[HTML][HTML] Presenilin couples the paired phosphorylation of β-catenin independent of axin: implications for β-catenin activation in tumorigenesis

DE Kang, S Soriano, X Xia, CG Eberhart… - Cell, 2002 - cell.com
DE Kang, S Soriano, X Xia, CG Eberhart, B De Strooper, H Zheng, EH Koo
Cell, 2002cell.com
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/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 …
Abstract
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/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.
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