A physiologic signaling role for the γ-secretase-derived intracellular fragment of APP

Malcolm A. Leissring, M. Paul Murphy, Tonya R. Mead, Yama Akbari, Michael C. Sugarman, Mehrdad Jannatipour, Brigitte Anliker, Ulrike Müller, Paul Saftig, Bart De Strooper, Michael S. Wolfe, Todd E. Golde, Frank M. LaFerla

Research output: Contribution to journalArticlepeer-review

235 Scopus citations

Abstract

Presenilins mediate an unusual intramembranous proteolytic activity known as γ-secretase, two substrates of which are the Notch receptor (Notch) and the β-amyloid precursor protein (APP). γ-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 γ-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 γ-secretase-dependent signaling pathway, suggesting that the intramembranous proteolysis of APP may play a signaling role analogous to that of Notch.

Original languageEnglish (US)
Pages (from-to)4697-4702
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number7
DOIs
StatePublished - Apr 2 2002

ASJC Scopus subject areas

  • General

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