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Title: A physiologic signaling role for the gamma -secretase-derived intracellular fragment of APP
Authors: Leissring, Malcolm A ×
Murphy, M Paul
Mead, Tonya R
Akbari, Yama
Sugarman, Michael C
Jannatipour, Mehrdad
Anliker, Brigitte
Müller, Ulrike
Saftig, Paul
De Strooper, Bart
Wolfe, Michael S
Golde, Todd E
LaFerla, Frank M #
Issue Date: Apr-2002
Series Title: Proceedings of the National Academy of Sciences of the United States of America vol:99 issue:7 pages:4697-702
Abstract: Presenilins mediate an unusual intramembranous proteolytic activity known as gamma-secretase, two substrates of which are the Notch receptor (Notch) and the beta-amyloid precursor protein (APP). Gamma-secretase-mediated cleavage of APP, like that of Notch, yields an intracellular fragment [APP intracellular domain (AICD)] that forms a transcriptively active complex. We now demonstrate a functional role for AICD in regulating phosphoinositide-mediated calcium signaling. Genetic ablation of the presenilins or pharmacological inhibition of gamma-secretase activity (and thereby AICD production) attenuated calcium signaling in a dose-dependent and reversible manner through a mechanism involving the modulation of endoplasmic reticulum calcium stores. Cells lacking APP (and hence AICD) exhibited similar calcium signaling deficits, and-notably-these disturbances could be reversed by transfection with APP constructs containing an intact AICD, but not by constructs lacking this domain. Our findings indicate that the AICD regulates phosphoinositide-mediated calcium signaling through a gamma-secretase-dependent signaling pathway, suggesting that the intramembranous proteolysis of APP may play a signaling role analogous to that of Notch.
URI: 
ISSN: 0027-8424
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Molecular Genetics Section (-)
Department of Human Genetics - miscellaneous
× corresponding author
# (joint) last author

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