Journal
CELL
Volume 110, Issue 6, Pages 751-762Publisher
CELL PRESS
DOI: 10.1016/S0092-8674(02)00970-4
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Funding
- NIA NIH HHS [5T32 AG00216-10] Funding Source: Medline
- NINDS NIH HHS [NS28121, NS40039] Funding Source: Medline
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The Alzheimer's disease-linked gene presenilin 1 (PS1) is required for intramembrane proteolysis of APP and Notch. In addition, recent observations strongly implicate PS1 as a negative regulator of the Wnt/beta-catenin signaling pathway, although the mechanism underlying this activity is unknown. Here, we show that presenilin functions as a scaffold that rapidly couples beta-catenin phosphorylation through two sequential kinase activities independent of the Wnt-regulated Axin/ CK1alpha complex. Thus, presenilin deficiency results in increased beta-catenin stability in vitro and in vivo by disconnecting the stepwise phosphorylation of beta-catenin, both in the presence and absence of Wnt stimulation. These findings highlight an aspect of beta-catenin regulation outside of the canonical Writ-regulated pathway and a function of presenilin separate from intramembrane proteolysis.
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