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Signalling

γ-Secretase-mediated proteolysis in cell-surface-receptor signalling

Key Points

  • The presenilin–γ-secretase complex mediates the intramembrane proteolysis of the Notch receptor and the amyloid precursor protein (APP).

  • Several lines of evidence indicate that presenilin is likely to function as the catalytic core of the γ-secretase proteolytic activity.

  • APP and Notch have alternate intramembrane cleavage sites that depend on γ-secretase activity.

  • Intramembrane cleavage of γ-secretase substrates is preceded by ectodomain shedding that is mediated by extracellular cleavage events.

  • Several new putative γ-secretase substrates have recently been identified, including the ErbB4 receptor tyrosine kinase, the CD44 cell-surface protein, E-cadherin, and the low-density lipoprotein-receptor-related protein (LRP).

  • For APP, ErbB4, CD44 and LRP, intramembrane proteolysis apparently liberates a signalling fragment of the molecule, which is similar to the role of this cleavage event in the Notch pathway.

  • A newly characterized type of intramembrane proteolysis generates secreted ligands that activate the epidermal growth factor receptor (EGFR).

Abstract

Many cell-surface receptors transmit signals to the nucleus through complex protein cascades. By contrast, the Notch signalling pathway uses a relatively direct mechanism, in which the intracellular domain of the receptor is liberated by intramembrane cleavage and translocates to the nucleus. This critical cleavage is mediated by the γ-secretase complex, and new findings reveal that this mechanism is used by various receptors, although many questions remain about the biochemical details.

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Figure 1: Structures of representative Notch receptors and ligands, and of the putative γ-secretase-complex components.
Figure 2: Proteolytic regulation of Notch-receptor maturation and activation.
Figure 3: Role of secretases in APP processing.
Figure 4: Comparison of identified cleavage sites in the transmembrane domains of known and putative γ-secretase substrates.

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References

  1. Artavanis-Tsakonas, S., Rand, M. D. & Lake, R. J. Notch signaling: cell fate control and signal integration in development. Science 284, 770–776 (1999).

    Article  CAS  PubMed  Google Scholar 

  2. Fortini, M. E. Notch and Presenilin: a proteolytic mechanism emerges. Curr. Opin. Cell Biol. 13, 627–634 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Kopan, R. & Goate, A. A common enzyme connects Notch signaling and Alzheimer's disease. Genes Dev. 14, 2799–2806 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Weinmaster, G. Notch signal transduction: a real rip and more. Curr. Opin. Genet. Dev. 10, 363–369 (2000).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  6. Wharton, K. A., Johansen, K. M., Xu, T. & Artavanis-Tsakonas, S. Nucleotide sequence from the neurogenic locus Notch implies a gene product that shares homology with proteins containing EGF-like repeats. Cell 43, 567–581 (1985).

    Article  CAS  PubMed  Google Scholar 

  7. Kidd, S., Kelley, M. R. & Young, M. W. Sequence of the Notch locus of Drosophila melanogaster: relationship of the encoded protein to mammalian clotting and growth factors. Mol. Cell. Biol. 6, 3094–3108 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Blaumueller, C. M. & Artavanis-Tsakonas, S. Comparative aspects of Notch signaling in lower and higher eukaryotes. Perspect. Dev. Neurobiol. 4, 325–343 (1997).

    CAS  PubMed  Google Scholar 

  9. Artavanis-Tsakonas, S., Matsuno, K. & Fortini, M. E. Notch signaling. Science 268, 225–232 (1995).

    Article  CAS  PubMed  Google Scholar 

  10. Greenwald, I. Structure/function studies of Lin-12/Notch proteins. Curr. Opin. Genet. Dev. 4, 556–562 (1994).

    Article  CAS  PubMed  Google Scholar 

  11. Selkoe, D. J. The cell biology of β-amyloid precursor protein and presenilin in Alzheimer's disease. Trends Cell Biol. 8, 447–453 (1998).

    Article  CAS  PubMed  Google Scholar 

  12. Sisodia, S. S. & St George-Hyslop, P. H. γ-Secretase, Notch, Aβ and Alzheimer's disease: where do the presenilins fit in? Nature Rev. Neurosci. 3, 281–290 (2002).

    Article  CAS  Google Scholar 

  13. De Strooper, B. D. & Annaert, W. Presenilins and the intramembrane proteolysis of proteins: facts and fiction. Nature Cell Biol. 3, E221–E225 (2001).

    Article  CAS  Google Scholar 

  14. Selkoe, D. J. Translating cell biology into therapeutic advances in Alzheimer's disease. Nature 399, A23–A31 (1999).

    Article  CAS  PubMed  Google Scholar 

  15. L'Hernault, S. W. & Arduengo, P. M. Mutation of a putative sperm membrane protein in Caenorhabditis elegans prevents sperm differentiation but not its associated meiotic divisions. J. Cell Biol. 119, 55–68 (1992).

    Article  CAS  PubMed  Google Scholar 

  16. Levitan, D. & Greenwald, I. Facilitation of lin-12-mediated signalling by sel-12, a Caenorhabditis elegans S182 Alzheimer's disease gene. Nature 377, 351–354 (1995).

