γ-Secretase-mediated proteolysis in cell-surface-receptor signalling (original) (raw)

• 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
• Fortini, M. E. Notch and Presenilin: a proteolytic mechanism emerges. Curr. Opin. Cell Biol. 13, 627–634 (2001).
  Article CAS PubMed Google Scholar
• 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
• Weinmaster, G. Notch signal transduction: a real rip and more. Curr. Opin. Genet. Dev. 10, 363–369 (2000).
  Article CAS PubMed Google Scholar
• Greenwald, I. LIN-12/Notch signaling: lessons from worms and flies. Genes Dev. 12, 1751–1762 (1998).
  Article CAS PubMed Google Scholar
• 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
• 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
• 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
• Artavanis-Tsakonas, S., Matsuno, K. & Fortini, M. E. Notch signaling. Science 268, 225–232 (1995).
  Article CAS PubMed Google Scholar
• Greenwald, I. Structure/function studies of Lin-12/Notch proteins. Curr. Opin. Genet. Dev. 4, 556–562 (1994).
  Article CAS PubMed Google Scholar
• 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
• 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
• 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
• Selkoe, D. J. Translating cell biology into therapeutic advances in Alzheimer's disease. Nature 399, A23–A31 (1999).
  Article CAS PubMed Google Scholar
• 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
• 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
• Doan, A. et al. Protein topology of presenilin 1. Neuron 17, 1023–1030 (1996).
  Article CAS PubMed Google Scholar
• Li, X. & Greenwald, I. Membrane topology of the C. elegans SEL-12 presenilin. Neuron 17, 1015–1021 (1996).
  Article CAS PubMed Google Scholar
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Chen, F. et al. Nicastrin binds to membrane-tethered Notch. Nature Cell Biol. 3, 751–754 (2001).
  Article CAS PubMed Google Scholar
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Naruse, S. et al. Effects of PS1 deficiency on membrane protein trafficking in neurons. Neuron 21, 1213–1221 (1998).
  Article CAS PubMed Google Scholar
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Shen, J. et al. Skeletal and CNS defects in _Presenilin-1_-deficient mice. Cell 89, 629–639 (1997).
  Article CAS PubMed Google Scholar
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Annaert, W. & De Strooper, B. Presenilins: molecular switches between proteolysis and signal transduction. Trends Neurosci. 22, 439–443 (1999).
  Article CAS PubMed Google Scholar
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Mattson, M. P. A multi-talented secreted protein. Trends Neurosci. 24, 441–442 (2001).
  Article CAS PubMed Google Scholar
• 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
• 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
• Yarden, Y. & Sliwkowski, M. X. Untangling the ErbB signalling network. Nature Rev. Mol. Cell. Biol. 2, 127–137 (2001).
  Article CAS Google Scholar
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Huppert, S. & Kopan, R. Regulated intramembrane proteolysis takes another twist. Dev. Cell 1, 590–592 (2001).
  Article CAS PubMed Google Scholar
• 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
• 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
• 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
• 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
• 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
• Wasserman, J. D. & Freeman, M. Control of EGF receptor activation in Drosophila. Trends Cell Biol. 7, 773–784 (1997).
  Article Google Scholar
• 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
• 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
• 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
• 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
• 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
• 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
• 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