Iwatsubo, Takeshi

Publication Detail

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Requirement for presenilin 1 in facilitating lagged 2-mediated endoproteolysis and signaling of notch 1.

J L Martys-Zage; S H Kim; B Berechid; S J Bingham; S Chu; J Sklar; J Nye; S S Sisodia (Profiled Author: Sisodia, Sangram S)

Department of Neurobiology, Pharmacology, and Physiology, Howard Hughes Medical Institute, The University of Chicago, IL 60637, USA.
Journal of molecular neuroscience : MN 2000;15(3):189-204.

Presenilin 1 (PS1), a polytopic membrane protein, is required for endoproteolytic processing at gamma-secretase site within the transmembrane domain of amyloid precursor proteins (APP). In addition, PS1 and its orthologues facilitate signaling of Notch family members, cell-surface receptors that specify cell fates during development. To clarify the mechanism(s) by which PS facilitates Notch signaling, we examined human Jagged-2-dependent metabolism and activity of a chimeric full-length Notchl-GFP molecule expressed in fibroblasts with heterozygous, or homozygous deletions of PS1. We demonstrate that PS1 is required for facilitating Jagged 2-mediated proteolysis and that translocation and accumulation of NICD in the nucleus correlates with signaling activity. Moreover, in a ligand-independent, Ca2+-depletion paradigm, we demonstrate that PS1 facilitates endoproteolysis of a plasma-membrane-associated, Notch1-GFP derivative. Finally, we report that NICD production is inhibited by L-685,458, a potent and selective inhibitor that blocks solubilized gamma-secretase activity and Abeta production in cultured cells. These findings strongly suggest that intramembranous processing of APP and Notch 1 are mediated by similar, if not identical, proteases that require PS1 for their activation.

2 Originating Grant

• 1.

  PRICE, DONALD L

  PRESENILINS IN MODELS OF FAMILIAL ALZHEIMERS DISEASE

  12 March 1997 - 28 February 2002

  NATIONAL INSTITUTE ON AGING

  Total Funding: $ 2,001,677

• 2.

  Sisodia, Sangram S

  PRESENILINS IN MODELS OF FAMILIAL ALZHEIMERS DISEASE

  Total Funding: $ 1,966,810

Scientific Context

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