    Article  CAS  PubMed  Google Scholar 

  17. Doan, A. et al. Protein topology of presenilin 1. Neuron 17, 1023–1030 (1996).

    Article  CAS  PubMed  Google Scholar 

  18. Li, X. & Greenwald, I. Membrane topology of the C. elegans SEL-12 presenilin. Neuron 17, 1015–1021 (1996).

    Article  CAS  PubMed  Google Scholar 

  19. Li, X. & Greenwald, I. Additional evidence for an eight-transmembrane-domain topology for Caenorhabditis elegans and human presenilins. Proc. Natl Acad. Sci. USA 95, 7109–7114 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ye, Y. & Fortini, M. E. Characterization of Drosophila Presenilin and its colocalization with Notch during development. Mech. Dev. 79, 199–211 (1998).

    Article  CAS  PubMed  Google Scholar 

  21. Ray, W. J. et al. Cell surface presenilin-1 participates in the γ-secretase-like proteolysis of Notch. J. Biol. Chem. 274, 36801–36807 (1999).Describes the association of presenilin and Notch in the secretory pathway and their co-transport to the cell surface.

    Article  CAS  PubMed  Google Scholar 

  22. Nowotny, P. et al. Posttranslational modification and plasma membrane localization of the Drosophila melanogaster Presenilin. Mol. Cell. Neurosci. 15, 88–98 (2000).

    Article  CAS  PubMed  Google Scholar 

  23. Levitan, D. et al. PS1 N- and C-terminal fragments form a complex that functions in APP processing and Notch signaling. Proc. Natl Acad. Sci. USA 98, 12186–12190 (2001).Separate amino- and carboxy-terminal fragments of presenilin were engineered and co-expressed in a presenilin loss-of-function genetic background to show that, in the absence of intact holoprotein, the cleaved fragments can together constitute functional presenilin.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Morihara, T. et al. Absence of endoproteolysis but no effects on amyloid β production by alternative splicing forms of presenilin-1, which lack exon 8 and replace D257A. Mol. Brain Res. 85, 85–90 (2000).

    Article  CAS  PubMed  Google Scholar 

  25. Thinakaran, G. et al. Evidence that levels of presenilins (PS1 and PS2) are coordinately regulated by competition for limiting cellular factors. J. Biol. Chem. 272, 28415–28422 (1997).

    Article  CAS  PubMed  Google Scholar 

  26. Ratovitski, T. et al. Endoproteolytic processing and stabilization of wild-type and mutant presenilin. J. Biol. Chem. 272, 24536–24541 (1997).References 25 and 26 describe evidence that a minor fraction of presenilin is endoproteolysed and stabilized through interactions with limiting cellular factors.

    Article  CAS  PubMed  Google Scholar 

  27. Yu, G. et al. The presenilin 1 protein is a component of a high molecular weight intracellular complex that contains β-catenin. J. Biol. Chem. 273, 16470–16475 (1998).

    Article  CAS  PubMed  Google Scholar 

  28. Yu, G. et al. Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and βAPP processing. Nature 407, 48–54 (2000).Describes the discovery and initial characterization of a new component of the presenilin complex that interacts with presenilin and presenilin substrates.

    Article  CAS  PubMed  Google Scholar 

  29. Li, Y. M. et al. Presenilin 1 is linked with γ-secretase activity in the detergent solubilized state. Proc. Natl Acad. Sci. USA 97, 6138–6143 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Goutte, C., Hepler, W., Mickey, K. M. & Priess, J. R. aph-2 encodes a novel extracellular protein required for GLP-1-mediated signaling. Development 127, 2481–2492 (2000).

    Article  CAS  PubMed  Google Scholar 

  31. Chen, F. et al. Nicastrin binds to membrane-tethered Notch. Nature Cell Biol. 3, 751–754 (2001).

    Article  CAS  PubMed  Google Scholar 

  32. Esler, W. P. et al. Activity-dependent isolation of the presenilin-γ-secretase complex reveals nicastrin and a γ substrate. Proc. Natl Acad. Sci. USA 99, 2720–2725 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Hu, Y., Ye, Y. & Fortini, M. E. Nicastrin is required for γ-secretase cleavage of the Drosophila Notch receptor. Dev. Cell 2, 69–78 (2002).

    Article  CAS  PubMed  Google Scholar 

  34. Chung, H. M. & Struhl, G. Nicastrin is required for Presenilin-mediated transmembrane cleavage in Drosophila. Nature Cell Biol. 3, 1129–1132 (2001).

    Article  CAS  PubMed  Google Scholar 

  35. Lopez-Schier, H. & St Johnston, D. Drosophila Nicastrin is essential for the intramembranous cleavage of Notch. Dev. Cell 2, 79–89 (2002).References 33–35 show that the Drosophila γ-secretase complex member nicastrin is essential for Notch proteolysis and signalling, as well as for proper stabilization and cell-surface localization of presenilin.

