γ-Secretase and the intramembrane proteolysis of Notch

Current Topics in Developmental Biology

Volumn 92, Issue C, 2010, Pages 201-230

  Jorissen, Ellen ^a   De Strooper, Bart ^a  

^a UNIVERSITY OF LEUVEN   (Belgium)

Author keywords

[No Author keywords available]

Indexed keywords

NOTCH RECEPTOR; SECRETASE;

ALZHEIMER DISEASE; ANIMAL; BOOK; CHEMISTRY; DRUG ANTAGONISM; HUMAN; METABOLISM; NEOPLASM; PHYSIOLOGY; PROTEIN PROCESSING; SIGNAL TRANSDUCTION;

ALZHEIMER DISEASE; AMYLOID PRECURSOR PROTEIN SECRETASES; ANIMALS; HUMANS; NEOPLASMS; PROTEIN PROCESSING, POST-TRANSLATIONAL; RECEPTORS, NOTCH; SIGNAL TRANSDUCTION;

EID: 77956315469     PISSN: 00702153     EISSN: None     Source Type: Book Series    
DOI: 10.1016/S0070-2153(10)92006-1     Document Type: Book

References (207)

1. The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families. Nat. Genet. 1995, 11:219-222. Alzheimer's_Disease_Collaborative_Group.
2. Anderson J.J., Holtz G., Baskin P.P., Turner M., Rowe B., Wang B., Kounnas M.Z., Lamb B.T., Barten D., Felsenstein K., McDonald I., Srinivasan K., et al. Reductions in beta-amyloid concentrations in vivo by the gamma-secretase inhibitors BMS-289948 and BMS-299897. Biochem. Pharmacol. 2005, 69:689-698.
3. Anderton B.H., Dayanandan R., Killick R., Lovestone S. Does dysregulation of the Notch and wingless/Wnt pathways underlie the pathogenesis of Alzheimer's disease?. Mol. Med. Today 2000, 6:54-59.
4. Annaert W., De Strooper B. Presenilins: molecular switches between proteolysis and signal transduction. Trends. Neurosci. 1999, 22:439-443.
5. Annaert W.G., Esselens C., Baert V., Boeve C., Snellings G., Cupers P., Craessaerts K., De Strooper B. Interaction with telencephalin and the amyloid precursor protein predicts a ring structure for presenilins. Neuron 2001, 32:579-589.
6. Araki W., Saito S., Takahashi-Sasaki N., Shiraishi H., Komano H., Murayama K.S. Characterization of APH-1 mutants with a disrupted transmembrane GxxxG motif. J. Mol. Neurosci. 2006, 29:35-43.
7. Bachmair A., Finley D., Varshavsky A. In vivo half-life of a protein is a function of its amino-terminal residue. Science 1986, 234:179-186.
8. Barten D.M., Guss V.L., Corsa J.A., Loo A., Hansel S.B., Zheng M., Munoz B., Srinivasan K., Wang B., Robertson B.J., Polson C.T., Wang J., et al. Dynamics of {beta}-amyloid reductions in brain, cerebrospinal fluid, and plasma of {beta}-amyloid precursor protein transgenic mice treated with a {gamma}-secretase inhibitor. J. Pharmacol. Exp. Ther. 2005, 312:635-643.
9. Bateman R.J., Siemers E.R., Mawuenyega K.G., Wen G., Browning K.R., Sigurdson W.C., Yarasheski K.E., Friedrich S.W., Demattos R.B., May P.C., Paul S.M., Holtzman D.M. A gamma-secretase inhibitor decreases amyloid-beta production in the central nervous system. Ann. Neurol. 2009, 66:48-54.
10. Baulac S., LaVoie M.J., Kimberly W.T., Strahle J., Wolfe M.S., Selkoe D.J., Xia W. Functional gamma-secretase complex assembly in Golgi/trans-Golgi network: interactions among presenilin, nicastrin, Aph1, Pen-2, and gamma-secretase substrates. Neurobiol. Dis. 2003, 14:194-204.
11. Beher D., Clarke E.E., Wrigley J.D., Martin A.C., Nadin A., Churcher I., Shearman M.S. Selected non-steroidal anti-inflammatory drugs and their derivatives target gamma-secretase at a novel site. Evidence for an allosteric mechanism. J. Biol. Chem. 2004, 279:43419-43426.
12. Bentahir M., Nyabi O., Verhamme J., Tolia A., Horre K., Wiltfang J., Esselmann H., De Strooper B. Presenilin clinical mutations can affect gamma-secretase activity by different mechanisms. J. Neurochem. 2006, 96:732-742.
13. Berechid B.E., Thinakaran G., Wong P.C., Sisodia S.S., Nye J.S. Lack of requirement for presenilin1 in Notch1 signaling. Curr. Biol. 1999, 9:1493-1496.
14. Berezovska O., Jack C., McLean P., Aster J.C., Hicks C., Xia W., Wolfe M.S., Kimberly W.T., Weinmaster G., Selkoe D.J., Hyman B.T. Aspartate mutations in presenilin and gamma-secretase inhibitors both impair notch1 proteolysis and nuclear translocation with relative preservation of notch1 signaling. J. Neurochem. 2000, 75:583-593.
15. Berezovska O., Lleo A., Herl L.D., Frosch M.P., Stern E.A., Bacskai B.J., Hyman B.T. Familial Alzheimer's disease presenilin 1 mutations cause alterations in the conformation of presenilin and interactions with amyloid precursor protein. J. Neurosci. 2005, 25:3009-3017.
16. Bergman A., Laudon H., Winblad B., Lundkvist J., Naslund J. The extreme C terminus of presenilin 1 is essential for gamma-secretase complex assembly and activity. J. Biol. Chem. 2004, 279:45564-45572.
17. Best J.D., Jay M.T., Otu F., Ma J., Nadin A., Ellis S., Lewis H.D., Pattison C., Reilly M., Harrison T., Shearman M.S., Williamson T.L., et al. Quantitative measurement of changes in amyloid-beta(40) in the rat brain and cerebrospinal fluid following treatment with the gamma-secretase inhibitor LY-411575 [N2-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-ox o-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide]. J. Pharmacol. Exp. Ther. 2005, 313:902-908.
18. Bihel F., Das C., Bowman M.J., Wolfe M.S. Discovery of a Subnanomolar helical D-tridecapeptide inhibitor of gamma-secretase. J. Med. Chem. 2004, 47:3931-3933.
19. Blaumueller C.M., Qi H., Zagouras P., Artavanis-Tsakonas S. Intracellular cleavage of Notch leads to a heterodimeric receptor on the plasma membrane. Cell 1997, 90:281-291.
20. Boucheix C., Rubinstein E. Tetraspanins. Cell Mol. Life Sci. 2001, 58:1189-1205.
21. Bozkulak E.C., Weinmaster G. Selective use of ADAM10 and ADAM17 in activation of Notch1 signaling. Mol Cell Biol. 2009, 29(21):5679-5695.
