Skip to main content
SpringerLink
Log in

The NEXT Step in Notch Processing and its Relevance to Amyloid Precursor Protein

  • Conference paper
Neurodegenerative Disorders: Loss of Function Through Gain of Function

Part of the book series: Research and Perspectives in Alzheimer’s Disease ((ALZHEIMER))

  • 141 Accesses

Abstract

The last Nobel Prize in Physiology and Medicine awarded in the twentieth century went to Günter Blobel for his discovery that proteins have intrinsic signals governing their transport and localization in the cell. It is only fitting that, at the close of the millennium, the confluence of several unrelated fields resulted in the emergence of a new paradigm for signal transduction: regulated intramembranous proteolysis (RIP: Brown et al. 2000) of “dual address” proteins. Scientists working in topics as unrelated as Alzheimer’s disease, bacterial sporulation, lipid metabolism, Notch signaling and unfolded protein response all contributed to this realization. “Dual address” proteins contain two intrinsic signals: the first directs proteins to a holding site where — in response to stimulus — they undergo intramembranous proteolysis, releasing a subdomain that rides a second intrinsic signal to its site of action, often the nucleus. To researchers in the Alzheimer’s field, this realization provides new insight into the biological function of presenilin, which was discovered in humans due to its involvement in familial Alzheimer’s disease (FAD) and in the worm C. elegans for its role in Notch signaling. This article will describe these developments from the perspective of the Notch protein, in particular the advances that have occurred over the last five years in the Notch field. This period was critical in shaping our current understanding of how a signal is transduced through the Notch receptor. Defining Notch as a substrate for presenilin, and the emergence of additional substrates, has helped elucidate the role of presinilin proteins in the cell and will assist in the search for a treatment for Alzheimer’s disease.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Angerer LM, Angerer RC (1999) Regulative development of the sea urchin embryo: Signalling cascades and morphogen gradients [Review]. Sem Cell Dev Biol 10: 327–334

    Article  CAS  Google Scholar 

  • Artavanis-Tsakonas S, Simpson P ( 1991 Choosing a cell fate: a view from the Notch locus. [Review]. Trends Genet 7: 403–408

    Article  PubMed  CAS  Google Scholar 

  • Artavanis-Tsakonas S, Rand MD, Lake RJ (1999) Notch signaling: cell fate control and signal integration in development. [Review] Science 284: 770–776

    Article  PubMed  CAS  Google Scholar 

  • Bailey AM, Posakony JW (1995) Suppressor of Hairless directly activates transcription of Enhancer of split complex genes in response to Notch receptor activity. Genes Dev 9: 2609–2622

    Article  PubMed  CAS  Google Scholar 

  • Blaumueller CM, Qi HL, Zagouras P, Artavanis-Tsakonas S (1997) Intracellular cleavage of Notch leads to a heterodimeric receptor on the plasma membrane. Cell 90: 281–291

    Article  PubMed  CAS  Google Scholar 

  • Bray S (1998) Notch signalling in Drosophila: three ways to use a pathway. Sem Cell Dev Biol 9: 591–597

    Article  CAS  Google Scholar 

  • Brou C, Logeat F, Gupt N, Bessia C, LeBail O, Doedens JR, Cumano A, Roux P, Black RA, Israel A (2000) A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE. Molecular Cell 5: 207–216

    Article  PubMed  CAS  Google Scholar 

  • Brown MS, Ye J, Rawson RB, Goldstein JL (2000) Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans includes the SREBPs (sterol regulatory elementbinding proteins), transmembrane proteins of the ER whose cytosolic ( Review ). Cell 100: 391–398

    Article  PubMed  CAS  Google Scholar 

  • Collier JR, Monk NAM, Maini PK, Lewis JH (1996) Pattern formation by lateral inhibition with feedback–a mathematical model of Delta-Notch intercellular signalling. J Theoret Biol 183: 429–446

    Article  CAS  Google Scholar 

  • Delapompa J, Wakeham A, Correia KM, Samper E, Brown S, Aguilera RJ, Nakano T, Honjo T, Mak TW, Rossant J, Conlon RA (1997) Conservation of the Notch signalling pathway in mammalian neurogenesis. Development 124: 1139–1148