    Article  CAS  PubMed  Google Scholar 

  36. Levitan, D., Yu, G., St George Hyslop, P. & Goutte, C. APH-2/nicastrin functions in LIN-12/Notch signaling in the Caenorhabditis elegans somatic gonad. Dev. Biol. 240, 654–661 (2001).

    Article  CAS  PubMed  Google Scholar 

  37. 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. USA 99, 775–779 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Francis, R. et al. 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 (2002).References 37 and 38 describe two additional proteins — the multipass transmembrane proteins Aph-1 and Pen-2 — that are involved in γ–secretase function.

    Article  CAS  PubMed  Google Scholar 

  39. Wolfe, M. S. et al. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and γ-secretase activity. Nature 398, 513–517 (1999).Proposes that presenilin might function as an intramembrane protease based on the effects of presenilin transmembrane domain amino-acid substitutions on APP metabolism.

    Article  CAS  PubMed  Google Scholar 

  40. Wolfe, M. S., De Los Angeles, J., Miller, D. D., Xia, W. & Selkoe, D. J. Are presenilins intramembrane-cleaving proteases? Implications for the molecular mechanism of Alzheimer's disease. Biochemistry 38, 11223–11230 (1999).

    Article  CAS  PubMed  Google Scholar 

  41. Lin, X. et al. Sequence and analysis of chromosome 2 of the plant Arabidopsis thaliana. Nature 402, 761–768 (1999).

    Article  CAS  PubMed  Google Scholar 

  42. Wolfe, M. S. et al. Peptidomimetic probes and molecular modeling suggest that Alzheimer's γ-secretase is an intramembrane-cleaving aspartyl protease. Biochemistry 38, 4720–4727 (1999).

    Article  CAS  PubMed  Google Scholar 

  43. De Strooper, B. et al. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 391, 387–390 (1998).

    Article  CAS  PubMed  Google Scholar 

  44. Naruse, S. et al. Effects of PS1 deficiency on membrane protein trafficking in neurons. Neuron 21, 1213–1221 (1998).

    Article  CAS  PubMed  Google Scholar 

  45. Yu, G. et al. Mutation of conserved aspartates affect maturation of presenilin 1 and presenilin 2 complexes. Acta Neurol. Scand. Suppl. 176, 6–11 (2000).

    Article  CAS  PubMed  Google Scholar 

  46. Yu, G. et al. Mutation of conserved aspartates affects maturation of both aspartate mutant and endogenous presenilin 1 and presenilin 2 complexes. J. Biol. Chem. 275, 27348–27353 (2000).

    Article  CAS  PubMed  Google Scholar 

  47. Kim, S. H. et al. Multiple effects of aspartate mutant presenilin 1 on the processing and trafficking of amyloid precursor protein. J. Biol. Chem. 276, 43343–43350 (2001).

    Article  CAS  PubMed  Google Scholar 

  48. Li, Y. M. et al. Photoactivated γ-secretase inhibitors directed to the active site covalently label presenilin 1. Nature 405, 689–694 (2000).

    Article  CAS  PubMed  Google Scholar 

  49. Esler, W. P. et al. Transition-state analogue inhibitors of γ-secretase bind directly to presenilin-1. Nature Cell Biol. 2, 428–434 (2000).

    Article  CAS  PubMed  Google Scholar 

  50. Seiffert, D. et al. Presenilin-1 and -2 are molecular targets for γ-secretase inhibitors. J. Biol. Chem. 275, 34086–34091 (2000).References 48–50 show that certain pharmacological γ-secretase inhibitor compounds bind directly to presenilin.

    Article  CAS  PubMed  Google Scholar 

  51. Steiner, H. et al. Glycine 384 is required for presenilin-1 function and is conserved in bacterial polytopic aspartyl proteases. Nature Cell Biol. 2, 848–851 (2000).Notes similarities between presenilin and a class of bacterial membrane-embedded aspartyl proteases.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  53. Ye, Y., Lukinova, N. & Fortini, M. E. Neurogenic phenotypes and altered Notch processing in Drosophila Presenilin mutants. Nature 398, 525–529 (1999).

    Article  CAS  PubMed  Google Scholar 

  54. Guo, Y., Livne-Bar, I., Zhou, L. & Boulianne, G. L. Drosophila presenilin is required for neuronal differentiation and affects Notch subcellular localization and signaling. J. Neurosci. 19, 8435–8442 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Wong, P. C. et al. Presenilin 1 is required for Notch1 and DII1 expression in the paraxial mesoderm. Nature 387, 288–292 (1997).

    Article  CAS  PubMed  Google Scholar 

  56. Shen, J. et al. Skeletal and CNS defects in Presenilin-1-deficient mice. Cell 89, 629–639 (1997).

    Article  CAS  PubMed  Google Scholar 

  57. Donoviel, D. B. et al. Mice lacking both presenilin genes exhibit early embryonic patterning defects. Genes Dev. 13, 2801–2810 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. De Strooper, B. et al. A presenilin-1-dependent γ-secretase-like protease mediates release of Notch intracellular domain. Nature 398, 518–522 (1999).