22. Brou C., Logeat F., Gupta N., Bessia C., LeBail O., Doedens J.R., Cumano A., Roux P., Black R.A., Israel A. A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE. Mol. Cell 2000, 5:207-216.
23. Brown M.S., Ye J., Rawson R.B., Goldstein J.L. Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans. Cell 2000, 100:391-398.
24. Cagavi Bozkulak E., Weinmaster G. Selective use of Adam10 and Adam17 in activation of Notch1 signaling. Mol. Cell. Biol. 2009, 29(21):5679-5695.
25. Cai D., Netzer W.J., Zhong M., Lin Y., Du G., Frohman M., Foster D.A., Sisodia S.S., Xu H., Gorelick F.S., Greengard P. Presenilin-1 uses phospholipase D1 as a negative regulator of beta-amyloid formation. Proc. Natl. Acad. Sci. U.S.A. 2006, 103:1941-1946.
26. Chandu D., Huppert S.S., Kopan R. Analysis of transmembrane domain mutants is consistent with sequential cleavage of Notch by gamma-secretase. J. Neurochem. 2006, 96:228-235.
27. Chavez-Gutierrez L., Tolia A., Maes E., Li T., Wong P.C., de Strooper B. Glu(332) in the Nicastrin ectodomain is essential for gamma-secretase complex maturation but not for its activity. J. Biol. Chem. 2008, 283:20096-20105.
28. Chen F., Yu G., Arawaka S., Nishimura M., Kawarai T., Yu H., Tandon A., Supala A., Song Y.Q., Rogaeva E., Milman P., Sato C., et al. Nicastrin binds to membrane-tethered Notch. Nat. Cell Biol. 2001, 3:751-754.
29. Cheng H., Vetrivel K.S., Drisdel R.C., Meckler X., Gong P., Leem J.Y., Li T., Carter M., Chen Y., Nguyen P., Iwatsubo T., Tomita T., et al. S-palmitoylation of gamma-secretase subunits nicastrin and APH-1. J. Biol. Chem. 2009, 284:1373-1384.
30. Chung H.M., Struhl G. Nicastrin is required for Presenilin-mediated transmembrane cleavage in Drosophila. Nat. Cell Biol. 2001, 3:1129-1132.
31. Cole S.L., Vassar R. BACE1 structure and function in health and Alzheimer's disease. Curr. Alzheimer Res. 2008, 5:100-120.
32. Crystal A.S., Morais V.A., Pierson T.C., Pijak D.S., Carlin D., Lee V.M., Doms R.W. Membrane topology of gamma-secretase component PEN-2. J. Biol. Chem. 2003, 278:20117-20123.
33. Cullion K., Draheim K.M., Hermance N., Tammam J., Sharma V.M., Ware C., Nikov G., Krishnamoorthy V., Majumder P.K., Kelliher M.A. Targeting the Notch1 and mTOR pathways in a mouse T-ALL model. Blood 2009, 113:6172-6181.
34. Dang T.P., Gazdar A.F., Virmani A.K., Sepetavec T., Hande K.R., Minna J.D., Roberts J.R., Carbone D.P. Chromosome 19 translocation, overexpression of Notch3, and human lung cancer. J. Natl. Cancer Inst. 2000, 92:1355-1357.
35. Das C., Berezovska O., Diehl T.S., Genet C., Buldyrev I., Tsai J.Y., Hyman B.T., Wolfe M.S. Designed helical peptides inhibit an intramembrane protease. J. Am. Chem. Soc. 2003, 125:11794-11795.
36. de la Pompa J.L., Wakeham A., Correia K.M., Samper E., Brown S., Aguilera R.J., Nakano T., Honjo T., Mak T.W., Rossant J., Conlon R.A. Conservation of the Notch signalling pathway in mammalian neurogenesis. Development 1997, 124:1139-1148.
37. De Strooper B. Aph-1, Pen-2, and Nicastrin with Presenilin generate an active gamma-Secretase complex. Neuron 2003, 38:9-12.
38. De Strooper B., Annaert W. Where Notch and Wnt signaling meet. The presenilin hub. J. Cell Biol. 2001, 152:F17-F20.
39. De Strooper B., Annaert W., Cupers P., Saftig P., Craessaerts K., Mumm J.S., Schroeter E.H., Schrijvers V., Wolfe M.S., Ray W.J., Goate A., Kopan R. A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature 1999, 398:518-522.
40. De Strooper B., Saftig P., Craessaerts K., Vanderstichele H., Guhde G., Annaert W., Von Figura K., Van Leuven F. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 1998, 391:387-390.
41. DeAngelo D.J., Stone R.M., Heaney M.L., Nimer S.D., Paquette R.L., Klisovic R.B., Caligiuri M.A., Cooper M.R., Lecerf J.M., Karol M.D., Sheng S., Holford N., et al. Phase 1 clinical results with tandutinib (MLN518), a novel FLT3 antagonist, in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome: safety, pharmacokinetics, and pharmacodynamics. Blood 2006, 108:3674-3681.
42. Dejaegere T., Serneels L., Schafer M.K., Van Biervliet J., Horre K., Depboylu C., Alvarez-Fischer D., Herreman A., Willem M., Haass C., Hoglinger G.U., D'Hooge R., 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. U.S.A. 2008, 105:9775-9780.
43. Demehri S., Turkoz A., Kopan R. Epidermal Notch1 loss promotes skin tumorigenesis by impacting the stromal microenvironment. Cancer Cell. 2009, 16:55-66.
44. Donoviel D.B., Hadjantonakis A.K., Ikeda M., Zheng H., Hyslop P.S., Bernstein A. Mice lacking both presenilin genes exhibit early embryonic patterning defects. Genes Dev. 1999, 13:2801-2810.
45. Dovey H.F., John V., Anderson J.P., Chen L.Z., de Saint Andrieu P., Fang L.Y., Freedman S.B., Folmer B., Goldbach E., Holsztynska E.J., Hu K.L., Johnson-Wood K.L., et al. Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain. J. Neurochem. 2001, 76:173-181.
46. Dries D.R., Shah S., Han Y.H., Yu C., Yu S., Shearman M.S., Yu G. Glu-333 of nicastrin directly participates in gamma-secretase activity. J. Biol. Chem. 2009, 284:29714-29724.
47. D'Souza B., Miyamoto A., Weinmaster G. The many facets of Notch ligands. Oncogene 2008, 27:5148-5167.
48. Edbauer D., Winkler E., Haass C., Steiner H. Presenilin and nicastrin regulate each other and determine amyloid beta-peptide production via complex formation. Proc. Natl. Acad. Sci. U.S.A. 2002, 99:8666-8671.
49. Edbauer D., Winkler E., Regula J.T., Pesold B., Steiner H., Haass C. Reconstitution of gamma-secretase activity. Nat. Cell Biol. 2003, 5:486-488.
50. Engin F., Bertin T., Ma O., Jiang M.M., Wang L., Sutton R.E., Donehower L.A., Lee B. Notch signaling contributes to the pathogenesis of human osteosarcomas. Hum. Mol. Genet. 2009, 18:1464-1470.
