title: A physiologic signaling role for the gamma -secretase-derived intracellular fragment of APP.
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.
authors.affiliation: Laboratory of Molecular Neuropathogenesis, Department of Neurobiology and Behavior, University of California, Irvine, CA 92697, USA.
authors.forename: Malcolm A
authors.initials: MA
authors.lastname: Leissring
authors.forename: M Paul
authors.initials: MP
authors.lastname: Murphy
authors.forename: Tonya R
authors.initials: TR
authors.lastname: Mead
authors.forename: Yama
authors.initials: Y
authors.lastname: Akbari
authors.forename: Michael C
authors.initials: MC
authors.lastname: Sugarman
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Jannatipour
authors.forename: Brigitte
authors.initials: B
authors.lastname: Anliker
authors.forename: Ulrike
authors.initials: U
authors.lastname: Müller
authors.forename: Paul
authors.initials: P
authors.lastname: Saftig
authors.forename: Bart
authors.initials: B
authors.lastname: De Strooper
authors.forename: Michael S
authors.initials: MS
authors.lastname: Wolfe
authors.forename: Todd E
authors.initials: TE
authors.lastname: Golde
authors.forename: Frank M
authors.initials: FM
authors.lastname: LaFerla
mesh_terms: D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D020013:Calcium Signaling; D002478:Cells, Cultured; D010450:Endopeptidases / Q000502:physiology*; D051379:Mice; D010446:Peptide Fragments / Q000502:physiology*
chemical_list: D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse