Identity and Function of γ-Secretase

Journal of Neuroscience Research

Volumn 74, Issue 3, 2003, Pages 353-360

  Kimberly, W Taylor ^a   Wolfe, Michael S ^a,b  

^a HARVARD MEDICAL SCHOOL   (United States)

^b HARVARD INSTITUTES OF MEDICINE   (United States)

Author keywords

secretase; Amyloid precursor protein; Cell surface signaling

Indexed keywords

AMYLOID PRECURSOR PROTEIN; ANTERIOR PHARYNX DEFECTIVE 1 PROTEIN; GAMMA SECRETASE; GENE PRODUCT; MEMBRANE PROTEIN; NICASTRIN; NOTCH RECEPTOR; PRESENILIN 1; PROTEIN PEN2; PROTEINASE; UNCLASSIFIED DRUG;

ALZHEIMER DISEASE; ANIMAL CELL; ARTICLE; CATALYSIS; CELL SURFACE; COMPLEX FORMATION; ENZYME ACTIVITY; ENZYME ANALYSIS; ENZYME MECHANISM; HUMAN; HUMAN CELL; MEMBRANE BINDING; NONHUMAN; PATHOGENESIS; PRIORITY JOURNAL; PROTEIN DEGRADATION; RECEPTOR BINDING; SIGNAL TRANSDUCTION;

ALZHEIMER DISEASE; AMYLOID BETA-PROTEIN PRECURSOR; AMYLOID PRECURSOR PROTEIN SECRETASES; ANIMALS; ASPARTIC ENDOPEPTIDASES; ENDOPEPTIDASES; EVOLUTION; HUMANS; MEMBRANE PROTEINS; SIGNAL TRANSDUCTION;

EID: 0242361783     PISSN: 03604012     EISSN: None     Source Type: Journal    
DOI: 10.1002/jnr.10736     Document Type: Article

References (74)