    Article  CAS  PubMed  Google Scholar 

  59. Song, W. et al. 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 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Berechid, B. E., Thinakaran, G., Wong, P. C., Sisodia, S. S. & Nye, J. S. Lack of requirement for presenilin1 in Notch1 signaling. Curr. Biol. 9, 1493–1496 (1999).

    Article  CAS  PubMed  Google Scholar 

  61. Berezovska, O. et al. Aspartate mutations in presenilin and γ-secretase inhibitors both impair Notch1 proteolysis and nuclear translocation with relative preservation of Notch1 signaling. J. Neurochem. 75, 583–593 (2000).

    Article  CAS  PubMed  Google Scholar 

  62. Herreman, A. et al. Total inactivation of γ-secretase activity in presenilin-deficient embryonic stem cells. Nature Cell Biol. 2, 461–462 (2000).

    Article  CAS  PubMed  Google Scholar 

  63. Zhang, Z. et al. Presenilins are required for γ-secretase cleavage of β-APP and transmembrane cleavage of Notch-1. Nature Cell Biol. 2, 463–465 (2000).

    Article  CAS  PubMed  Google Scholar 

  64. Jack, C., Berezovska, O., Wolfe, M. S. & Hyman, B. T. Effect of PS1 deficiency and an APP γ-secretase inhibitor on Notch1 signaling in primary mammalian neurons. Mol. Brain Res. 87, 166–174 (2001).

    Article  CAS  PubMed  Google Scholar 

  65. Martys-Zage, J. L. et al. Requirement for Presenilin 1 in facilitating Jagged 2-mediated endoproteolysis and signaling of Notch 1. J. Mol. Neurosci. 15, 189–204 (2000).

    Article  CAS  PubMed  Google Scholar 

  66. Capell, A. et al. Presenilin-1 differentially facilitates endoproteolysis of the β-amyloid precursor protein and Notch. Nature Cell Biol. 2, 205–211 (2000).

    Article  CAS  PubMed  Google Scholar 

  67. Kulic, L. et al. Separation of presenilin function in amyloid β-peptide generation and endoproteolysis of Notch. Proc. Natl Acad. Sci. USA 97, 5913–5918 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Okochi, M. et al. A loss of function mutant of the presenilin homologue SEL-12 undergoes aberrant endoproteolysis in Caenorhabditis elegans and increases Aβ42 generation in human cells. J. Biol. Chem. 275, 40925–40932 (2000).

    Article  CAS  PubMed  Google Scholar 

  69. Zhang, D. M. et al. Mutation of the conserved N-terminal cysteine (Cys92) of human presenilin 1 causes increased Aβ42 secretion in mammalian cells but impaired Notch/lin-12 signalling in C. elegans. Neuroreport 11, 3227–3230 (2000).

    Article  CAS  PubMed  Google Scholar 

  70. Armogida, M. et al. Endogenous β-amyloid production in presenilin-deficient embryonic mouse fibroblasts. Nature Cell Biol. 3, 1030–1033 (2001).

    Article  CAS  PubMed  Google Scholar 

  71. Berechid, B. E. et al. Identification and characterization of presenilin-independent Notch signaling. J. Biol. Chem. 277, 8154–8165 (2002).

    Article  CAS  PubMed  Google Scholar 

  72. Wilson, C. A., Doms, R. W., Zheng, H. & Lee, V. M. -Y. Presenilins are not required for Aβ42 production in the early secretory pathway. Nature Neurosci. 5, 849–855 (2002).

    Article  CAS  PubMed  Google Scholar 

  73. Taniguchi, Y. et al. Notch receptor cleavage depends on but is not directly executed by presenilins. Proc. Natl Acad. Sci. USA 99, 4014–4019 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Schroeter, E. H., Kisslinger, J. A. & Kopan, R. Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain. Nature 393, 382–386 (1998).

    Article  CAS  PubMed  Google Scholar 

  75. Huppert, S. S. et al. Embryonic lethality in mice homozygous for a processing-deficient allele of Notch1. Nature 405, 966–970 (2000).

    Article  CAS  PubMed  Google Scholar 

  76. Murphy, M. P. et al. γ-secretase, evidence for multiple proteolytic activities and influence of membrane positioning of substrate on generation of amyloid β peptides of varying length. J. Biol. Chem. 274, 11914–11923 (1999).

    Article  CAS  PubMed  Google Scholar 

  77. Struhl, G. & Adachi, A. Requirements for Presenilin-dependent cleavage of Notch and other transmembrane proteins. Mol. Cell 6, 625–636 (2000).

    Article  CAS  PubMed  Google Scholar 

  78. Yu, C. et al. Characterization of a presenilin-mediated amyloid precursor protein carboxyl-terminal fragment γ. Evidence for distinct mechanisms involved in γ-secretase processing of the APP and Notch1 transmembrane domains. J. Biol. Chem. 276, 43756–43760 (2001).

    Article  CAS  PubMed  Google Scholar 

  79. Gu, Y. et al. Distinct intramembrane cleavage of the β-amyloid precursor protein family resembling γ-secretase-like cleavage of Notch. J. Biol. Chem. 276, 35235–35238 (2001).