51. Eriksen J.L., Sagi S.A., Smith T.E., Weggen S., Das P., McLendon D.C., Ozols V.V., Jessing K.W., Zavitz K.H., Koo E.H., Golde T.E. NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta 42 in vivo. J. Clin. Invest. 2003, 112:440-449.
52. Esler W.P., Kimberly W.T., Ostaszewski B.L., Diehl T.S., Moore C.L., Tsai J.Y., Rahmati T., Xia W., Selkoe D.J., Wolfe M.S. Transition-state analogue inhibitors of gamma-secretase bind directly to presenilin-1. Nat. Cell Biol. 2000, 2:428-434.
53. Esler W.P., Kimberly W.T., Ostaszewski B.L., Ye W., Diehl T.S., Selkoe D.J., Wolfe M.S. Activity-dependent isolation of the presenilin- gamma -secretase complex reveals nicastrin and a gamma substrate. Proc. Natl. Acad. Sci. U.S.A. 2002, 99:2720-2725.
54. Fagan T. DC: New γ Secretase Inhibitors Hit APP, Spare Notch. The AlzGene Database 2008, Alzheimer Research Forum [online]. http://www.alzforum.org/new/detail.asp?id=1992.
55. Fortna R.R., Crystal A.S., Morais V.A., Pijak D.S., Lee V.M., Doms R.W. Membrane topology and nicastrin-enhanced endoproteolysis of APH-1, a component of the gamma-secretase complex. J. Biol. Chem. 2004, 279:3685-3693.
56. Fraering P.C., Ye W., LaVoie M.J., Ostaszewski B.L., Selkoe D.J., Wolfe M.S. gamma-Secretase substrate selectivity can be modulated directly via interaction with a nucleotide-binding site. J. Biol. Chem. 2005, 280:41987-41996.
57. Fraering P.C., Ye W., Strub J.M., Dolios G., LaVoie M.J., Ostaszewski B.L., van Dorsselaer A., Wang R., Selkoe D.J., Wolfe M.S. Purification and characterization of the human gamma-secretase complex. Biochemistry 2004, 43:9774-9789.
58. Francis R., McGrath G., Zhang J., Ruddy D.A., Sym M., Apfeld J., Nicoll M., Maxwell M., Hai B., Ellis M.C., Parks A.L., Xu W., 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.
59. Freeman M. Rhomboid proteases and their biological functions. Annu. Rev. Genet. 2008, 42:191-210.
60. Galasko D.R., Graff-Radford N., May S., Hendrix S., Cottrell B.A., Sagi S.A., Mather G., Laughlin M., Zavitz K.H., Swabb E., Golde T.E., Murphy M.P., et al. Safety, tolerability, pharmacokinetics, and Abeta levels after short-term administration of R-flurbiprofen in healthy elderly individuals. Alzheimer Dis. Assoc. Disord. 2007, 21:292-299.
61. Gallahan D., Callahan R. The mouse mammary tumor associated gene INT3 is a unique member of the NOTCH gene family (NOTCH4). Oncogene 1997, 14:1883-1890.
62. Gonda D.K., Bachmair A., Wunning I., Tobias J.W., Lane W.S., Varshavsky A. Universality and structure of the N-end rule. J. Biol. Chem. 1989, 264:16700-16712.
63. Gordon W.R., Vardar-Ulu D., Histen G., Sanchez-Irizarry C., Aster J.C., Blacklow S.C. Structural basis for autoinhibition of Notch. Nat. Struct. Mol. Biol. 2007, 14:295-300.
64. Goutte C., Hepler W., Mickey K.M., Priess J.R. aph-2 encodes a novel extracellular protein required for GLP-1-mediated signaling. Development 2000, 127:2481-2492.
65. Goutte C., Tsunozaki M., Hale V.A., Priess J.R. APH-1 is a multipass membrane protein essential for the Notch signaling pathway in Caenorhabditis elegans embryos. Proc. Natl. Acad. Sci. U.S.A. 2002, 99:775-779.
66. Grabher C., von Boehmer H., Look A.T. Notch 1 activation in the molecular pathogenesis of T-cell acute lymphoblastic leukaemia. Nat. Rev. Cancer. 2006, 6:347-359.
67. Green R.C., Schneider L.S., Amato D.A., Beelen A.P., Wilcock G., Swabb E.A., Zavitz K.H. Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial. J. Am. Med. Assoc. 2009, 302:2557-2564.
68. Gu Y., Chen F., Sanjo N., Kawarai T., Hasegawa H., Duthie M., Li W., Ruan X., Luthra A., Mount H.T., Tandon A., Fraser P.E., et al. APH-1 interacts with mature and immature forms of presenilins and nicastrin and may play a role in maturation of presenilin.nicastrin complexes. J. Biol. Chem. 2003, 278:7374-7380.
69. Ha Y. Structural principles of intramembrane proteases. Curr. Opin. Struct. Biol. 2007, 17:405-411.
70. Haass C. Take five-BACE and the gamma-secretase quartet conduct Alzheimer's amyloid beta-peptide generation. EMBO J. 2004, 23:483-488.
71. Haass C., Selkoe D.J. Cellular processing of beta-amyloid precursor protein and the genesis of amyloid beta-peptide. Cell 1993, 75:1039-1042.
72. Hadland B.K., Manley N.R., Su D., Longmore G.D., Moore C.L., Wolfe M.S., Schroeter E.H., Kopan R. Gamma -secretase inhibitors repress thymocyte development. Proc. Natl. Acad. Sci. U.S.A. 2001, 98:7487-7491.
73. Hartmann D., De Strooper B., Saftig P. Presenilin-1 deficiency leads to loss of Cajal-Retzius neurons and cortical dysplasia similar to human type 2 lissencephaly. Curr. Biol. 1999, 9:719-727.
74. Hartmann D., de Strooper B., Serneels L., Craessaerts K., Herreman A., Annaert W., Umans L., Lubke T., Lena Illert A., von Figura K., Saftig P. The disintegrin/metalloprotease ADAM 10 is essential for Notch signalling but not for alpha-secretase activity in fibroblasts. Hum. Mol. Genet. 2002, 11:2615-2624.
75. Hasegawa H., Sanjo N., Chen F., Gu Y.J., Shier C., Petit A., Kawarai T., Katayama T., Schmidt S.D., Mathews P.M., Schmitt-Ulms G., Fraser P.E., et al. Both the sequence and length of the C terminus of PEN-2 are critical for intermolecular interactions and function of presenilin complexes. J. Biol. Chem. 2004, 279:46455-46463.
76. Hayashi I., Urano Y., Fukuda R., Isoo N., Kodama T., Hamakubo T., Tomita T., Iwatsubo T. Selective reconstitution and recovery of functional gamma-secretase complex on budded baculovirus particles. J. Biol. Chem. 2004, 279:38040-38046.
77. Hebert S.S., Serneels L., Dejaegere T., Horre K., Dabrowski M., Baert V., Annaert W., Hartmann D., De Strooper B. Coordinated and widespread expression of gamma-secretase in vivo: evidence for size and molecular heterogeneity. Neurobiol. Dis. 2004, 17:260-272.