    CAS  Google Scholar 

  • 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-l-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature 398: 518–522

    Article  PubMed  Google Scholar 

  • Donoviel DB, Hadjantonakis AK, Ikeda M, Zheng H, Hyslop PS, Bernstein A (1999) Mice lacking both presenilin genes exhibit early embryonic patterning defects. Genes Dev 13: 2801–2810

    Article  PubMed  CAS  Google Scholar 

  • Greenwald I (1994) Structure/function studies of lin-12/Notch proteins [Review]. Curr Opin Genet Dev 4: 556–562

    Article  PubMed  CAS  Google Scholar 

  • Greenwald I (1998) Lin-12/Notch signaling–lessons from worms and flies. Genes Dev 12: 1751–1762

    Article  PubMed  CAS  Google Scholar 

  • Haass RN (1997) Sanctioning madness. Foreign Affairs 76: 74–85

    Article  Google Scholar 

  • Hardy J (1997) The amyloid cascade hypothesis of AD - decoy or real McCoy - Reply. Trends Neurosci 20: 559

    Article  CAS  Google Scholar 

  • Heitzler P, Simpson P (1991) The choice of cell fate in the epidermis of Drosophila. Cell 64: 1083–1092

    Article  PubMed  CAS  Google Scholar 

  • Heitzler P, Simpson P (1993) Altered epidermal growth factor-like sequences provide evidence for a role of Notch as a receptor in cell fate decisions. Development 117: 1113–1123

    PubMed  CAS  Google Scholar 

  • Herreman A, Hartmann D, Annaert W, Saftig P, Craessaerts K, Serneels L, Umans L, Schrijvers V, Checler F, Vanderstichele H, Baekelandt V, Dressel R, Cupers P, Huylebroeck D, Zwijsen A, Van Leuven F, De Strooper B (1999) 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 96: 11872–11877

    Article  PubMed  CAS  Google Scholar 

  • Hsieh JJD, Hayward SD (1995) Masking of the CBF 1/RBPjx transcriptional repression domain by Epstein-Barr virus EBNA2. Science 268: 560–563

    Article  PubMed  CAS  Google Scholar 

  • Hsieh JJ, Henkel T, Salmon P, Robey E, Peterson MG, Hayward SD (1996) Truncated mammalian Notch 1 activates CBF I /RBPJk-repressed genes by a mechanism resembling that of Epstein-Barr virus EBNA2. Mol Cell Biol 16: 952–959

    PubMed  CAS  Google Scholar 

  • Hsieh JJD, Zhou SF, Chen L, Young DB, Hayward SD (1999) CIR, a corepressor linking the DNA binding factor CBF1 to the histone deacetylase complex. Proc Natl Acad Sci USA 96: 23–28

    Article  PubMed  CAS  Google Scholar 

  • Huppert SS, Le A, Schroeter EH, Mumm JS, Saxena MT, Milner LA, Kopan R (2000) Embryonic lethality in mice homozygous for a processing-deficient allele of Notchl. Nature 405: 966–970

    Article  PubMed  CAS  Google Scholar 

  • Jarriault S, Brou C, Logeat F, Schroeter EH, Kopan R, Israel A (1995) Signalling downstream of activated mammalian Notch. Nature 377: 355–358

    Article  PubMed  CAS  Google Scholar 

  • Joutel A, Tournier-Lasserve E (1998) Notch signalling pathway and human diseases [Review]. Sem Cell Dev 9: 619–625

    Article  CAS  Google Scholar 

  • Kao HY, Ordentlich P, Koyanonakagawa N, Tang Z, Downes M, Kintner CR, Evans RM, Kadesch T (1998) A histone deacetylase corepressor complex regulates the Notch signal transduction pathway. Genes Dev 12: 2269–2277

    Article  PubMed  CAS  Google Scholar 

  • Kidd S, Lieber T, Young MW (1998) Ligand-induced cleavage and regulation of nuclear entry of Notch in Drosophila melanogaster embryos. Genes Dev 12: 3728–3740

    Article  PubMed  CAS  Google Scholar 

  • Kimble J, Henderson S, Crittenden S (1998) Notch/Lin-12 signaling–transduction by regulated protein slicing. Trends Biochem Sci 23: 353–357