    Article  CAS  PubMed  Google Scholar 

  80. Sastre, M. et al. Presenilin-dependent γ-secretase processing of β-amyloid precursor protein at a site corresponding to the S3 cleavage of Notch. EMBO Rep. 2, 835–841 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Weidemann, A. et al. A novel ɛ-cleavage within the transmembrane domain of the Alzheimer amyloid precursor protein demonstrates homology with Notch processing. Biochemistry 41, 2825–2835 (2002).

    Article  CAS  PubMed  Google Scholar 

  82. Moehlmann, T. et al. Presenilin-1 mutations of leucine 166 equally affect the generation of the Notch and APP intracellular domains independent of their effect on Aβ42 production. Proc. Natl Acad. Sci. USA 99, 8025–8030 (2002).References 78–82 describe a γ-secretase cleavage site in the APP transmembrane domain that is distinct from the usual Aβ40/42 cleavage sites and that is similar to the cytoplasmically oriented intramembrane cleavage site in Notch.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Lichtenthaler, S. F. et al. The intramembrane cleavage site of the amyloid precursor protein depends on the length of its transmembrane domain. Proc. Natl Acad. Sci. USA 99, 1365–1370 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Zhang, J. et al. Proteolysis of chimeric β-amyloid precursor proteins containing the Notch transmembrane domain yields amyloid β-like peptides. J. Biol. Chem. 277, 15069–15075 (2002).

    Article  CAS  PubMed  Google Scholar 

  85. Esler, W. P. et al. Amyloid-lowering isocoumarins are not direct inhibitors of γ-secretase. Nature Cell Biol. 4, E110–E111 (2002).

    Article  CAS  PubMed  Google Scholar 

  86. Petit, A. et al. New protease inhibitors prevent γ-secretase-mediated production of Aβ40/42 without affecting Notch cleavage. Nature Cell Biol. 3, 507–511 (2001).References 85 and 86 characterize a new class of compounds that effectively modulate amyloid production from APP with little effect on Notch proteolysis.

    Article  CAS  PubMed  Google Scholar 

  87. Blaumueller, C. M., Qi, H., Zagouras, P. & Artavanis-Tsakonas, S. Intracellular cleavage of Notch leads to a heterodimeric receptor on the plasma membrane. Cell 90, 281–291 (1997).

    Article  CAS  PubMed  Google Scholar 

  88. Logeat, F. et al. The Notch1 receptor is cleaved constitutively by a furin-like convertase. Proc. Natl Acad. Sci. USA 95, 8108–8112 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Rand, M. D. et al. Calcium depletion dissociates and activates heterodimeric Notch receptors. Mol. Cell. Biol. 20, 1825–1835 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Schlondorff, J. & Blobel, C. P. Metalloprotease-disintegrins: modular proteins capable of promoting cell–cell interactions and triggering signals by protein-ectodomain shedding. J. Cell Sci. 112, 3603–3617 (1999).

    Article  CAS  PubMed  Google Scholar 

  91. Rooke, J., Pan, D., Xu, T. & Rubin, G. M. KUZ, a conserved metalloprotease-disintegrin protein with two roles in Drosophila neurogenesis. Science 273, 1227–1231 (1996).

    Article  CAS  PubMed  Google Scholar 

  92. Pan, D. & Rubin, G. M. Kuzbanian controls proteolytic processing of Notch and mediates lateral inhibition during Drosophila and vertebrate neurogenesis. Cell 90, 271–280 (1997).

    Article  CAS  PubMed  Google Scholar 

  93. Sotillos, S., Roch, F. & Campuzano, S. The metalloprotease-disintegrin Kuzbanian participates in Notch activation during growth and patterning of Drosophila imaginal discs. Development 124, 4769–4779 (1997).

    Article  CAS  PubMed  Google Scholar 

  94. Lieber, T., Kidd, S. & Young, M. W. kuzbanian-mediated cleavage of Drosophila Notch. Genes Dev. 16, 209–221 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Wen, C., Metzstein, M. M. & Greenwald, I. SUP-17, a Caenorhabditis elegans ADAM protein related to Drosophila KUZBANIAN, and its role in LIN-12/NOTCH signalling. Development 124, 4759–4767 (1997).

    Article  CAS  PubMed  Google Scholar 

  96. Mumm, J. S. et al. A ligand-induced extracellular cleavage regulates γ-secretase-like proteolytic activation of Notch1. Mol. Cell 5, 197–206 (2000).

    Article  CAS  PubMed  Google Scholar 

  97. Brou, C. et al. A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE. Mol. Cell 5, 207–216 (2000).

    Article  CAS  PubMed  Google Scholar 

  98. Seugnet, L., Simpson, P. & Haenlin, M. Requirement for dynamin during Notch signaling in Drosophila neurogenesis. Dev. Biol. 192, 585–598 (1997).

    Article  CAS  PubMed  Google Scholar 

  99. Parks, A. L., Klueg, K. M., Stout, J. R. & Muskavitch, M. A. T. Ligand endocytosis drives receptor dissociation and activation in the Notch pathway. Development 127, 1373–1385 (2000).