78. Hemler M.E. Targeting of tetraspanin proteins-potential benefits and strategies. Nat. Rev. Drug Discov. 2008, 7:747-758.
79. Henricson A., Kall L., Sonnhammer E.L. A novel transmembrane topology of presenilin based on reconciling experimental and computational evidence. FEBS J. 2005, 272:2727-2733.
80. Herreman A., Hartmann D., Annaert W., Saftig P., Craessaerts K., Serneels L., Umans L., Schrijvers V., Checler F., Vanderstichele H., Baekelandt V., Dressel R., 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. U.S.A. 1999, 96:11872-11877.
81. Herreman A., Serneels L., Annaert W., Collen D., Schoonjans L., De Strooper B. Total inactivation of gamma-secretase activity in presenilin-deficient embryonic stem cells. Nat. Cell Biol. 2000, 2:461-462.
82. Herreman A., Van Gassen G., Bentahir M., Nyabi O., Craessaerts K., Mueller U., Annaert W., De Strooper B. gamma-Secretase activity requires the presenilin-dependent trafficking of nicastrin through the Golgi apparatus but not its complex glycosylation. J. Cell. Sci. 2003, 116:1127-1136.
83. Hu Y., Ye Y., Fortini M.E. Nicastrin is required for gamma-secretase cleavage of the Drosophila Notch receptor. Dev. Cell 2002, 2:69-78.
84. Ikeuchi T., Sisodia S.S. The Notch ligands, Delta1 and Jagged2, are substrates for presenilin-dependent "gamma-secretase" cleavage. J. Biol. Chem. 2003, 278:7751-7754.
85. Jacobsen H., Reinhardt D., Brockhaus M., Bur D., Kocyba C., Kurt H., Grim M.G., Baumeister R., Loetscher H. The influence of endoproteolytic processing of familial Alzheimer's disease presenilin 2 on abeta42 amyloid peptide formation. J. Biol. Chem. 1999, 274:35233-35239.
86. Jorissen E., Prox J., Bernreuther C., Weber S., Schwanbeck R., Serneels L., Snellinx A., Craessaerts K., Thathiah A., Tesseur I., Bartsch U., Weskamp G., et al. J. Neurosci. 2010, 30(14):4833-4844.
87. Kaether C., Scheuermann J., Fassler M., Zilow S., Shirotani K., Valkova C., Novak B., Kacmar S., Steiner H., Haass C. Endoplasmic reticulum retention of the gamma-secretase complex component Pen2 by Rer1. EMBO Rep. 2007, 8:743-748.
88. Kakuda N., Funamoto S., Yagishita S., Takami M., Osawa S., Dohmae N., Ihara Y. Equimolar production of amyloid beta-protein and amyloid precursor protein intracellular domain from beta-carboxyl-terminal fragment by gamma-secretase. J. Biol. Chem. 2006, 281:14776-14786.
89. Kim S.H., Sisodia S.S. A sequence within the first transmembrane domain of PEN-2 is critical for PEN-2-mediated endoproteolysis of presenilin 1. J. Biol. Chem. 2005, 280:1992-2001.
90. Kimberly W.T., LaVoie M.J., Ostaszewski B.L., Ye W., Wolfe M.S., Selkoe D.J. Complex N-linked glycosylated nicastrin associates with active gamma-secretase and undergoes tight cellular regulation. J. Biol. Chem. 2002, 277:35113-35117.
91. Kimberly W.T., LaVoie M.J., Ostaszewski B.L., Ye W., Wolfe M.S., Selkoe D.J. Gamma-secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2. Proc. Natl. Acad. Sci. U.S.A. 2003, 100:6382-6387.
92. Kimberly W.T., Xia W., Rahmati T., Wolfe M.S., Selkoe D.J. The transmembrane aspartates in presenilin 1 and 2 are obligatory for gamma-secretase activity and amyloid beta-protein generation. J. Biol. Chem. 2000, 275:3173-3178.
93. Kopan R., Ilagan M.X. Gamma-secretase: proteasome of the membrane?. Nat. Rev. Mol. Cell Biol. 2004, 5:499-504.
94. Kopan R., Ilagan M.X. The canonical Notch signaling pathway: unfolding the activation mechanism. Cell 2009, 137:216-233.
95. Kornilova A.Y., Bihel F., Das C., Wolfe M.S. The initial substrate-binding site of gamma-secretase is located on presenilin near the active site. Proc. Natl. Acad. Sci. U.S.A. 2005, 102:3230-3235.
96. Kukar T.L., Ladd T.B., Bann M.A., Fraering P.C., Narlawar R., Maharvi G.M., Healy B., Chapman R., Welzel A.T., Price R.W., Moore B., Rangachari V., et al. Substrate-targeting gamma-secretase modulators. Nature 2008, 453:925-929.
97. LaVoie M.J., Selkoe D.J. The Notch ligands, Jagged and Delta, are sequentially processed by alpha-secretase and presenilin/gamma-secretase and release signaling fragments. J. Biol. Chem. 2003, 278:34427-34437.
98. Lammich S., Okochi M., Takeda M., Kaether C., Capell A., Zimmer A.K., Edbauer D., Walter J., Steiner H., Haass C. Presenilin-dependent intramembrane proteolysis of CD44 leads to the liberation of its intracellular domain and the secretion of an Abeta-like peptide. J. Biol. Chem. 2002, 277:44754-44759.
99. Laudon H., Hansson E.M., Melen K., Bergman A., Farmery M.R., Winblad B., Lendahl U., von Heijne G., Naslund J. A nine-transmembrane domain topology for presenilin 1. J. Biol. Chem. 2005, 280:35352-35360.
100. Laudon H., Mathews P.M., Karlstrom H., Bergman A., Farmery M.R., Nixon R.A., Winblad B., Gandy S.E., Lendahl U., Lundkvist J., Naslund J. Co-expressed presenilin 1 NTF and CTF form functional gamma-secretase complexes in cells devoid of full-length protein. J. Neurochem. 2004, 89:44-53.
101. Lazarov O., Peterson L.D., Peterson D.A., Sisodia S.S. Expression of a familial Alzheimer's disease-linked presenilin-1 variant enhances perforant pathway lesion-induced neuronal loss in the entorhinal cortex. J. Neurosci. 2006, 26:429-434.
102. Lee S.F., Shah S., Li H., Yu C., Han W., Yu G. Mammalian APH-1 interacts with presenilin and nicastrin and is required for intramembrane proteolysis of amyloid-beta precursor protein and Notch. J. Biol. Chem. 2002, 277:45013-45019.
103. Lee S.F., Shah S., Yu C., Wigley W.C., Li H., Lim M., Pedersen K., Han W., Thomas P., Lundkvist J., Hao Y.H., Yu G. A conserved GXXXG motif in APH-1 is critical for assembly and activity of the gamma-secretase complex. J. Biol. Chem. 2004, 279:4144-4152.
104. Levitan D., Greenwald I. Facilitation of lin-12-mediated signalling by sel-12, a Caenorhabditis elegans S182 Alzheimer's disease gene. Nature 1995, 377:351-354.