    Article  PubMed  Google Scholar 

  • Kopan R, Turner DL (1996) The Notch pathway: democracy and aristocracy in the selection of cell fate. Curr Opin Neurobiol6: 594–601

    Google Scholar 

  • Kopan R, Schroeter EH, Weintraub H, Nye JS (1996) Signal transduction by activated mNotch: Importance of proteolytic processing and its regulation by the extracellular domain. Proc Natl Acad Sci USA 93: 1683–1687

    Google Scholar 

  • Kroos L, Kunkel B, Losick R (1989) Switch protein alters specificity of RNA polymerase containing a compartment-specific sigma factor. Science 243: 526–529

    Article  PubMed  CAS  Google Scholar 

  • LaBell TL, Trempy JE, Haldenwang WG (1987) Sporulation-specific sigma factor sigma 29 of Bacillus subtilis is synthesized from a precursor protein, P31. Proc Natl Acad Sci USA 84: 1784–1788

    Article  PubMed  CAS  Google Scholar 

  • Lecourtois M, Schweisguth F (1998) Indirect evidence for Delta-dependent intracellular processing of Notch in Drosophila embryos. Curr Biol 8: 771–774

    Article  PubMed  CAS  Google Scholar 

  • Levitan D, Greenwald I (1998) Effects of SEL-12 presenilin on LIN-12 localization and function in Caenorhabditis elegans. Development 125: 3599–3606

    PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Lewis J (1996) Neurogenic genes and vertebrate neurogenesis. Curr Opin Neurobiol 6: 3–10 Lewis J (1998a) Notch signalling–a short cut to the nucleus. Nature 393: 304–305

    Google Scholar 

  • Lewis J (1998b) Notch signalling and the control of cell fate choices in vertebrates. Sem Cell Dev Biol 9: 583–589

    Article  CAS  Google Scholar 

  • Li XJ, Greenwald I (1997) 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 94: 12204–12209

    Article  PubMed  CAS  Google Scholar 

  • Lieber T, Kidd S, Alcamo E, Corbin V, Young MW (1993) 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 7: 1949–1965

    Article  PubMed  CAS  Google Scholar 

  • Logeat F, Bessia C, Brou C, Lebail O, Jarriault S. Seidah NG, Israel A (1998) The Notchl receptor is cleaved constitutively by a furin-like convertase. Proc Natl Acad Sci USA 95: 8108–8112

    Article  PubMed  CAS  Google Scholar 

  • Lu S, Halberg R, Kroos L (1990) Processing of the mother-cell sigma factor, sigma K, may depend on events occurring in the forespore during Bacillus subtilis development. Proc Natl Acad Sci USA 87: 9722–9726

    Article  PubMed  CAS  Google Scholar 

  • Lu S, Cutting S, Kroos L (1995) Sporulation protein Spo1VFB from Bacillus subtilis enhances processing of the sigma facto precursor Pro-sigma K in the absence of other sporulation gene products. J Bacteriol 177: 1082–1085

    PubMed  CAS  Google Scholar 

  • Miele L, Osborne B (1999) Arbiter of differentiation and death: Notch signaling meets apoptosis [Review]. J Cell Physiol 181: 393–409

    Google Scholar 

  • Morel V, Schweisguth F (2000) Repression by suppressor of Hairless and activation by Notch are required to define a single row of single-minded expressing cells in the Drosophila embryo. Genes Dev 14: 377–388

    PubMed  CAS  Google Scholar 

  • Mumm JS, Schroeter EH, Saxena MT, Griesemer A, Tian X, Pan DJ, Ray WJ, Kopan R (2000) A ligand-induced extracellular cleavage regulates y-secretase-like proteolytic activation of Notch 1. Mol Cell 5: 197–206

    Article  PubMed  CAS  Google Scholar 

  • Naruse S, Thinakaran G, Luo JJ, Kusiak JW, Tomita T, Iwatsubo T, Qian XZ, Ginty DD, Price DL, Borchelt DR, Wong PC, Sisodia SS (1998) Effects of PS 1 deficiency on membrane protein trafficking in neurons. Neuron 21: 1213–1221

    Article  PubMed  CAS  Google Scholar 

  • Nishimura M, Yu G, Levesque G, Zhang DM, Ruel L, Chen F, Milman P, Holmes E, Liang Y, Kawarai T, Jo E, Supala A, Rogaeva E, Xu DM, Janus C, Levesque L, Bi Q, Duthie M, Rozmahel R, Mattila K, Lannfelt L, Westaway D, Mount HTJ, Woodgett J, Fraser PE, St George-Hyslop P (1999) Presenilin mutations associated with Alzheimer disease cause defective intracellular trafficking of beta-catenin, a component of the presenilin protein complex. Nature Med 5: 164–169

    Article  PubMed  CAS  Google Scholar 

  • Oka C, Nakano T, Wakeham A, Delapompa JL, Mori C, Sakai T, Okazaki S, Kawaichi M, Shiota K, Mak TW, Honjo T (1996) Disruption of the mouse Rbp-J(Kappa) gene results in early embryonic death (Vol 121, Pg 3291, 1995). Development 122: 405–407

    CAS  Google Scholar 

  • Olave I, Reinberg D, Vales LD (1998) The mammalian transcriptional repressor Rbp ( Cbfl) targets Tfiid and Tfiia to prevent activated transcription. Genes Dev 12: 1621–1637

    Google Scholar 

  • Posakony JW (1994) Nature versus nurture: asymmetric cell divisions in Drosophila bristle development [comment]. [Review]. Cell 76: 415–418

    Article  PubMed  CAS  Google Scholar 

  • Radtke F, Wilson A, Stark G, Bauer M, van Meerwijk J, MacDonald HR, Aguet M (1999) Deficient T cell fate specification in mice with an induced inactivation of Notchl. Immunity 10: 547–558

    Article  PubMed  CAS  Google Scholar 

  • Rand DM, Grimm MLM, Artavanis-Tsakonas S, Patriub V, Blacklow CS, Sklar CJ, Aster CJ (2000). Calcium depletion dissociates and activates heterodimeric Notch receptors. Mol Cell Biol 20

    Google Scholar 

  • Ray WJ, Yao M, Mumm J, Schroeter EH, Saftig P, Wolfe M, Selkoe DJ, Kopan R, Goate AM (1999a) Cell surface presenilin-1 participates in the gamma-secretase-like proteolysis of notch. J Biol Chem 274: 36801–36807

    Article  PubMed  CAS  Google Scholar 

  • Ray WJ, Yao M, Nowotny P, Mumm J, Zhang WJ, Wu JY, Kopan R, Goate AM (1999b) Evidence for a physical interaction between presenilin and Notch. Proc Natl Acad Sci USA 96: 3263–3268

    Article  PubMed  CAS  Google Scholar 

  • Robey E (1999) Regulation of T Cell fate by Notch [Review]. Ann Rev Immunol 17: 283–295

    Article  CAS  Google Scholar 

  • Rooke JE, Xu T (1998) Positive and negative signals between interacting cells for establishing neural fate [Review]. Bioessays 20: 209–214

    Article  PubMed  CAS  Google Scholar 

  • Rudner DZ, Fawcet P, Losick R (1999) A family of membrane-embedded metalloproteases involved in regulated proteolysis of membrane-associated transcription factor. Proc Ntl Acad Sci USA 96: 14765–14770

    Article  CAS  Google Scholar 

  • Saito T, Watanabe N (1998) Positive and negative thymocyte selection. Crit Rev Immunol 18: 359–370

    Article  PubMed  CAS  Google Scholar 

  • Schroeter EH, Kisslinger JA, Kopan R (1998) Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain [see comments]. Nature 393: 382–386

    Article  PubMed  CAS  Google Scholar 

  • Selkoe DJ (1998) The cell biology of beta-amyloid precursor protein and presenilin in Alzheimer’s disease. Trends Cell Biol 8: 447–453

    Article  PubMed  CAS  Google Scholar 

  • Selkoe DJ (1999) Translating cell biology into therapeutic advances in Alzheimer’s disease [Review]. Nature 399: A23 - A31

