Abstract
Presenilin 1 (PS1), a polytopic membrane protein, is required for endoproteolytic processing at γ-secretase site within the transmembrane domain of amyloid precursor proteins (APP). In addition, PS1 and its orthologues facilitate signaling of Notch family members, cell-surface receptors that specify cell fates during development. To clarify the mechanism(s) by which PS facilitates Notch signaling, we examined human Jagged-2-dependent metabolism and activity of a chimeric full-length Notch1-GFP molecule expressed in fibroblasts with heterozygous, or homozygous deletions of PS1. We demonstrate that PS1 is required for facilitating Jagged 2-mediated proteolysis and that translocation and accumulation of NICD in the nucleus correlates with signaling activity. Moreover, in a ligand-independent, Ca2+-depletion paradigm, we demonstrate that PS1 facilitates endoproteolysis of a plasma-membrane-associated, Notch1-GFP derivative. Finally, we report that NICD production is inhibited by L-685,458, a potent and selective inhibitor that blocks solubilized γ-secretase activity and Aβ production in cultured cells. These findings strongly suggest that intramembranous processing of APP and Notch 1 are mediated by similar, if not identical, proteases that require PS1 for their activation.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Artavanis-Tsakonas S., Rand M. D., and Lake R. J. (1999) Notch signaling: cell fate control and signal integration in development. Science 284, 770–776.
Berechid B. E., Thinakaran G., Wong P. C., Sisodia S. S., and Nye J. S. (1999) Lack of requirement for presenilin1 in Notch1 signaling. Curr. Biol. 9, 1493–1496.
Brou C., Logeat F., Gupta N., Bessia C., LeBail O., Doedens J. R., et al. (2000) A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE. Mol. Cell 5, 207–216.
Chan Y. M. and Jan Y. N. (1999) Presenilins, processing of beta-amyloid precursor protein, and notch signaling. Neuron 2, 201–204.
Chen C. and Okayama H. (1987) High-efficiency transformation of mammalian cells by plasmid DNA. Mol. Cell Biol. 7, 2745–2752.
DeStrooper B., Annaert W., Cupers P., Saftig P., Craessaerts K., Mumm J. S., et al. (1999) A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature 398, 518–522.
DeStrooper B., Saftig P., Craessaerts K., Vanderstichele H., Guhde G., Annaert W., et al. (1998) Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 391, 387–390.
Esler W. P., Kimberly W. T., Ostaszewski B. L., Diehl T. S., Moore C. L., Tsai J.-Y., et al. (2000) Transition-state analogue inhibitors of -secretase bind directly to presenilin-1. Nature Cell Biol. 2, 428–434.
Hartmann D., DeStrooper B., and Saftig P. (1999) Presenilin-1 deficiency leads to loss of Cajal-Retzius neurons and cortical dysplasia similar to human type 2 lissencephaly. Curr. Biol. 9, 719–727.
Huppert S. S., Le A., Schroeter E. H., Mumm J. S., Saxena M. T., Milner L. A., and Kopan R. (2000) Embryonic lethality in mice homozygous for a processing-deficient allele of Notch1. Nature 405, 966–970.
Kim S. H., Wang R., Gordon D. J., Bass J., Steiner D. F., Lynn D. G., et al. (1999) Furin mediates enhanced production of fibrillogenic A Bri peptides in familial British dementia. Nat. Neurosci. 2, 984–988.
Lecourtois M. and Schweisguth F. (1998) Indirect evidence for Delta-dependent intracellular processing of notch in Drosophila embryos. Curr. Biol. 8, 771–774.
Levitan D. and Greenwald I. (1995) Facilitation of lin-12-mediated signalling by sel-12, a Caenorhabditis elegans S182 Alzheimer’s disease gene. Nature 377, 351–354.
Li Y. M., Lai M. T., Xu M., Huang Q., DiMuzio-Mower J., Sardana M. K., et al. (2000a) Presenilin 1 is linked with gamma -secretase activity in the deter-gent solubilized state. Proc. Natl. Acad. Sci. USA 97, 6138–6143.
Li Y. M., Xu M., Lai M. T., Huang Q., Castro J. L., DiMuzio-Mower J., et al. (2000b) Photoactivated gamma-secretase inhibitors directed to the active site covalently label presenilin 1. Nature 405, 689–694.
Logeat F., Bessia C., Brou C., LeBail O., Jarriault S., Seidah N. G., and Israel A. (1998) The Notch1 receptor is cleaved constitutively by a furin-like convertase. Proc. Natl. Acad. Sci. USA 95, 8108–8112.