105. Levitan D., Lee J., Song L., Manning R., Wong G., Parker E., Zhang L. PS1 N- and C-terminal fragments form a complex that functions in APP processing and Notch signaling. Proc. Natl. Acad. Sci. U.S.A. 2001, 98:12186-12190.
106. Levy-Lahad E., Wasco W., Poorkaj P., Romano D.M., Oshima J., Pettingell W.H., Yu C.E., Jondro P.D., Schmidt S.D., Wang K., et al. Candidate gene for the chromosome 1 familial Alzheimer's disease locus [see comments]. Science 1995, 269:973-977.
107. Li J., Fici G.J., Mao C.A., Myers R.L., Shuang R., Donoho G.P., Pauley A.M., Himes C.S., Qin W., Kola I., Merchant K.M., Nye J.S. Positive and negative regulation of the gamma-secretase activity by nicastrin in a murine model. J. Biol. Chem. 2003, 278:33445-33449.
108. 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. U.S.A. 1997, 94:12204-12209.
109. Li T., Ma G., Cai H., Price D.L., Wong P.C. Nicastrin is required for assembly of presenilin/gamma-secretase complexes to mediate Notch signaling and for processing and trafficking of beta-amyloid precursor protein in mammals. J. Neurosci. 2003, 23:3272-3277.
110. Li Y.M., Xu M., Lai M.T., Huang Q., Castro J.L., DiMuzio-Mower J., Harrison T., Lellis C., Nadin A., Neduvelil J.G., Register R.B., Sardana M.K., et al. Photoactivated gamma-secretase inhibitors directed to the active site covalently label presenilin 1. Nature 2000, 405:689-694.
111. Lleo A., Berezovska O., Herl L., Raju S., Deng A., Bacskai B.J., Frosch M.P., Irizarry M., Hyman B.T. Nonsteroidal anti-inflammatory drugs lower Abeta42 and change presenilin 1 conformation. Nat. Med. 2004, 10:1065-1066.
112. Logeat F., Bessia C., Brou C., LeBail O., Jarriault S., Seidah N.G., Israel A. The Notch1 receptor is cleaved constitutively by a furin-like convertase. Proc. Natl. Acad. Sci. U.S.A. 1998, 95:8108-8112.
113. Lopez-Schier H., St Johnston D. Drosophila nicastrin is essential for the intramembranous cleavage of notch. Dev. Cell 2002, 2:79-89.
114. Ma G., Li T., Price D.L., Wong P.C. APH-1a is the principal mammalian APH-1 isoform present in gamma-secretase complexes during embryonic development. J. Neurosci. 2005, 25:192-198.
115. Marambaud P., Shioi J., Serban G., Georgakopoulos A., Sarner S., Nagy V., Baki L., Wen P., Efthimiopoulos S., Shao Z., Wisniewski T., Robakis N.K. A presenilin-1/gamma-secretase cleavage releases the E-cadherin intracellular domain and regulates disassembly of adherens junctions. EMBO J. 2002, 21:1948-1956.
116. Mastrangelo P., Mathews P.M., Chishti M.A., Schmidt S.D., Gu Y., Yang J., Mazzella M.J., Coomaraswamy J., Horne P., Strome B., Pelly H., Levesque G., et al. Dissociated phenotypes in presenilin transgenic mice define functionally distinct gamma-secretases. Proc. Natl. Acad. Sci. U.S.A. 2005, 102:8972-8977.
117. Mayer S.C., Kreft A.F., Harrison B., Abou-Gharbia M., Antane M., Aschmies S., Atchison K., Chlenov M., Cole D.C., Comery T., Diamantidis G., Ellingboe J., et al. Discovery of begacestat, a Notch-1-sparing gamma-secretase inhibitor for the treatment of Alzheimer's disease. J Med Chem. 2008, 51:7348-7351.
118. McCarthy J.V., Twomey C., Wujek P. Presenilin-dependent regulated intramembrane proteolysis and gamma-secretase activity. Cell Mol. Life Sci. 2009, 66:1534-1555.
119. Meng R.D., Shelton C.C., Li Y.M., Qin L.X., Notterman D., Paty P.B., Schwartz G.K. gamma-Secretase inhibitors abrogate oxaliplatin-induced activation of the Notch-1 signaling pathway in colon cancer cells resulting in enhanced chemosensitivity. Cancer Res. 2009, 69:573-582.
120. Milano J., McKay J., Dagenais C., Foster-Brown L., Pognan F., Gadient R., Jacobs R.T., Zacco A., Greenberg B., Ciaccio P.J. Modulation of notch processing by gamma-secretase inhibitors causes intestinal goblet cell metaplasia and induction of genes known to specify gut secretory lineage differentiation. Toxicol. Sci. 2004, 82:341-358.
121. Mumm J.S., Kopan R. Notch signaling: from the outside in. Dev. Biol. 2000, 228:151-165.
122. Munter L.M., Voigt P., Harmeier A., Kaden D., Gottschalk K.E., Weise C., Pipkorn R., Schaefer M., Langosch D., Multhaup G. GxxxG motifs within the amyloid precursor protein transmembrane sequence are critical for the etiology of Abeta42. EMBO J. 2007, 26:1702-1712.
123. Netzer W.J., Dou F., Cai D., Veach D., Jean S., Li Y., Bornmann W.G., Clarkson B., Xu H., Greengard P. Gleevec inhibits beta-amyloid production but not Notch cleavage. Proc. Natl. Acad. Sci. U.S.A. 2003, 100:12444-12449.
124. Ni Y., Zhao X., Bao G., Zou L., Teng L., Wang Z., Song M., Xiong J., Bai Y., Pei G. Activation of beta2-adrenergic receptor stimulates gamma-secretase activity and accelerates amyloid plaque formation. Nat. Med. 2006, 12:1390-1396.
125. Nicolas M., Wolfer A., Raj K., Kummer J.A., Mill P., van Noort M., Hui C.C., Clevers H., Dotto G.P., Radtke F. Notch1 functions as a tumor suppressor in mouse skin. Nat. Genet. 2003, 33:416-421.
126. Niimura M., Isoo N., Takasugi N., Tsuruoka M., Ui-Tei K., Saigo K., Morohashi Y., Tomita T., Iwatsubo T. Aph-1 contributes to the stabilization and trafficking of the gamma-secretase complex through mechanisms involving intermolecular and intramolecular interactions. J. Biol. Chem. 2005, 280:12967-12975.
127. Nitsch R.M., Blusztajn J.K., Pittas A.G., Slack B.E., Growdon J.H., Wurtman R.J. Evidence for a membrane defect in Alzheimer disease brain. Proc. Natl. Acad. Sci. U.S.A. 1992, 89:1671-1675.
128. Nyabi O., Bentahir M., Horre K., Herreman A., Gottardi-Littell N., Van Broeckhoven C., Merchiers P., Spittaels K., Annaert W., De Strooper B. Presenilins mutated at Asp-257 or Asp-385 restore Pen-2 expression and Nicastrin glycosylation but remain catalytically inactive in the absence of wild type Presenilin. J. Biol. Chem. 2003, 278:43430-43436.