1. Annaert WG, Levesque L, Craessaerts K, Dierinck I, Snellings G, Westaway D, George-Hyslop PS, Cordell B, Fraser P, De Strooper B. 1999. Presenilin 1 controls γ-secretase processing of amyloid precursor protein in pre-golgi compartments of hippocampal neurons. J Cell Biol 147:277-294.
2. Artavanis-Tsakonas S, Rand MD, Lake RJ. 1999. Notch signaling: cell fate control and signal integration in development. Science 284:770-776.
3. Baek SH, Ohgi KA, Rose DW, Koo EH, Glass CK, Rosenfeld MG. 2002. Exchange of N-CoR corepressor and Tip60 coactivator complexes links gene expression by NF-κB and β-amyloid precursor protein. Cell 110:55-67.
4. Brown MS, Ye J, Rawson RB, Goldstein JL. 2000. Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans. Cell 100:391-398.
5. Cao X, Sudhof TC. 2001. A transcriptionally active complex of APP with Fe65 and histone acetyltransferase Tip60. Science 293:115-120.
6. Capell A, Grunberg J, Pesold B, Diehlmann A, Citron M, Nixon R., Beyreuther K, Selkoe DJ, Haass C. 1998. The proteolytic fragments of the Alzheimer's disease-associated presenilin-1 form heterodimers and occur as a 100-150-kDa molecular mass complex. J Biol Chem 273:3205-3211.
7. Chung HM, Struhl G. 2001. Nicastrin is required for Presenilin-mediated transmembrane cleavage in Drosophila. Nat Cell Biol 3:1129-1132.
8. Cook DG, Forman MS, Sung JC, Leight S, Kolson DL, Iwatsubo T, Lee VM, Doms RW. 1997. Alzheimer's A β(1-42) is generated in the endoplasmic reticulum/intermediate compartment of NT2N cells. Nat Med 3:1021-1023.
9. Crystal AS, Morais VA, Pierson TC, Pijak DS, Carlin D, Lee VM, Doms RW. 2003. Membrane topology of γ-secretase component PEN-2. J Biol Chem 278:20117-20123.
10. Cupers P, Bentahir M, Craessaerts K, Orlans I, Vanderstichele H, Saftig P, De Strooper B, Annaert W. 2001. The discrepancy between presenilin subcellular localization and γ-secretase processing of amyloid precursor protein. J Cell Biol 154:731-740.
11. De Strooper B, Annaert W, Cupers P, Saftig P, Craessaerts K, Mumm JS, Schroeter EH, Schrijvers V, Wolfe MS, Ray WJ, Goate A, Kopan R. 1999. A presenilin-1-dependent γ-secretase-like protease mediates release of Notch intracellular domain. Nature 398:518-522.
12. De Strooper B, Saftig P, Craessaerts K, Vanderstichele H, Guhde G, Annaert W, Von Figura K, Van Leuven F. 1998. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 391:387-390.
13. Edbauer D, Winkler E, Haass C, Steiner H. 2002. Presenilin and nicastrin regulate each other and determine amyloid β-peptide production via complex formation. Proc Natl Acad Sci USA 99:8666-8671.
14. Edbauer D, Winkler E, Regula JT, Pesold B, Steiner H, Haass C. 2003. Reconstitution of gamma-secretase activity. Nat Cell Biol 5:486-488.
15. Esler WP, Das C, Campbell WA, Kimberly WT, Kornilova AY, Diehl TS, Ye W, Ostaszewski BL, Xia W, Selkoe DJ, Wolfe MS. 2002a. Amyloid-lowering isocoumarins are not direct inhibitors of γ-secretase. Nat Cell Biol 4:110-111.
16. Esler WP, Kimberly WT, Ostaszewski BL, Diehl TS, Moore CL, Tsai JY, Rahmati T, Xia W, Selkoe DJ, Wolfe MS. 2000. Transition-state analogue inhibitors of γ-secretase bind directly to presenilin-1. Nat Cell Biol 2:428-434.
17. Esler WP, Kimberly WT, Ostaszewski BL, Ye W, Diehl TS, Selkoe DJ, Wolfe MS. 2002b. Activity-dependent isolation of the presenilin/γ-secretase complex reveals nicastrin and a γ substrate. Proc Natl Acad Sci USA 99:2720-2725.
18. Esler WP, Wolfe MS. 2001. A portrait of Alzheimer secretases - new features and familiar faces. Science 293:1449-1454.
19. Francis R, McGrath G, Zhang J, Ruddy DA, Sym M, Apfeld J, Nicoll M, Maxwell M, Hai B, Ellis MC, Parks AL, Xu W, Li J, Gurney M, Myers RL, Himes CS, Hiebsch R, Ruble C, Nye JS, Curtis D. 2002. Aph-1 and pen-2 are required for notch pathway signaling, γ-secretase cleavage of βAPP, and presenilin protein accumulation. Dev Cell 3:85-97.
