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Titolo:
Implication of APP secretases in notch signaling
Autore:
Hartmann, D; Tournoy, J; Saftig, P; Annaert, W; De Strooper, B;
Indirizzi:
Katholieke Univ Leuven, Neuronal Cell Biol Lab, Ctr Human Genet, B-3000 Louvain, Belgium Katholieke Univ Leuven Louvain Belgium B-3000 t, B-3000 Louvain, Belgium Flanders Interuniv Inst Biotechnol, B-3000 Louvain, Belgium Flanders Interuniv Inst Biotechnol Louvain Belgium B-3000 uvain, Belgium Univ Gottingen, Zentrum Biochem & Mol Zellbiol Biochem 2, D-3400 Gottingen, Germany Univ Gottingen Gottingen Germany D-3400 hem 2, D-3400 Gottingen, Germany
Titolo Testata:
JOURNAL OF MOLECULAR NEUROSCIENCE
fascicolo: 2, volume: 17, anno: 2001,
pagine: 171 - 181
SICI:
0895-8696(200110)17:2<171:IOASIN>2.0.ZU;2-C
Fonte:
ISI
Lingua:
ENG
Soggetto:
AMYLOID PRECURSOR PROTEIN; ALZHEIMERS-DISEASE; CAENORHABDITIS-ELEGANS; DISINTEGRIN-METALLOPROTEASE; PRESENILIN-1 DEFICIENCY; INTRACELLULAR DOMAIN; MUTANT PRESENILIN-1; PROTEOLYTIC RELEASE; CADASIL PATIENTS; TRANSGENIC MICE;
Keywords:
APP; notch; notch ligands; alpha-secretase; gamma-secretase; presenilins; regulated intramembrane proteolysis; Alzheimer's disease;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
91
Recensione:
Indirizzi per estratti:
Indirizzo: De Strooper, B Katholieke Univ Leuven, Neuronal Cell Biol Lab, Ctr Human Genet, Campus Gasthuisberg,Herestr 49, B-3000 Louvain, Belgium Katholieke Univ Leuven Campus Gasthuisberg,Herestr 49 Louvain Belgium B-3000
Citazione:
D. Hartmann et al., "Implication of APP secretases in notch signaling", J MOL NEURO, 17(2), 2001, pp. 171-181

Abstract

Signaling via notch receptors and their ligands is an evolutionary ancientand highly conserved mechanism governing cell-fate decisions throughout the animal kingdom. Upon ligand binding, notch receptors are subject to a two-step proteolysis essential for signal transduction. First, the ectodomain is removed by an enzyme cleaving near the outer-membrane surface ("site2"). Consecutively, the notch intracellular domain is liberated by a second protease cutting within the transmembrane sequence ("site3"). The intracellular domain is then transferred to the nucleus to act as a transcriptional coactivator. The proteases involved in notch receptor activation are shared with other proteins undergoing regulated intramembrane proteolysis, with intriguing parallels to APP. Specifically, site3 cleavage of Notch, as well as gamma -secretase processing of APP depend both critically on presenilins 1 and 2. Moreover, ADAM 10 and ADAM 17, the proteases proposed to perform site2 cleavage, are also the most probable candidate alpha -secretases to cleave APP. While the biological significance of APP processing remains to be further elucidated, interference with notch signaling has been shown to have severeconsequences both in small animal models as well as in humans. Thus a growing number of long known genetic syndromes like Alagille syndrome or Fallot's tetralogy can be caused by mutations of genes relevant for the notch signaling pathway. Likewise, the anticipated interference of gamma -secretase inhibitors with site3 cleavage may turn out to be a major obstacle for thistherapeutic approach to Alzheimer's disease.

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Documento generato il 25/01/20 alle ore 06:17:49