TY - JOUR
T1 - Presenilin couples the paired phosphorylation of β-catenin independent of axin
T2 - Implications for β-catenin activation in tumorigenesis
AU - Kang, David E.
AU - Soriano, Salvador
AU - Xia, Xuefeng
AU - Eberhart, Charles G.
AU - De Strooper, Bart
AU - Zheng, Hui
AU - Koo, Edward H.
N1 - Funding Information:
We thank Dr. Paul Robbins for gift of melanoma cell lines, Dr. S. Takada for Wnt-3a-transfected cells, Dr. F. Costantini for axin cDNA, Dr. A. Barth for mouse β-catenin cDNA, Dr. Christopher Salvadore (Cell Signaling) for phospho-β-catenin peptides, Dr. H. Land for pBABE-puro cDNA, Dr. H. Mori for PSN2 antibody, and Dr. J. Gleeson for helpful discussions. This work was supported by NIH NS28121 (E.H.K.), NS40039 (H.Z.), AHAF A2002-035 (S.S.), and 5T32 AG00216-10 (D.E.K.).
PY - 2002/9/20
Y1 - 2002/9/20
N2 - 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.
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/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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U2 - 10.1016/S0092-8674(02)00970-4
DO - 10.1016/S0092-8674(02)00970-4
M3 - Article
C2 - 12297048
AN - SCOPUS:0037145062
VL - 110
SP - 751
EP - 762
JO - Cell
JF - Cell
SN - 0092-8674
IS - 6
ER -