20. Goutte C, Hepler W, Mickey KM, Priess JR. 2000. Aph-2 encodes a novel extracellular protein required for GLP-1-mediated signaling. Development 127:2481-2492.
21. Goutte C, Tsunozaki M, Hale VA, Priess JR. 2002. APH-1 is a multipass membrane protein essential for the Notch signaling pathway in Caenorhabditis elegans embryos. Proc Natl Acad Sci USA 99:775-779.
22. Haass C, Koo EH, Mellon A, Hung AY, Selkoe DJ. 1992. Targeting of cell-surface β-amyloid precursor protein to lysosomes: alternative processing into amyloid-bearing fragments. Nature 357:500-503.
23. Hartmann T, Bieger SC, Bruhl B, Tienari PJ, Ida N, Allsop D, Roberts GW, Masters CL, Dotti CG, Unsicker K, Beyreuther K. 1997. Distinct sites of intracellular production for Alzheimer's disease A β40/42 amyloid peptides. Nat Med 3:1016-1020.
24. Herreman A, Serneels L, Annaert W, Collen D, Schoonjans L, De Strooper B. 2000. Total inactivation of γ-secretase activity in presenilin-deficient embryonic stem cells. Nat Cell Biol 2:461-462.
25. Higaki J, Quon D, Zhong Z, Cordell B. 1995. Inhibition of β-amyloid formation identifies proteolytic precursors and subcellular site of catabolism. Neuron 14:651-659.
26. Hu Y, Ye Y, Fortini ME. 2002. Nicastrin is required for gamma-secretase cleavage of the Drosophila Notch receptor. Dev Cell 2:69-78.
27. Ikeuchi T, Sisodia SS. 2003. The Notch ligands, delta1 and jagged2, are substrates for presenilin-dependent "γ-secretase" cleavage. J Biol Chem 278:7751-7754.
28. Kaether C, Lammich S, Edbauer D, Ertl M, Rietdorf J, Capell A, Steiner H, Haass C. 2002. Presenilin-1 affects trafficking and processing of βAPP and is targeted in a complex with nicastrin to the plasma membrane. J Cell Biol 158:551-561.
29. Kimberly WT, Esler WP, Ye W, Ostaszewski BL, Gao J, Diehl TS, Selkoe DJ, Wolfe MS. 2003a. Notch and amyloid precursor protein are cleaved by similar γ-secretase(s). Biochemistry 42:137-144.
30. Kimberly WT, LaVoie MJ, Ostaszewski BL, Ye W, Wolfe MS, Selkoe DJ. 2002. Complex N-linked glycosylated nicastrin associates with active γ-secretase and undergoes tight cellular regulation. J Biol Chem 277:35113-35117.
31. Kimberly WT, LaVoie MJ, Ostaszewski BL, Ye W, Wolfe MS, Selkoe DJ. 2003b. γ-Secretase is a membrane protein complex comprised of presenilin, nicastrin aph-1 and pen-2. Proc Natl Acad Sci USA 100:6382-6387.
32. Kimberly WT, Xia W, Rahmati T, Wolfe MS, Selkoe DJ. 2000. The transmembrane aspartates in presenilin 1 and 2 are obligatory for γ-secretase activity and amyloid β-protein generation. J Biol Chem 275:3173-3178.
33. Kimberly WT, Zheng JB, Guenette SY, Selkoe DJ. 2001. The intracellular domain of the β-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a Notch-like manner. J Biol Chem 276:40288-40292.
34. Lammich S, Okochi M, Takeda M, Kaether C, Capell A, Zimmer AK, Edbauer D, Walter J, Steiner H, Haass C. 2002. Presenilin dependent intramembrane proteolysis of CD44 leads to the liberation of its intracellular domain and the secretion of an Aβ-like peptide. J Biol Chem 277:44754-44759.
35. Leem JY, Vijayan S, Han P, Cai D, Machura M, Lopes KO, Veselits ML, Xu H, Thinakaran G. 2002. Presenilin 1 is required for maturation and cell surface accumulation of nicastrin. J Biol Chem 277:19236-192340.
36. Levitan D, Doyle TG, Brousseau D, Lee MK, Thinakaran G, Slunt HH, Sisodia SS, Greenwald I. 1996. Assessment of normal and mutant human presenilin function in Caenorhabditis elegans. Proc Natl Acad Sci USA 93:14940-14944.
37. Levitan D, Greenwald I. 1995. Facilitation of lin-12-mediated signalling by sel-12, a Caenorhabditis elegans S182 Alzheimer's disease gene. Nature 377:351-354.
38. Li YM, Xu M, Lai MT, Huang Q, Castro JL, DiMuzio-Mower J, Harrison T, Lellis C, Nadin A, Neduvelil JG, Register RB, Sardana MK, Shearman MS, Smith AL, Shi XP, Yin KC, Shafer JA, Gardell SJ. 2000. Photo-activated gamma-secretase inhibitors directed to the active site covalently label presenilin 1. Nature 405:689-694.
39. Lopez-Schier H, St Johnston D. 2002. Drosophila nicastrin is essential for the intramembranous cleavage of notch. Dev Cell 2:79-89.
40. Marambaud P, Shioi J, Serban G, Georgakopoulos A, Sarner S, Nagy V, Baki L, Wen P, Efthimiopoulos S, Shao Z, Wisniewski T, Robakis NK. 2002. A presenilin-1/γ-secretase cleavage releases the E-cadherin intracellular domain and regulates disassembly of adherens junctions. EMBO J 21:1948-1956.
41. McLendon C, Xin T, Ziani-Cherif C, Murphy MP, Findlay KA, Lewis PA, Pinnix I, Sambamurti K, Wang R, Fauq A, Golde TE. 2000. Cell-free assays for γ-secretase activity. FASEB J 14:2383-2386.
42. Murakami D, Okamoto I, Nagano O, Kawano Y, Tomita T, Iwatsubo T, De Strooper B, Yumoto E, Saya H. 2003. Presenilin-dependent γ-secretase activity mediates the intramembranous cleavage of CD44. Oncogene 22:1511-1516.
43. Ni CY, Murphy MP, Golde TE, Carpenter G. 2001. γ-Secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase. Science 294:2179-2181.
44. Perez RG, Soriano S, Hayes JD, Ostaszewski B, Xia W, Selkoe DJ, Chen X, Stokin GB, Koo EH. 1999. Mutagenesis identifies new signals for β-amyloid precursor protein endocytosis, turnover, and the generation of secreted fragments, including Aβ42. J Biol Chem 274:18851-18856.
45. Petit A, Bihel F, Alves da Costa C, Pourquie O, Checler F, Kraus JL. 2001. New protease inhibitors prevent γ-secretase-mediated production of Abeta40/42 without affecting Notch cleavage. Nat Cell Biol 3:507-511.
46. Ponting CP, Hutton M, Nyborg A, Baker M, Jansen K, Golde TE. 2002. Identification of a novel family of presenilin homologues. Hum Mol Genet 11:1037-1044.
47. Ratovitski T, Slunt HH, Thinakaran G, Price DL, Sisodia SS, Borchelt DR. 1997. Endoproteolytic processing and stabilization of wild-type and mutant presenilin. J Biol Chem 272:24536-24541.
48. Rawson RB, Zelenski NG, Nijhawan D, Ye J, Sakai J, Hasan MT, Chang TY, Brown MS, Goldstein JL. 1997. Complementation cloning of S2P, a gene encoding a putative metalloprotease required for intramembrane cleavage of SREBPs. Mol Cell 1:47-57.
49. Ray WJ, Yao M, Mumm J, Schroeter EH, Saftig P, Wolfe M, Selkoe DJ, Kopan R, Goate AM. 1999. Cell surface presenilin-1 participates in the γ-secretase-like proteolysis of Notch. J Biol Chem 274:36801-36807.
50. Rudner DZ, Fawcett P, Losick R. 1999. A family of membrane-embedded metalloproteases involved in regulated proteolysis of membrane-associated transcription factors. Proc Natl Acad Sci USA 96:14765-14770.
51. Sakai J, Duncan EA, Rawson RB, Hua X, Brown MS, Goldstein JL. 1996. Sterol-regulated release of SREBP-2 from cell membranes requires two sequential cleavages, one within a transmembrane segment. Cell 85:1037-1046.
52. Schroeter EH, Kisslinger JA, Kopan R. 1998. Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain. Nature 393:382-386.
53. Selkoe DJ. 1999. Translating cell biology into therapeutic advances in Alzheimer's disease. Nature 399:A23-31.
54. Selkoe DJ. 2001. Alzheimer's disease: genes, proteins, and therapy. Physiol Rev 81:741-766.
55. Simons M, Keller P, De Strooper B, Beyreuther K, Dotti CG, Simons K. 1998. Cholesterol depletion inhibits the generation of β-amyloid in hippocampal neurons. Proc Natl Acad Sci USA 95:6460-4.
56. Sinha S, Anderson JP, Barbour R, Basi GS, Caccavello R, Davis D, Doan M, Dovey HF, Frigon N, Hong J, Jacobson-Croak K, Jewett N, Keim P, Knops J, Lieberburg I, Power M, Tan H, Tatsuno G, Tung J, Schenk D, Seubert P, Suomensaari SM, Wang S, Walker D, John V. 1999. Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature 402:537-540.
57. Soriano S, Kang DE, Fu M, Pestell R, Chevallier N, Zheng H, Koo EH. 2001. Presenilin 1 negatively regulates β-catenin/T cell factor/lymphoid enhancer factor-1 signaling independently of β-amyloid precursor protein and notch processing. J Cell Biol 152:785-794.
58. Steiner H, Capell A, Pesold B, Citron M, Kloetzel PM, Selkoe DJ, Romig H, Mendla K, Haass C. 1998. Expression of Alzheimer's disease-associated presenilin-1 is controlled by proteolytic degradation and complex formation. J Biol Chem 273:32322-32331.
