaling to maintain skin appendages but is not required for their patterning or initial morphogenesis. Dev Cell 2004; 7: 731-43.
104. Ong CT, Cheng HT, Chang LW, et al. Target selectivity of vertebrate notch proteins. Collaboration between discrete domains and CSL-binding site architecture determines activation probability. J Biol Chem 2006; 281: 5106-19.
105. Varshavsky A. The N-end rule pathway of protein degradation. Genes Cells 1997; 2: 13-28.
106. Blat Y, Meredith JE, Wang Q, et al. Mutations at the P1' position of Notch1 decrease intracellular domain stability rather than cleavage by gamma-secretase. Biochem Biophys Res Commun 2002; 299: 569-73.
107. Chandu D, Huppert SS, Kopan R. Analysis of transmembrane domain mutants is consistent with sequential cleavage of Notch by gamma-secretase. J Neurochem 2006; 96: 228-35.
108. Kelly DF, Lake RJ, Middelkoop TC, et al. Molecular structure and dimeric organization of the Notch extracellular domain as revealed by electron microscopy. PLoS One 2010; 5: e10532.
109. Richter L, Munter LM, Ness J, et al. Amyloid beta 42 peptide (Abeta42)-lowering compounds directly bind to Abeta and interfere with amyloid precursor protein (APP) transmembrane dimerization. Proc Natl Acad Sci USA 2010; 107: 14597-602.
110. Liu H, Chi AW, Arnett KL, et al. Notch dimerization is required for leukemogenesis and T-cell development. Genes Dev 2010; 24: 2395-407.
111. Mizutani T, Taniguchi Y, Aoki T, Hashimoto N, Honjo T. Conservation of the biochemical mechanisms of signal transduction among mammalian Notch family members. Proc Natl Acad Sci USA 2001; 98: 9026-31.
112. Levitan D, Greenwald I. Facilitation of lin-12-mediated signalling by sel-12, a Caenorhabditis elegans S182 Alzheimer's disease gene. Nature 1995; 377: 351-4.
113. Li X, Greenwald I. HOP-1, a Caenorhabditis elegans presenilin, appears to be functionally redundant with SEL-12 presenilin and to facilitate LIN-12 and GLP-1 signaling. Proc Natl Acad Sci USA 1997; 94: 12204-9.
114. Levitan D, Greenwald I. Effects of SEL-12 presenilin on LIN-12 localization and function in Caenorhabditis elegans. Development 1998; 125: 3599-606.
115. Shen J, Bronson RT, Chen DF, et al. Skeletal and CNS defects in Presenilin-1-deficient mice. Cell 1997; 89: 629-39.
116. Wong PC, Zheng H, Chen H, et al. Presenilin 1 is required for Notch1 and DII1 expression in the paraxial mesoderm. Nature 1997; 387: 288-92.
117. Herreman A, Hartmann D, Annaert W, et al. Presenilin 2 deficiency causes a mild pulmonary phenotype and no changes in amyloid precursor protein processing but enhances the embryonic lethal phenotype of presenilin 1 deficiency. Proc Natl Acad Sci USA 1999; 96: 11872-7.
118. Herreman A, Serneels L, Annaert W, et al. Total inactivation of gamma-secretase activity in presenilin-deficient embryonic stem cells. Nat Cell Biol 2000; 2: 461-2.
119. Rozmahel R, Huang J, Chen F, et al. Normal brain development in PS1 hypomorphic mice with markedly reduced gamma-secretase cleavage of betaAPP. Neurobiol Aging 2002; 23: 187-94.
120. Rozmahel R, Mount HT, Chen F, et al. Alleles at the Nicastrin locus modify presenilin 1-deficiency phenotype. Proc Natl Acad Sci USA 2002; 99: 14452-7.
121. Mastrangelo P, Mathews PM, Chishti MA, et al. Dissociated phenotypes in presenilin transgenic mice define functionally distinct gamma-secretases. Proc Natl Acad Sci USA 2005; 102: 8972-7.
122. Netzer WJ, Dou F, Cai D, et al. Gleevec inhibits beta-amyloid production but not Notch cleavage. Proc Natl Acad Sci USA 2003; 100: 12444-9.
123. He G, Luo W, Li P, et al. Gamma-secretase activating protein is a therapeutic target for Alzheimer's disease. Nature 2010; 467: 95-8.
124. Takahashi Y, Hayashi I, Tominari Y, et al. Sulindac sulfide is a noncompetitive gamma-secretase inhibitor that preferentially reduces Abeta 42 generation. J Biol Chem 2003; 278: 18664-70.
125. Weggen S, Eriksen JL, Das P, et al. A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature 2001; 414: 212-6.
126. De Strooper B, Annaert W, Cupers P, et al. A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature 1999; 398: 518-22.
127. De Strooper B, Saftig P, Craessaerts K, et al. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 1998; 391: 387-90.
128. Ray WJ, Yao M, Nowotny P, et al. Evidence for a physical interaction between presenilin and Notch. Proc Natl Acad Sci USA 1999; 96: 3263-8.
129. Ye Y, Lukinova N, Fortini ME. Neurogenic phenotypes and altered Notch processing in Drosophila Presenilin mutants. Nature 1999; 398: 525-9.
130. Wolfe MS, Xia W, Ostaszewski BL, et al. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature 1999; 398: 513-7.
131. Ray WJ, Yao M, Mumm J, et al. Cell surface presenilin-1 participates in the gamma-secretase-like proteolysis of Notch. J Biol Chem 1999; 274: 36801-7.