    Article  CAS  PubMed  Google Scholar 

  100. Fehon, R. G., Johansen, K., Rebay, I. & Artavanis-Tsakonas, S. Complex cellular and subcellular regulation of Notch expression during embryonic and imaginal development of Drosophila: implications for Notch function. J. Cell Biol. 113, 657–669 (1991).

    Article  CAS  PubMed  Google Scholar 

  101. Bush, G. et al. Ligand-induced signaling in the absence of furin processing of Notch1. Dev. Biol. 229, 494–502 (2001).

    Article  CAS  PubMed  Google Scholar 

  102. Kidd, S. & Lieber, T. Furin cleavage is not a requirement for Drosophila Notch function. Mech. Dev. 115, 41–51 (2002).

    Article  CAS  PubMed  Google Scholar 

  103. Annaert, W. & De Strooper, B. Presenilins: molecular switches between proteolysis and signal transduction. Trends Neurosci. 22, 439–443 (1999).

    Article  CAS  PubMed  Google Scholar 

  104. Cupers, P. et al. The discrepancy between presenilin subcellular localization and γ-secretase processing of amyloid precursor protein. J. Cell Biol. 154, 731–740 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  106. Leem, J. Y. et al. Presenilin 1 is required for maturation and cell surface accumulation of nicastrin. J. Biol. Chem. 277, 19236–19240 (2002).

    Article  CAS  PubMed  Google Scholar 

  107. Edbauer, D., Winkler, E., Haass, C. & Steiner, H. Presenilin and nicastrin regulate each other and determine amyloid β-peptide production via complex formation. Proc. Natl Acad. Sci. USA 99, 8666–8671 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Tomita, T., Katayama, R., Takikawa, R. & Iwatsubo, T. Complex N-glycosylated form of nicastrin is stabilized and selectively bound to presenilin fragments. FEBS Lett. 520, 117–121 (2002).

    Article  CAS  PubMed  Google Scholar 

  109. Yang, D.-S. et al. Mature glycosylation and trafficking of nicastrin modulate its binding to presenilins. J. Biol. Chem. 277, 28135–28142 (2002).References 106–109 show that nicastrin undergoes complex N –glycosylation as it matures within the secretory pathway, and that this maturation depends on functional presenilin.

    Article  CAS  PubMed  Google Scholar 

  110. Cao, X. & Sudhof, T. C. A transcriptively active complex of APP with Fe65 and histone acetyltransferase Tip60. Science 293, 115–120 (2001).

    Article  CAS  PubMed  Google Scholar 

  111. Kimberly, W. T., Zheng, J. B., Guenette, S. Y. & Selkoe, D. J. 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 (2001).

    Article  CAS  PubMed  Google Scholar 

  112. Cupers, P., Orlans, I., Craessaerts, K., Annaert, W. & De Strooper, B. The amyloid precursor protein (APP)-cytoplasmic fragment generated by γ-secretase is rapidly degraded but distributes partially in a nuclear fraction of neurones in culture. J. Neurochem. 78, 1168–1178 (2001).

    Article  CAS  PubMed  Google Scholar 

  113. Gao, Y. & Pimplikar, S. W. The γ-secretase-cleaved C-terminal fragment of amyloid precursor protein mediates signaling to the nucleus. Proc. Natl Acad. Sci. USA 98, 14979–14984 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Leissring, M. A. et al. A physiologic signaling role for the γ-secretase-derived intracellular fragment of APP. Proc. Natl Acad. Sci. USA 99, 4697–4702 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Roncarati, R. et al. The γ-secretase-generated intracellular domain of β-amyloid precursor protein binds Numb and inhibits Notch signaling. Proc. Natl Acad. Sci. USA 99, 7102–7107 (2002).References 110–115 describe potential signalling functions of the intracellular domain of APP that is released from the membrane by γ-secretase-mediated processing.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. De Strooper, B. & Annaert, W. Proteolytic processing and cell biological functions of the amyloid precursor protein. J. Cell Sci. 113, 1857–1870 (2000).

    Article  CAS  PubMed  Google Scholar 

  117. Mattson, M. P. A multi-talented secreted protein. Trends Neurosci. 24, 441–442 (2001).

    Article  CAS  PubMed  Google Scholar 

  118. Ni, C. Y., Murphy, M. P., Golde, T. E. & Carpenter, G. γ-secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase. Science 294, 2179–2181 (2001).

    Article  CAS  PubMed  Google Scholar 

  119. Lee, H. J. et al. Presenilin-dependent γ-secretase-like intramembrane cleavage of ErbB4. J. Biol. Chem. 277, 6318–6323 (2002).References 118 and 119 describe the presenilin-dependent cleavage of a receptor tyrosine kinase, indicating a direct nuclear signalling mode for this type of receptor in addition to the canonical phosphorylation cascade.

    Article  CAS  PubMed  Google Scholar 

  120. Yarden, Y. & Sliwkowski, M. X. Untangling the ErbB signalling network. Nature Rev. Mol. Cell. Biol. 2, 127–137 (2001).