129. Ogura T., Mio K., Hayashi I., Miyashita H., Fukuda R., Kopan R., Kodama T., Hamakubo T., Iwatsubo T., Tomita T., Sato C. Three-dimensional structure of the gamma-secretase complex. Biochem. Biophys. Res. Commun. 2006, 343:525-534.
130. Oh Y.S., Turner R.J. Topology of the C-terminal fragment of human presenilin 1. Biochemistry 2005, 44:11821-11828.
131. Oka C., Nakano T., Wakeham A., de la Pompa J.L., Mori C., Sakai T., Okazaki S., Kawaichi M., Shiota K., Mak T.W., Honjo T. Disruption of the mouse RBP-J kappa gene results in early embryonic death. Development 1995, 121:3291-3301.
132. Okochi M., Steiner H., Fukumori A., Tanii H., Tomita T., Tanaka T., Iwatsubo T., Kudo T., Takeda M., Haass C. Presenilins mediate a dual intramembranous gamma-secretase cleavage of Notch-1. EMBO J. 2002, 21:5408-5416.
133. Osenkowski P., Li H., Ye W., Li D., Aeschbach L., Fraering P.C., Wolfe M.S., Selkoe D.J. Cryoelectron microscopy structure of purified gamma-secretase at 12A resolution. J. Mol. Biol. 2009, 385:642-652.
134. Pardossi-Piquard R., Yang S.P., Kanemoto S., Gu Y., Chen F., Bohm C., Sevalle J., Li T., Wong P.C., Checler F., Schmitt-Ulms G., St George-Hyslop P., et al. APH1 polar transmembrane residues regulate the assembly and activity of presenilin complexes. J. Biol. Chem. 2009, 284:16298-16307.
135. Park J.T., Li M., Nakayama K., Mao T.L., Davidson B., Zhang Z., Kurman R.J., Eberhart C.G., Shih Ie M., Wang T.L. Notch3 gene amplification in ovarian cancer. Cancer Res. 2006, 66:6312-6318.
136. Qi-Takahara Y., Morishima-Kawashima M., Tanimura Y., Dolios G., Hirotani N., Horikoshi Y., Kametani F., Maeda M., Saido T.C., Wang R., Ihara Y. Longer forms of amyloid beta protein: implications for the mechanism of intramembrane cleavage by gamma-secretase. J. Neurosci. 2005, 25:436-445.
137. Rand M.D., Grimm L.M., Artavanis-Tsakonas S., Patriub V., Blacklow S.C., Sklar J., Aster J.C. Calcium depletion dissociates and activates heterodimeric notch receptors. Mol. Cell. Biol. 2000, 20:1825-1835.
138. Ratovitski T., Slunt H.H., Thinakaran G., Price D.L., Sisodia S.S., Borchelt D.R. Endoproteolytic processing and stabilization of wild-type and mutant presenilin. J. Biol. Chem. 1997, 272:24536-24541.
139. Rawson R.B. The SREBP pathway-insights from Insigs and insects. Nat. Rev. Mol. Cell Biol. 2003, 4:631-640.
140. Real P.J., Tosello V., Palomero T., Castillo M., Hernando E., de Stanchina E., Sulis M.L., Barnes K., Sawai C., Homminga I., Meijerink J., Aifantis I., et al. Gamma-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia. Nat. Med. 2009, 15:50-58.
141. Rogaev E.I., Sherrington R., Rogaeva E.A., Levesque G., Ikeda M., Liang Y., Chi H., Lin C., Holman K., Tsuda T., et al. Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene. Nature 1995, 376:775-778.
142. Sato C., Morohashi Y., Tomita T., Iwatsubo T. Structure of the catalytic pore of gamma-secretase probed by the accessibility of substituted cysteines. J. Neurosci. 2006, 26:12081-12088.
143. Sato C., Takagi S., Tomita T., Iwatsubo T. The C-terminal PAL motif and transmembrane domain 9 of presenilin 1 are involved in the formation of the catalytic pore of the gamma-secretase. J. Neurosci. 2008, 28:6264-6271.
144. Saxena M.T., Schroeter E.H., Mumm J.S., Kopan R. Murine notch homologs (N1-4) undergo presenilin-dependent proteolysis. J. Biol. Chem. 2001, 276:40268-40273.
145. Schroeter E.H., Kisslinger J.A., Kopan R. Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain. Nature 1998, 393:382-386.
146. Searfoss G.H., Jordan W.H., Calligaro D.O., Galbreath E.J., Schirtzinger L.M., Berridge B.R., Gao H., Higgins M.A., May P.C., Ryan T.P. Adipsin, a biomarker of gastrointestinal toxicity mediated by a functional gamma-secretase inhibitor. J. Biol. Chem. 2003, 278:46107-46116.
147. Seiffert D., Bradley J.D., Rominger C.M., Rominger D.H., Yang F., Meredith J.E., Wang Q., Roach A.H., Thompson L.A., Spitz S.M., Higaki J.N., Prakash S.R., et al. Presenilin-1 and -2 are molecular targets for gamma-secretase inhibitors. J. Biol. Chem. 2000, 275:34086-34091.
148. Serneels L., Dejaegere T., Craessaerts K., Horre K., Jorissen E., Tousseyn T., Hebert S., Coolen M., Martens G., Zwijsen A., Annaert W., Hartmann D., et al. Differential contribution of the three Aph1 genes to gamma-secretase activity in vivo. Proc. Natl. Acad. Sci. U.S.A. 2005, 102:1719-1724.
149. Serneels L., Van Biervliet J., Craessaerts K., Dejaegere T., Horre K., Van Houtvin T., Esselmann H., Paul S., Schafer M.K., Berezovska O., Hyman B.T., Sprangers B., et al. gamma-Secretase heterogeneity in the Aph1 subunit: relevance for Alzheimer's disease. Science 2009, 324:639-642.
150. Shah S., Lee S.F., Tabuchi K., Hao Y.H., Yu C., LaPlant Q., Ball H., Dann C.E., Sudhof T., Yu G. Nicastrin functions as a gamma-secretase-substrate receptor. Cell 2005, 122:435-447.
151. Shen J., Bronson R.T., Chen D.F., Xia W., Selkoe D.J., Tonegawa S. Skeletal and CNS defects in Presenilin-1-deficient mice. Cell 1997, 89:629-639.
152. Sherrington R., Rogaev E.I., Liang Y., Rogaeva E.A., Levesque G., Ikeda M., Chi H., Lin C., Li G., Holman K., et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease [see comments]. Nature 1995, 375:754-760.
153. Shih Ie M., Wang T.L. Notch signaling, gamma-secretase inhibitors, and cancer therapy. Cancer Res. 2007, 67:1879-1882.
154. 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, 279:41340-41345.
155. Siemers E.R., Quinn J.F., Kaye J., Farlow M.R., Porsteinsson A., Tariot P., Zoulnouni P., Galvin J.E., Holtzman D.M., Knopman D.S., Satterwhite J., Gonzales C., et al. Effects of a gamma-secretase inhibitor in a randomized study of patients with Alzheimer disease. Neurology 2006, 66:602-604.
