Sci. STKE, 1 October 2002
Scaffolding Presenilin: A Bridge for β-Catenin Phosphorylation
β-Catenin can be stabilized at cell junctions as part of the cadherin complex or in response to Wnt, which inhibits the phosphorylation-dependent degradation of cytosolic, free β-catenin. β-Catenin phosphorylation, which is required for ubiquitin-mediated degradation, occurs over at least two steps: a priming phosphorylation at amino acid 45 (p-45) by casein kinase 1α, followed by phosphorylation at amino acids 33, 37, and 41 (p-33,37,41) by glycogen synthase kinase 3β (GSK-3β). Wnt signaling, which is important in embryonic development and tumorigenesis in adults, inhibits β-catenin phosphorylation, at least in part by inhibiting the activity of the Axin complex and promoting Axin degradation. Kang et al. found that presenilin 1 (PS1)--the protein known for its role in intramembrane hydrolysis that is implicated in the production of the amyloid β-peptide involved in Alzheimer's disease, as well as in activation of the Notch receptor--also appeared to serve as a scaffold to promote β-catenin phosphorylation by GSK-3β. In fibroblasts from PS1-/-mice, the p-45 form of β-catenin accumulated and the p-33,37,41 form was reduced. Immunoprecipitates of PS1 from wild-type fibroblasts contained GSK-3β activity that phosphorylated recombinant β-catenin. PS1 immunoprecipitates from cells pretreated with forskolin to activate protein kinase A exhibited enhanced production of p33,37,41 β-catenin. Recovery of β-catenin ubiquitination (measured when proteasome function was inhibited) after Wnt stimulation was delayed in PS1-/- cells compared with wild type, which suggests that the PS1 complex contributes to resetting the cell after Wnt stimulation. Overexpression of PS1 in cells that lack Axin also decreased soluble β-catenin and increased the ratio of p-33,37,41 to p-45. The authors suggest that PS1 serves to promote the formation of a second complex--protein kinase A, β-catenin, and GSK-3β--that acts as an alternative Wnt-independent mechanism to promote β-catenin phosphorylation and degradation. The importance of this second complex was underscored by (i) an increase in dermal hyperplasias and carcinomas in PS1-/- mice that had been rescued by a neuronally expressed PS1 construct and so survive to adulthood and by (ii) abnormalities in developing spinal cord of PS1-/- embryos that resembled a Wnt ovexpression phenotype.
D. E. Kang, S. Soriano, X. Xia, C. G. Eberhart, B. De Strooper, H. Zheng, E. H. Koo, Presenilin couples the paired phosphorylation of β-catenin independent of Axin: Implications for β-catenin activation in tumorigenesis. Cell 110, 751-762 (2002). [Online Journal]
Citation: Presenilin: A Bridge for β-Catenin Phosphorylation. Sci. STKE 2002, tw361 (2002).
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