Luo B., Aster J. C., Hasserjian R. P., Kuo F., and Sklar J. (1997) Isolation and functional analysis of a cDNA for human Jagged2, a gene encoding a ligand for the Notch1 receptor. Mol. Cell Biol. 17, 6057–6067.
Moehring J. M. and Moehring, T. J. (1983) Strains of CHO-K1 cells resistant to Pseudomonas exotoxin A and cross-resistant to diphtheria toxin and viruses. Infect. Immun. 41, 998–1009.
Moehring J. M., Inocencio N. M., Robertson B. J., and Moehring, T. J. (1993) Expression of mouse furin in a Chinese hamster cell resistant to Pseudomonas exotoxin A and viruses complements the genetic lesion. J. Biol. Chem. 268, 2590–2594.
Mumm J. S., Schroeter E. H., Saxena M. T., Griesemer A., Tian X., Pan D. J., Ray W. J., and Kopan R. (2000) Aligand-induced extracellular cleavage regulates γ-secretase-like proteolytic activation of Notch1. Molecular Cell 5, 197–206.
Naruse S., Thinakaran G., Luo J. J., Kusiak J. W., Tomita T., Iwatsubo T., et al. (1998) Effects of PS1 deficiency on membrane protein trafficking in neurons. Neuron 21, 1213–1221.
Price D. L. and Sisodia S. S. (1998) Mutant genes in familial Alzheimer’s disease and transgenic models. Annu. Rev. Neurosci. 21, 479–505.
Rand M. D., Grimm L. M., Artavanis-Tsakonas S., Patriub V., Blacklow S. C., Sklar J., and Aster J. C. (2000) Calcium depletion dissociates and activates heterodimeric notch receptors. Mol. Cell Biol. 20, 1825–1835.
Ray W. J., Yao M., Mumm J., Schroeter E. H., Saftig P., Wolfe M., et al. (1999) Cell surface presenilin-1 participates in the gamma-secretase-like proteolysis of Notch. J. Biol. Chem. 274, 36,801–36,807.
Redmond L., Oh S. R., Hicks C., Weinmaster G., and Ghosh A. (2000) Nuclear Notch1 signaling and the regulation of dendritic development. Nat. Neurosci. 3, 30–40.
Schroeter E. H., Kisslinger J. A., and Kopan R. (1998) Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain. Nature 393, 382–386.
Selkoe D. J. (2000) Notch and presenilins in vertebrates and invertebrates: implications for neuronal development and degeneration. Curr. Opin. Neurobiol. 10, 50–57.
Shen J., Bronson R. T., Chen D. F., Xia W., Selkoe D. J., and Tonegawa S. (1997) Skeletal and CNS defects in Presenilin-1-deficient mice. Cell 89, 629–639.
Sherrington R., Rogaev E. I., Liang Y., Rogaeva E. A., Levesque G., Ikeda M., et al. (1995) Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 375, 754–760.
Song W., Nadeau P., Yuan M., Yang X., Shen J., and Yankner B. A. (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.
Spence M. J., Sucic J. F., Foley B. T., and Moehring T. J. (1995) Analysis of mutations in alleles of the fur gene from an endoprotease-deficient Chinese hamster ovary cell strain. Somat. Cell Mol. Genet. 21, 1–18.
Struhl G. and Adachi A. (1998) Nuclear access and action of notch in vivo. Cell 93, 649–660.
Struhl G. and Greenwald I. (1999) Presenilin is required for activity and nuclear access of Notch in Drosophila. Nature 398, 522–525.
Thinakaran G., Teplow D. B., Siman R., Greenberg B., and Sisodia S. S. (1996) Metabolism of the “Swedish” amyloid precursor protein variant in Neuro2a (N2a) cells. J. Biol. Chem. 271, 9390–9397.
Vidal R., Frangione B., Rostagno A., Mead S., Revesz T., Plant, G., and Ghiso J. (1999) A stopcodon mutation in the BRI gene associated with familial British dementia. Nature 399, 776–781.
Wong P. C., Zheng H., Chen H., Becher M. W., Sirinathsinghji D. J., Trumbauer M. E., et al. (1997) Presenilin 1 is required for Notch1 and DII1 expression in the paraxial mesoderm. Nature 387, 288–292.
Ye Y., Lukinova N., and Fortini M. E. (1999) Neurogenic phenotypes and altered Notch processing in Drosophila Presenilin mutants. Nature 398, 525–529.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Martys-Zage, J.L., Kim, SH., Berechid, B. et al. Requirement for presenilin 1 in facilitating jagged 2-mediated endoproteolysis and signaling of notch 1. J Mol Neurosci 15, 189–204 (2000). https://doi.org/10.1385/JMN:15:3:189
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1385/JMN:15:3:189