    Article  CAS  Google Scholar 

  121. Rio, C., Buxbaum, J. D., Peschon, J. J. & Corfas, G. Tumor necrosis factor-α-converting enzyme is required for cleavage of ErbB4/HER4. J. Biol. Chem. 275, 10379–10387 (2000).

    Article  CAS  PubMed  Google Scholar 

  122. Vecchi, M. & Carpenter, G. Constitutive proteolysis of the ErbB-4 receptor tyrosine kinase by a unique, sequential mechanism. J. Cell Biol. 139, 995–1003 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Lin, S. Y. et al. Nuclear localization of EGF receptor and its potential new role as a transcription factor. Nature Cell Biol. 3, 802–808 (2001).

    Article  CAS  PubMed  Google Scholar 

  124. Srinivasan, R., Gillett, C. E., Barnes, D. M. & Gullick, W. J. Nuclear expression of the c-erbB-4/HER-4 growth factor receptor in invasive breast cancers. Cancer Res. 60, 1483–1487 (2000).

    CAS  PubMed  Google Scholar 

  125. Okamoto, I. et al. Proteolytic release of CD44 intracellular domain and its role in the CD44 signaling pathway. J. Cell Biol. 155, 755–762 (2001).Describes a γ-secretase-like cleavage of the CD44 cell-surface protein and its relevance to a proposed nuclear-signalling activity of the molecule.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. May, P., Reddy, Y. K. & Herz, J. Proteolytic processing of low density lipoprotein receptor-related protein mediates regulated release of its intracellular domain. J. Biol. Chem. 277, 18736–18743 (2002).Presents evidence that the low-density lipoprotein-receptor-related protein is also cleaved by γ-secretase.

    Article  CAS  PubMed  Google Scholar 

  127. Naot, D., Sionov, R. V. & Ish-Shalom, D. CD44: structure, function, and association with the malignant process. Adv. Cancer Res. 71, 241–319 (1997).

    Article  Google Scholar 

  128. Okamoto, I. et al. Regulated CD44 cleavage under the control of protein kinase C, calcium influx, and the Rho family of small G proteins. J. Biol. Chem. 274, 25525–25534 (1999).

    Article  CAS  PubMed  Google Scholar 

  129. Okamoto, I. et al. Proteolytic cleavage of the CD44 adhesion molecule in multiple human tumors. Am. J. Pathol. 160, 441–447 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Kajita, M. et al. Membrane-type 1 matrix metalloproteinase cleaves CD44 and promotes cell migration. J. Cell Biol. 153, 893–904 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Okamoto, I. et al. CD44 cleavage induced by a membrane-associated metalloprotease plays a critical role in tumor cell migration. Oncogene 18, 1435–1446 (1999).

    Article  CAS  PubMed  Google Scholar 

  132. Wolfe, M. S. & Haass, C. The role of presenilins in γ-secretase activity. J. Biol. Chem. 276, 5413–5416 (2001).

    Article  CAS  PubMed  Google Scholar 

  133. Huppert, S. & Kopan, R. Regulated intramembrane proteolysis takes another twist. Dev. Cell 1, 590–592 (2001).

    Article  CAS  PubMed  Google Scholar 

  134. Weihofen, A., Binns, K., Lemberg, M. K., Ashman, K. & Martoglio, B. Identification of signal peptide peptidase, a presenilin-type aspartic protease. Science 296, 2215–2218 (2002).Biochemical identification of signal-peptide peptidase reveals that it is structurally related to presenilin and is likely to use a related mechanism of intramembrane proteolysis to cleave signal-peptide fragments within the membrane bilayer.

    Article  CAS  PubMed  Google Scholar 

  135. Kamal, A., Almenar-Queralt, A., LeBlanc, J. F., Roberts, E. A. & Goldstein, L. S. Kinesin-mediated axonal transport of a membrane compartment containing β-secretase and presenilin-1 requires APP. Nature 414, 643–648 (2001).

    Article  CAS  PubMed  Google Scholar 

  136. Gunawardena, S. & Goldstein, L. S. Disruption of axonal transport and neuronal viability by amyloid precursor protein mutations in Drosophila. Neuron 32, 389–401 (2001).

    Article  CAS  PubMed  Google Scholar 

  137. Marambaud, P. et al. A presenilin-1/γ-secretase cleavage releases the E-cadherin intracellular domain and regulates disassembly of adherens junctions. EMBO J. 21, 1948–1956 (2002).Demonstrates an involvement of presenilin in the cleavage and disassembly of E-cadherin, a putative cell-biological function for presenilin that apparently does not involve signalling.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Ponting, C. P. et al. Identification of a novel family of presenilin homologues. Hum. Mol. Genet. 11, 1037–1044 (2002).

    Article  CAS  PubMed  Google Scholar 

  139. Wasserman, J. D. & Freeman, M. Control of EGF receptor activation in Drosophila. Trends Cell Biol. 7, 773–784 (1997).

