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Implication of APP secretases in notch signaling

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Abstract

Signaling via notch receptors and their ligands is an evolutionary ancient and 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 γ-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 α-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 severe consequences 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 γ-secretase inhibitors with site3 cleavage may turn out to be a major obstacle for this therapeutic approach to Alzheimer’s disease.

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Authors and Affiliations

  1. Center for Human Genetics, Neuronal Cell Biology Laboratory, K.U.Leuven and Flanders Interuniversity Institute for Biotechnology, Campus Gasthuisberg, Herestraat 49, B-3000, Leuven, Belgium

    Dieter Hartmann, Jos Tournoy, Wim Annaert & Bart De Strooper

  2. Zentrum Biochemie und Molekulare Zellbiologie, Biochemie II, Universität Göttingen, Göttingen, Germany

    Paul Saftig

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  1. Dieter Hartmann
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  2. Jos Tournoy
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  3. Paul Saftig
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  4. Wim Annaert
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  5. Bart De Strooper
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Correspondence to Wim Annaert or Bart De Strooper.

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J.T. is Aspirant of the Fonds voor Wetenschappelijk Onderzoek (FWO)

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Hartmann, D., Tournoy, J., Saftig, P. et al. Implication of APP secretases in notch signaling. J Mol Neurosci 17, 171–181 (2001). https://doi.org/10.1385/JMN:17:2:171

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