TI - Presenilin couples the paired phosphorylation of beta-catenin independent of axin : implications for beta-catenin activation in tumorigenesis . AB - 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 Wnt -regulated pathway and a function of presenilin separate from intramembrane proteolysis .