    Article  Google Scholar 

  140. Schweitzer, R. & Shilo, B. Z. A thousand and one roles for the Drosophila EGF receptor. Trends Genet. 13, 191–196 (1997).

    Article  CAS  PubMed  Google Scholar 

  141. Lee, J. R., Urban, S., Garvey, C. F. & Freeman, M. Regulated intracellular ligand transport and proteolysis control EGF signal activation in Drosophila. Cell 107, 161–171 (2001).

    Article  CAS  PubMed  Google Scholar 

  142. Urban, S., Lee, J. R. & Freeman, M. Drosophila Rhomboid-1 defines a family of putative intramembrane serine proteases. Cell 107, 173–182 (2001).

    Article  CAS  PubMed  Google Scholar 

  143. Tsruya, R. et al. Intracellular trafficking by Star regulates cleavage of the Drosophila EGF receptor ligand Spitz. Genes Dev. 16, 222–234 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Pascall, J. C., Luck, J. E. & Brown, K. D. Expression in mammalian cell cultures reveals interdependent, but distinct, functions for Star and Rhomboid proteins in the processing of the Drosophila transforming-growth-factor-α homologue Spitz. Biochem. J. 363, 347–352 (2002).References 141–144 elucidate the roles of two proteins — Star and Rhomboid-1 — in the intracellular transport and intramembrane cleavage of a secreted ligand for the Drosophila epidermal growth factor receptor.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Rather, P. N., Ding, X., Baca-DeLancey, R. R. & Siddiqui, S. Providencia stuartii genes activated by cell-to-cell signaling and identification of a gene required for production or activity of an extracellular factor. J. Bacteriol. 181, 7185–7191 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Gallio, M. & Kylsten, P. Providencia may help find a function for a novel, widespread protein family. Curr. Biol. 10, R693–R694 (2000).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

I am grateful to members of my lab for helpful discussions, and to J. Nye and D. Curtis for sharing their results before publication. This work was supported by a grant from the National Institutes of Health and intramural funding from the National Cancer Institute.

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DATABASES

FlyBase

Aph-1

Delta

E(spl)

nicastrin

Notch

Numb

Pen-2

presenilin

Rhomboid-1

Serrate

Spitz

Star

Suppressor of Hairless

LocusLink

α2-macroglobulin

ADAM

APP

α-catenin

β-catenin

cadherin

CD44

CREB-binding protein

E-cadherin

EGF

ErbB4

Fe65

Jagged

kinesin I

LRP

p300

protein kinase C

PS1

PS2

TGF-α

TIP60

TNF-α

OMIM

Alzheimer's disease

WormBase

Apx-1

Glp-1

Lag-1

Lag-2

Lin-12

sel-12

spe-4

Glossary

TYPE I INTEGRAL MEMBRANE PROTEIN

A protein that is tightly associated with the membrane, has at most one hydrophobic region that completely or partially resides in the lipid bilayer, and is oriented with its amino-terminal segment inserted into the extracellular/lumenal space (as opposed to type II proteins, which have a carboxy-terminal extracellular/lumenal orientation).

HOLOPROTEIN

The entire protein in its intact form, before post-translational modifications, that remove portions of the polypeptide chain or cleave the polypeptide into smaller fragments.

ENDOPROTEOLYTIC CLEAVAGE

A proteolytic cleavage event that occurs at an internal site of a protease, as opposed to the proteolytic cleavage of a different substrate molecule.

BACTERIAL TYPE 4 PREPILIN PROTEASES

A family of polytopic aspartyl proteases that are needed for the cleavage of precursor proteins, which are assembled into certain filamentous cell-surface structures, termed type 4 pili, and which are important for motility, antigenicity and other contact-dependent processes of many Gram-negative bacteria.

FURIN-LIKE CONVERTASE

A type of protease that belongs to the family of subtilisin/kexin-like, calcium-dependent enzymes that process proproteins in the secretory pathway.

FAST ANTEROGRADE TRANSPORT

Rapid energy-dependent movement of material in a proximal-to-distal direction in a cell or organelle (for example, from the cell body towards the axon terminus of a neuron).

RETROGRADE TRANSPORT

Movement of material in a distal-to-proximal direction in a cell or organelle (for example, from peripheral regions towards the cell body of a neuron).

PROTEASOME

A large multiprotein complex that is responsible for the proteolytic degradation of many intracellular proteins that have been targeted for destruction by the covalent addition of ubiquitin.

AXONOGENESIS

The formation and growth of thin thread-like neuronal extensions that conduct signals from the neuronal cell body to the specialized cellular sites where the neuron contacts other neurons.

DENDRITIC ARBORIZATION

The formation of finely branched tree-like structures on dendrites, which are long extensions of the neuronal cell body that receive signals from other neurons.

SYNAPTIC DIFFERENTIATION

The process by which a morphologically and biologically distinct junction between the axon of one neuron and the dendrite of another forms during development and becomes specialized for the transmission of signals between neurons.

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Fortini, M. γ-Secretase-mediated proteolysis in cell-surface-receptor signalling. Nat Rev Mol Cell Biol 3, 673–684 (2002). https://doi.org/10.1038/nrm910

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