SCAFFOLDING Presenilin: A Bridge for ß-Catenin Phosphorylation

ß-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 ß-catenin. ß-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 1, followed by phosphorylation at amino acids 33, 37, and 41 (p-33,37,41) by glycogen synthase kinase 3ß (GSK-3ß). Wnt signaling, which is important in embryonic development and tumorigenesis in adults, inhibits ß-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 ß-peptide involved in Alzheimer's disease, as well as in activation of the Notch receptor--also appeared to serve as a scaffold to promote ß-catenin phosphorylation by GSK-3ß. In fibroblasts from PS1^-/-mice, the p-45 form of ß-catenin accumulated and the p-33,37,41 form was reduced. Immunoprecipitates of PS1 from wild-type fibroblasts contained GSK-3ß activity that phosphorylated recombinant ß-catenin. PS1 immunoprecipitates from cells pretreated with forskolin to activate protein kinase A exhibited enhanced production of p33,37,41 ß-catenin. Recovery of ß-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 ß-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, ß-catenin, and GSK-3ß--that acts as an alternative Wnt-independent mechanism to promote ß-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 ß-catenin independent of Axin: Implications for ß-catenin activation in tumorigenesis. Cell 110, 751-762 (2002). [Online Journal]