132. Podlisny MB, Citron M, Amarante P, et al. Presenilin proteins undergo heterogeneous endoproteolysis between Thr291 and Ala299 and occur as stable N-and C-terminal fragments in normal and Alzheimer brain tissue. Neurobiol Dis 1997; 3: 325-37.
133. Thinakaran G, Borchelt DR, Lee MK, et al. Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo. Neuron 1996; 17: 181-90.
134. Levitan D, Lee J, Song L, et al. PS1 N-and C-terminal fragments form a complex that functions in APP processing and Notch signaling. Proc Natl Acad Sci USA 2001; 98: 12186-90.
135. Yu G, Nishimura M, Arawaka S, et al. Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing. Nature 2000; 407: 48-54.
136. Chen F, Yu G, Arawaka S, et al. Nicastrin binds to membrane-tethered Notch. Nat Cell Biol 2001; 3: 751-4.
137. Shirotani K, Edbauer D, Prokop S, Haass C, Steiner H. Identification of distinct gamma-secretase complexes with different APH-1 variants. J Biol Chem 2004; 279: 41340-5.
138. Goutte C, Tsunozaki M, Hale VA, Priess JR. APH-1 is a multipass membrane protein essential for the Notch signaling pathway in Caenorhabditis elegans embryos. Proc Natl Acad Sci USA 2002; 99: 775-9.
139. Francis R, McGrath G, Zhang J, et al. aph-1 and pen-2 are required for Notch pathway signaling, gamma-secretase cleavage of betaAPP, and presenilin protein accumulation. Dev Cell 2002; 3: 85-97.
140. Esler WP, Kimberly WT, Ostaszewski BL, et al. Activitydependent isolation of the presenilin-gamma-secretase complex reveals nicastrin and a gamma substrate. Proc Natl Acad Sci USA 2002; 99: 2720-5.
141. Edbauer D, Winkler E, Regula JT, et al. Reconstitution of gamma-secretase activity. Nat Cell Biol 2003; 5: 486-8.
142. Kimberly WT, LaVoie MJ, Ostaszewski BL, et al. Gammasecretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2. Proc Natl Acad Sci USA 2003; 100: 6382-7.
143. Shah S, Lee SF, Tabuchi K, et al. Nicastrin functions as a gamma-secretase-substrate receptor. Cell 2005; 122: 435-47.
144. Zhao G, Liu Z, Ilagan MX, Kopan R. Gamma-secretase composed of PS1/Pen2/Aph1a can cleave notch and amyloid precursor protein in the absence of nicastrin. J Neurosci 2010; 30: 1648-56.
145. Hebert SS, Serneels L, Dejaegere T, et al. Coordinated and widespread expression of gamma-secretase in vivo: evidence for size and molecular heterogeneity. Neurobiol Dis 2004; 17: 260-72.
146. Dejaegere T, Serneels L, Schafer MK, et al. Deficiency of Aph1B/C-gamma-secretase disturbs Nrg1 cleavage and sensorimotor gating that can be reversed with antipsychotic treatment. Proc Natl Acad Sci USA 2008; 105: 9775-80.
147. Ma G, Li T, Price DL, Wong PC. APH-1a is the principal mammalian APH-1 isoform present in gamma-secretase complexes during embryonic development. J Neurosci 2005; 25: 192-8.
148. Serneels L, Dejaegere T, Craessaerts K, et al. Differential contribution of the three Aph1 genes to gamma-secretase activity in vivo. Proc Natl Acad Sci USA 2005; 102: 1719-24.
149. Sato T, Diehl TS, Narayanan S, et al. Active gammasecretase complexes contain only one of each component. J Biol Chem 2007; 282: 33985-93.
150. Takasugi N, Tomita T, Hayashi I, et al. The role of presenilin cofactors in the gamma-secretase complex. Nature 2003; 422: 438-41.
151. Ahn K, Shelton CC, Tian Y, et al. Activation and intrinsic {gamma}-secretase activity of presenilin 1. Proc Natl Acad Sci USA 2010; 107: 21435-40.
152. De Strooper B, Annaert W. Novel research horizons for presenilins and gamma-secretases in cell biology and disease. Annu Rev Cell Dev Biol 2010; 26: 235-60.
153. Berechid BE, Kitzmann M, Foltz DR, et al. Identification and characterization of presenilin-independent Notch signaling. J Biol Chem 2002; 277: 8154-65.
154. Huppert SS, Ilagan MX, De Strooper B, Kopan R. Analysis of Notch function in presomitic mesoderm suggests a gammasecretase-independent role for presenilins in somite differentiation. Dev Cell 2005; 8: 677-88.
155. Okochi M, Steiner H, Fukumori A, et al. Presenilins mediate a dual intramembranous gamma-secretase cleavage of Notch-1. EMBO J 2002; 21: 5408-16.
156. Tanii H, Jiang J, Fukumori A, et al. Effect of valine on the efficiency and precision at S4 cleavage of the Notch-1 transmembrane domain. J Neurosci Res 2006; 84: 918-25.
157. Gupta-Rossi N, Six E, LeBail O, et al. Monoubiquitination and endocytosis direct gamma-secretase cleavage of activated Notch receptor. J Cell Biol 2004; 166: 73-83.
158. Tagami S, Okochi M, Yanagida K, et al. Regulation of Notch signaling by dynamic changes in the precision of S3 cleavage of Notch-1. Mol Cell Biol 2008; 28: 165-76.