156. Siemers E., Skinner M., Dean R.A., Gonzales C., Satterwhite J., Farlow M., Ness D., May P.C. Safety, tolerability, and changes in amyloid beta concentrations after administration of a gamma-secretase inhibitor in volunteers. Clin. Neuropharmacol. 2005, 28:126-132.
157. Song W., Nadeau P., Yuan M., Yang X., Shen J., Yankner B.A. Proteolytic release and nuclear translocation of Notch-1 are induced by presenilin-1 and impaired by pathogenic presenilin-1 mutations. Proc. Natl. Acad. Sci. U.S.A. 1999, 96:6959-6963.
158. Spasic D., Raemaekers T., Dillen K., Declerck I., Baert V., Serneels L., Fullekrug J., Annaert W. Rer1p competes with APH-1 for binding to nicastrin and regulates gamma-secretase complex assembly in the early secretory pathway. J. Cell Biol. 2007, 176:629-640.
159. Spasic D., Tolia A., Dillen K., Baert V., De Strooper B., Vrijens S., Annaert W. Presenilin-1 maintains a nine-transmembrane topology throughout the secretory pathway. J. Biol. Chem. 2006, 281:26569-26577.
160. Steiner H., Kostka M., Romig H., Basset G., Pesold B., Hardy J., Capell A., Meyn L., Grim M.L., Baumeister R., Fechteler K., Haass C. Glycine 384 is required for presenilin-1 function and is conserved in bacterial polytopic aspartyl proteases. Nat. Cell Biol. 2000, 2:848-851.
161. Steiner H., Romig H., Grim M.G., Philipp U., Pesold B., Citron M., Baumeister R., Haass C. The biological and pathological function of the presenilin-1 Deltaexon 9 mutation is independent of its defect to undergo proteolytic processing. J. Biol. Chem. 1999, 274:7615-7618.
162. Steiner H., Romig H., Pesold B., Philipp U., Baader M., Citron M., Loetscher H., Jacobsen H., Haass C. Amyloidogenic function of the Alzheimer's disease-associated presenilin 1 in the absence of endoproteolysis. Biochemistry 1999, 38:14600-14605.
163. Steiner H., Winkler E., Edbauer D., Prokop S., Basset G., Yamasaki A., Kostka M., Haass C. PEN-2 is an integral component of the gamma-secretase complex required for coordinated expression of presenilin and nicastrin. J. Biol. Chem. 2002, 277:39062-39065.
164. Struhl G., Adachi A. Requirements for presenilin-dependent cleavage of notch and other transmembrane proteins. Mol Cell. 2000, 6:625-636.
165. Struhl G., Greenwald I. Presenilin is required for activity and nuclear access of Notch in Drosophila. Nature 1999, 398:522-525.
166. Tagami S., Okochi M., Yanagida K., Ikuta A., Fukumori A., Matsumoto N., Ishizuka-Katsura Y., Nakayama T., Itoh N., Jiang J., Nishitomi K., Kamino K., et al. Regulation of Notch signaling by dynamic changes in the precision of S3 cleavage of Notch-1. Mol. Cell. Biol. 2008, 28:165-176.
167. Takami M., Nagashima Y., Sano Y., Ishihara S., Morishima-Kawashima M., Funamoto S., Ihara Y. gamma-Secretase: successive tripeptide and tetrapeptide release from the transmembrane domain of beta-carboxyl terminal fragment. J. Neurosci. 2009, 29:13042-13052.
168. Takasugi N., Tomita T., Hayashi I., Tsuruoka M., Niimura M., Takahashi Y., Thinakaran G., Iwatsubo T. The role of presenilin cofactors in the gamma-secretase complex. Nature 2003, 422:438-441.
169. Teng L., Zhao J., Wang F., Ma L., Pei G. A GPCR/secretase complex regulates beta- and gamma-secretase specificity for Abeta production and contributes to AD pathogenesis. Cell Res. 2010, 20:138-153.
170. Thathiah A., Spittaels K., Hoffmann M., Staes M., Cohen A., Horre K., Vanbrabant M., Coun F., Baekelandt V., Delacourte A., Fischer D.F., Pollet D., et al. The orphan G protein-coupled receptor 3 modulates amyloid-beta peptide generation in neurons. Science 2009, 323:946-951.
171. Thinakaran G., Borchelt D.R., Lee M.K., Slunt H.H., Spitzer L., Kim G., Ratovitsky T., Davenport F., Nordstedt C., Seeger M., Hardy J., Levey A.I., et al. Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo. Neuron 1996, 17:181-190.
172. Thinakaran G., Harris C.L., Ratovitski T., Davenport F., Slunt H.H., Price D.L., Borchelt D.R., Sisodia S.S. Evidence that levels of presenilins (PS1 and PS2) are coordinately regulated by competition for limiting cellular factors. J. Biol. Chem. 1997, 272:28415-28422.
173. Tolia A., Chavez-Gutierrez L., De Strooper B. Contribution of presenilin transmembrane domains 6 and 7 to a water-containing cavity in the gamma-secretase complex. J. Biol. Chem. 2006, 281:27633-27642.
174. Tolia A., Horre K., De Strooper B. Transmembrane domain 9 of presenilin determines the dynamic conformation of the catalytic site of gamma-secretase. J. Biol. Chem. 2008, 283:19793-19803.
175. Tomita T., Katayama R., Takikawa R., Iwatsubo T. Complex N-glycosylated form of nicastrin is stabilized and selectively bound to presenilin fragments. FEBS Lett. 2002, 520:117-121.
176. Tournoy J., Bossuyt X., Snellinx A., Regent M., Garmyn M., Serneels L., Saftig P., Craessaerts K., De Strooper B., Hartmann D. Partial loss of presenilins causes seborrheic keratosis and autoimmune disease in mice. Hum. Mol. Genet. 2004, 13:1321-1331.
177. Uemura K., Lill C.M., Li X., Peters J.A., Ivanov A., Fan Z., DeStrooper B., Bacskai B.J., Hyman B.T., Berezovska O. Allosteric modulation of PS1/gamma-secretase conformation correlates with amyloid beta(42/40) ratio. PLoS One 2009, 4:e7893.
178. Urban S. Making the cut: central roles of intramembrane proteolysis in pathogenic microorganisms. Nat. Rev. Microbiol. 2009, 7:411-423.
179. Urban S., Shi Y. Core principles of intramembrane proteolysis: comparison of rhomboid and site-2 family proteases. Curr. Opin. Struct. Biol. 2008, 18:432-441.
180. van Es J.H., van Gijn M.E., Riccio O., van den Born M., Vooijs M., Begthel H., Cozijnsen M., Robine S., Winton D.J., Radtke F., Clevers H. Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 2005, 435:959-963.
181. van Tetering G., van Diest P., Verlaan I., van der Wall E., Kopan R., Vooijs M. The metalloprotease ADAM10 is required for notch1 S2 cleavage. J. Biol. Chem. 2009.