59. Steiner H, Duff K, Capell A, Romig H, Grim MG, Lincoln S, Hardy J, Yu X, Picciano M, Fechteler K, Citron M, Kopan R, Pesold B, Keck S, Baader M, Tomita T, Iwatsubo T, Baumeister R, Haass C. 1999. A loss of function mutation of presenilin-2 interferes with amyloid β-peptide production and notch signaling. J Biol Chem 274:28669-28673.
60. Steiner H, Winkler E, Edbauer D, Prokop S, Basset G, Yamasaki A, Kostka M, Haass C. 2002. PEN-2 is an integral component of the γ-secretase complex required for the coordinated expression of presenilin and nicastrin. J Biol Chem 277:39062-39065.
61. Takasugi N, Tomita T, Hayashi I, Tsuruoka M, Niimura M, Takahashi Y, Thinakaran G, Iwatsubo T. 2003. The role of presenilin cofactors in the γ-secretase complex. Nature 422:438-441.
62. Thinakaran G, Borchelt DR, Lee MK, Slunt HH, Spitzer L, Kim G, Ratovitsky T, Davenport F, Nordstedt C, Seeger M, Hardy J, Levey AI, Gandy SE, Jenkins NA, Copeland NG, Price DL, Sisodia SS. 1996. Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo. Neuron 17:181-190.
63. Thinakaran G, Harris CL, Ratovitski T, Davenport F, Slunt HH, Price DL, Borchelt DR, Sisodia SS. 1997. Evidence that levels of presenilins (PS1 and PS2) are coordinately regulated by competition for limiting cellular factors. J Biol Chem 272:28415-28422.
64. Tomita T, Katayama R, Takikawa R, Iwatsubo T. 2002. Complex N-glycosylated form of nicastrin is stabilized and selectively bound to presenilin fragments. FEBS Lett 520:117-121.
65. Urban S, Lee JR, Freeman M. 2001. Drosophila rhomboid-1 defines a family of putative intramembrane serine proteases. Cell 107:173-182.
66. Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, Luo Y, Fisher S, Fuller J, Edenson S, Lile J, Jarosinski MA, Biere AL, Curran E, Burgess T, Louis JC, Collins F, Treanor J, Rogers G, Citron M. 1999. β-Secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286:735-741.
67. Weihofen A, Binns K, Lemberg MK, Ashman K, Martoglio B. 2002. Identification of signal peptide peptidase, a presenilin-type aspartic protease. Science 296:2215-2218.
68. Wild-Bode C, Yamazaki T, Capell A, Leimer U, Steiner H, Ihara Y, Haass C. 1997. Intracellular generation and accumulation of amyloid β-peptide terminating at amino acid 42. J Biol Chem 272:16085-16088.
69. Wolfe MS, Xia W, Moore CL, Leatherwood DD, Ostaszewski B, Donkor IO, Selkoe DJ. 1999a. Peptidomimetic probes and molecular modeling suggest Alzheimer's γ-secretases are intramembrane-cleaving aspartyl proteases. Biochemistry 38:4720-4727.
70. Wolfe MS, Xia W, Ostaszewski BL, Diehl TS, Kimberly WT, Selkoe DJ. 1999b. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and γ-secretase activity. Nature 398:513-517.
71. Yan R, Bienkowski MJ, Shuck ME, Miao H, Tory MC, Pauley AM, Brashier JR, Stratman NC, Mathews WK, Buhl AE, Carter DB, Tomasselli AG, Parodi LA, Heinrikson RL, Gurney ME. 1999. Membrane-anchored aspartyl protease with Alzheimer's disease β-secretase activity. Nature 402:533-537.
72. Yu G, Chen F, Levesque G, Nishimura M, Zhang DM, Levesque L, Rogaeva E, Xu D, Liang Y, Duthie M, St George-Hyslop PH, Fraser PE. 1998. The presenilin 1 protein is a component of a high molecular weight intracellular complex that contains β-catenin. J Biol Chem 273:16470-16475.
73. Yu G, Nishimura M, Arawaka S, Levitan D, Zhang L, Tandon A, Song YQ, Rogaeva E, Chen F, Kawarai T, Supala A, Levesque L, Yu H, Yang DS, Holmes E, Milman P, Liang Y, Zhang DM, Xu DH, Sato C, Rogaev E, Smith M, Janus C, Zhang Y, Aebersold R, Farrer LS, Sorbi S, Bruni A, Fraser P, St George-Hyslop P. 2000. Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and βAPP processing. Nature 407:48-54.
74. Zhang Z, Nadeau P, Song W, Donoviel D, Yuan M, Bernstein A, Yankner BA. 2000. Presenilins are required for γ-secretase cleavage of β-APP and transmembrane cleavage of Notch-1. Nat Cell Biol 2:463-465.