Nature Cell Biology
3, 751 - 754 (2001)
Published online: 12 July 2001; | doi:10.1038/35087069
Nicastrin binds to membrane-tethered NotchFusheng Chen1, 5, Gang Yu1, 5, Shigeki Arawaka1, 5, Masaki Nishimura1, 2, Toshitaka Kawarai1, Haung Yu1, Anurag Tandon1, Agnes Supala1, You Qiang Song1, Ekaterina Rogaeva1, Paul Milman1, Christine Sato1, Cong Yu1, Christopher Janus1, Julie Lee3, Lixin Song3, Lili Zhang3, Paul E. Fraser1
& P. H. St George-Hyslop1, 41
Centre for Research in Neurodegenerative Diseases; Departments of Medicine and Medical Biophysics, University of Toronto, Tanz Neuroscience Building, 6 Queen's Park Crescent West, Toronto, Ontario M5S 3H2, Canada
2
Molecular Neuroscience Research Center, Shiga University of Medical Science, Shiga 520-2192, Japan
3
Department of CNS and Cardiovascular Research, Schering Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033-0539, USA
4
Department of Medicine (Neurology), The University Health Network (Toronto Western Hospital), 399 Bathurst Street, Toronto, Ontario M5T 2S8, Canada
5
These authors contributed equally to this work
Correspondence should be addressed to P. H. St George-Hyslop p.hyslop@utoronto.caThe presenilins1,
2 and nicastrin3, a type 1 transmembrane glycoprotein, form high molecular weight complexes that are involved in cleaving the  -amyloid precursor protein (APP)3,
4,
5,
6,
7 and Notch8,
9,
10,
11 in their transmembrane domains. The former process (termed  -secretase cleavage) generates amyloid -peptide (A), which is involved in the pathogenesis of Alzheimer's disease. The latter process (termed S3-site cleavage) generates Notch intracellular domain (NICD), which is involved in intercellular signalling. Nicastrin binds both full-length APP and the substrates of -secretase (C99- and C83-APP fragments), and modulates the activity of -secretase. Although absence of the Caenorhabditis elegans nicastrin homologue (aph-2) is known to cause an embryonic-lethal glp-1 phenotype3,
12, the role of nicastrin in this process has not been explored. Here we report that nicastrin binds to membrane-tethered forms of Notch (substrates for S3-site cleavage of Notch), and that, although mutations in the conserved 312−369 domain of nicastrin strongly modulate -secretase, they only weakly modulate the S3-site cleavage of Notch. Thus, nicastrin has a similar role in processing Notch and APP, but the 312−369 domain may have differential effects on these activities. In addition, we report that the Notch and APP pathways do not significantly compete with each other.
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