182. Vetrivel K.S., Cheng H., Kim S.H., Chen Y., Barnes N.Y., Parent A.T., Sisodia S.S., Thinakaran G. Spatial segregation of gamma-secretase and substrates in distinct membrane domains. J. Biol. Chem. 2005, 280:25892-25900.
183. Vetrivel K.S., Cheng H., Lin W., Sakurai T., Li T., Nukina N., Wong P.C., Xu H., Thinakaran G. Association of gamma-secretase with lipid rafts in post-Golgi and endosome membranes. J. Biol. Chem. 2004, 279:44945-44954.
184. Wakabayashi T., Craessaerts K., Bammens L., Bentahir M., Borgions F., Herdewijn P., Staes A., Timmerman E., Vandekerckhove J., Rubinstein E., Boucheix C., Gevaert K., et al. Analysis of the gamma-secretase interactome and validation of its association with tetraspanin-enriched microdomains. Nat. Cell Biol. 2009, 11:1340-1346.
185. Wakabayashi T., De Strooper B. Presenilins: members of the gamma-secretase quartets, but part-time soloists too. Physiology (Bethesda) 2008, 23:194-204.
186. Weggen S., Eriksen J.L., Das P., Sagi S.A., Wang R., Pietrzik C.U., Findlay K.A., Smith T.E., Murphy M.P., Bulter T., Kang D.E., Marquez-Sterling N., et al. A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature 2001, 414:212-216.
187. Weggen S., Eriksen J.L., Sagi S.A., Pietrzik C.U., Ozols V., Fauq A., Golde T.E., Koo E.H. Evidence that nonsteroidal anti-inflammatory drugs decrease amyloid beta 42 production by direct modulation of gamma-secretase activity. J. Biol. Chem. 2003, 278:31831-31837.
188. Weng A.P., Ferrando A.A., Lee W., Morris J.Pt., Silverman L.B., Sanchez-Irizarry C., Blacklow S.C., Look A.T., Aster J.C. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 2004, 306:269-271.
189. Westlund B., Parry D., Clover R., Basson M., Johnson C.D. Reverse genetic analysis of Caenorhabditis elegans presenilins reveals redundant but unequal roles for sel-12 and hop-1 in Notch-pathway signaling. Proc. Natl. Acad. Sci. U.S.A. 1999, 96:2497-2502.
190. Wolfe M.S. gamma-Secretase modulators. Cur.r Alzheimer Res. 2007, 4:571-573.
191. Wolfe M.S., Kopan R. Intramembrane proteolysis: theme and variations. Science 2004, 305:1119-1123.
192. Wolfe M.S., Xia W., Ostaszewski B.L., Diehl T.S., Kimberly W.T., Selkoe D.J. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature 1999, 398:513-517.
193. Wong G.T., Manfra D., Poulet F.M., Zhang Q., Josien H., Bara T., Engstrom L., Pinzon-Ortiz M., Fine J.S., Lee H.J., Zhang L., Higgins G.A., et al. Chronic treatment with the gamma-secretase inhibitor LY-411,575 inhibits beta-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J. Biol. Chem. 2004, 279:12876-12882.
194. Wong P.C., Zheng H., Chen H., Becher M.W., Sirinathsinghji D.J., Trumbauer M.E., Chen H.Y., Price D.L., Van der Ploeg L.H., Sisodia S.S. Presenilin 1 is required for Notch1 and DII1 expression in the paraxial mesoderm. Nature 1997, 387:288-292.
195. Xia W. From presenilinase to gamma-secretase, cleave to capacitate. Curr. Alzheimer Res. 2008, 5:172-178.
196. Xia W., Wolfe M.S. Intramembrane proteolysis by presenilin and presenilin-like proteases. J. Cell. Sci. 2003, 116:2839-2844.
197. Xu H., Lu Y.F., Partilla J.S., Pinto J., Calderon S.N., Matecka D., Rice K.C., Lai J., Porreca F., Ananthan S., Rothman R.B. Opioid peptide receptor studies. 8. One of the mouse brain deltaNCX binding sites is similar to the cloned mouse opioid delta receptor: further evidence for heterogeneity of delta opioid receptors. Peptides 1998, 19:343-350.
198. Yagishita S., Morishima-Kawashima M., Tanimura Y., Ishiura S., Ihara Y. DAPT-induced intracellular accumulations of longer amyloid beta-proteins: further implications for the mechanism of intramembrane cleavage by gamma-secretase. Biochemistry 2006, 45:3952-3960.
199. Yanagida K., Okochi M., Tagami S., Nakayama T., Kodama T.S., Nishitomi K., Jiang J., Mori K., Tatsumi S., Arai T., Ikeuchi T., Kasuga K., et al. The 28-amino acid form of an APLP1-derived Abeta-like peptide is a surrogate marker for Abeta42 production in the central nervous system. EMBO Mol. Med. 2009, 1:223-235.
200. Yang D.S., Tandon A., Chen F., Yu G., Yu H., Arawaka S., Hasegawa H., Duthie M., Schmidt S.D., Ramabhadran T.V., Nixon R.A., Mathews P.M., et al. Mature glycosylation and trafficking of nicastrin modulate its binding to presenilins. J. Biol. Chem. 2002, 277:28135-28142.
201. Ye Y., Fortini M.E. Apoptotic activities of wild-type and Alzheimer's disease-related mutant presenilins in Drosophila melanogaster. J. Cell Biol. 1999, 146:1351-1364.
202. Yu G., Nishimura M., Arawaka S., Levitan D., Zhang L., Tandon A., Song Y.Q., Rogaeva E., Chen F., Kawarai T., Supala A., Levesque L., et al. Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing. Nature 2000, 407:48-54.
203. Zhang L., Lee J., Song L., Sun X., Shen J., Terracina G., Parker E.M. Characterization of the reconstituted gamma-secretase complex from Sf9 cells co-expressing presenilin 1, nicastrin [correction of nacastrin], aph-1a, and pen-2. Biochemistry 2005, 44:4450-4457.
204. Zhang Z., Nadeau P., Song W., Donoviel D., Yuan M., Bernstein A., Yankner B.A. Presenilins are required for gamma-secretase cleavage of beta-APP and transmembrane cleavage of Notch-1. Nat. Cell Biol. 2000, 2:463-465.
205. Zhao G., Cui M.Z., Mao G., Dong Y., Tan J., Sun L., Xu X. gamma-Cleavage is dependent on zeta-cleavage during the proteolytic processing of amyloid precursor protein within its transmembrane domain. J. Biol. Chem. 2005, 280:37689-37697.
206. Zhao G., Liu Z., Ilagan M.X., Kopan R. {gamma}-Secretase Composed of PS1/Pen2/Aph1a Can Cleave Notch and Amyloid Precursor Protein in the Absence of Nicastrin. J. Neurosci. 2010, 30:1648-1656.
207. Zhao G., Tan J., Mao G., Cui M.Z., Xu X. The same gamma-secretase accounts for the multiple intramembrane cleavages of APP. J. Neurochem. 2007, 100:1234-1246.