    Article  PubMed  CAS  Google Scholar 

  • Song WH, Nadeau P, Yuan ML, Yang XD, Shen J, Yankner BA (1999) Proteolytic release and nuclear translocation of Notch-1 are induced by presenilin-1 and impaired by pathogenic presenilin-1 mutations. Proc Natl Acad Sci USA 96: 6959–6963

    Article  PubMed  CAS  Google Scholar 

  • 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 beta-peptide production and notch signaling. J Biol Chem 274: 28669–28673

    Article  PubMed  CAS  Google Scholar 

  • Struhl G, Adachi A (1998) Nuclear access and action of Notch in vivo. Cell 93: 649–660

    Article  PubMed  CAS  Google Scholar 

  • Struhl G, Greenwald I (1999) Presenilin is required for activity and nuclear access of Notch in Drosophila. Nature 398: 522–525

    Article  PubMed  CAS  Google Scholar 

  • Varnum-Finney B, Purton LE, Yu M, Brashemstein C, Flowers D, Staats S, Moore KA, Leroux I, Mann R, Gray G, Artavanis-Tsakonas S, Bernstein ID (1998) The Notch ligand, Jagged-1, influences the development of primitive hematopoietic precursor cells. Blood 91: 4084–4091

    PubMed  CAS  Google Scholar 

  • Westlund B, Parry D, Clover R, Basson M, Johnson CD (1999) Reverse genetic analysis of Caenorhabditis elegans presenilins reveals redundant but unequal roles for set-12 and hop-1 in Notch-pathway signaling. Proc Natl Acad Sci USA 96: 2497–2502

    Article  PubMed  CAS  Google Scholar 

  • Wolfe MS, De los Angeles J, Miller DD, Xia WM, Selkoe DJ (1999a) Are presenilins intramembranecleaving proteases? Implications for the molecular mechanism of Alzheimer’s disease. Biochemistry 38: 11223–11230

    Article  PubMed  CAS  Google Scholar 

  • Wolfe MS, Xia WM, Ostaszewski BL, Diehl TS, Kimberley WT, Selkoe DJ (1999b) Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature 398: 513–517

    Article  PubMed  CAS  Google Scholar 

  • Wu JY, Rao Y (1999) Fringe: defining borders by regulating the Notch pathway. Curr Opin Neurobiol 9: 537–543

    Article  PubMed  CAS  Google Scholar 

  • Ye YH, Fortini ME (1999) Apoptotic activities of wild-type and Alzheimer’s disease-related mutant presenilins in Drosopila melanogaster. J Cell Biol 146: 1351–1364

    Article  PubMed  CAS  Google Scholar 

  • Ye YH, Lukinova N, Fortini ME (1999) Neurogenic phenotypes and altered Notch processing in Drosophila presenilin mutants. Nature 398: 525–529

    Article  PubMed  CAS  Google Scholar 

Download references

Authors
  1. R. Kopan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. Huppert
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J. S. Mumm
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. T. Saxena
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. E. H. Schroeter
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. W. J. Ray
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A. Goate
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. ZMBH, University of Heidelberg, Im Neuenheimer Feld 282, 69120, Heidelberg, Germany

    Konrad Beyreuther

  2. Pour la Recherche Thérapeutique, Fondation IPSEN, 24, rue Erlanger, 75781, Paris Cedex 16, France

    Yves Christen Ph. D.

  3. Department of Pathology and The Mental Health Institute of Victoria, The University of Melbourne, 3052, Parkville, Victoria, Australia

    Colin L. Masters M. D.

Rights and permissions

Reprints and permissions

Copyright information

© 2001 Springer-Verlag Berlin Heidelberg

About this paper

Cite this paper

Kopan, R. et al. (2001). The NEXT Step in Notch Processing and its Relevance to Amyloid Precursor Protein. In: Beyreuther, K., Christen, Y., Masters, C.L. (eds) Neurodegenerative Disorders: Loss of Function Through Gain of Function. Research and Perspectives in Alzheimer’s Disease. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-04399-8_8

Download citation

  • DOI: https://doi.org/10.1007/978-3-662-04399-8_8

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-07448-6

  • Online ISBN: 978-3-662-04399-8

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation