Presenilin Couples the Paired Phosphorylation of β-Catenin Independent of Axin: Implications for β-Catenin Activation in Tumorigenesis

The Alzheimerʹs 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/β-catenin signaling pathway, although the mechanism underlying this activity is unknown. Here, we show that presenilin functions as a scaffold that rapidly couples β-catenin phosphorylation through two sequential kinase activities independent of the Wnt-regulated Axin/CK1α complex. Thus, presenilin deficiency results in increased β-catenin stability in vitro and in vivo by disconnecting the stepwise phosphorylation of β-catenin, both in the presence and absence of Wnt stimulation. These findings highlight an aspect of β-catenin regulation outside of the canonical Wnt-regulated pathway and a function of presenilin separate from intramembrane proteolysis.