Where Notch and WNT Signaling Meet

The presenilins (PSs) 1 are part of the molecular machinery responsible for cleaving proteins like the ␤-amyloid precursor protein (APP) and Notch in the plane of the membrane (Annaert and De Strooper, 1999). Mutations in PS1 are one of the major causes of familiar Alzheimer's disease. PSs are also involved in regulating the Wnt/ ␤-catenin signaling pathway, but how exactly remains a highly controversial issue (for full discussion see www.alzforum.org/ members/forums/journal/catenin/index.html). In this issue, Soriano et al. (2001) provide results to tip the scales definitively in favor of the concept that PS1 operates as a negative regulator of the Wnt/ ␤-catenin signaling pathway. ␤-catenin, neural plakophilin related armadillo protein (NPRAP, also called ␦-catenin), and p0071 previously were known to bind to the large cytoplasmic loop domain of PS1 (see www.alzforum.org/members/forums/journal/ catenin/index.html). These proteins are all characterized by repeats of the armadillo motif, a 42 amino acid sequence involved in protein–protein interactions, however, only the function of ␤-catenin has been fairly well established. One pool of ␤-catenin is bound at the cell membrane to the cell adhesion molecule E-cadherin and provides a link to the actin cytoskeleton. A second pool is located in the cytoplasm in complex with axin, adenoma-tous polyposis coli (APC), and glycogen-synthase-kinase-3 ␤ (GSK-3 ␤). Phosphorylation of ␤-catenin by GSK-3 ␤ promotes its binding to the ␤-transducing repeat-containing protein (␤-TrCP), an F-box protein, and part of the E2/E3 ubiquitin ligase complex (Maniatis, 1999). Upon ubiquitination, ␤-catenin becomes rapidly degraded by the proteasome (Fig. 1). Binding of the soluble ligand Wnt to the membrane receptor frizzled inhibits GSK-3 ␤ via a pathway involving casein kinases and the protein dishev-eled. This results in the accumulation of unphosphorylated ␤-catenin in the cytoplasm and its subsequent transloca-tion to the cell nucleus. Here, ␤-catenin binds to members of the LEF/TCF (T cell-specific transcription factor 1) family of transcriptional regulators and activates Wnt target genes like cyclin D1, c-myc, and metalloproteases. Thus, a finely tuned balance between the three ␤-catenin pools at the cell membrane, in the cytoplasm, and in the nucleus, determines the final outcome of the Wnt signal-ing pathway (Fig. 1, for a detailed overview see www. stanford.edu/ ‫ف‬ rnusse/wntwindow.html). However, when the functional relevance of the PS-␤-catenin interaction was investigated, contradictory results were obtained. PS1 appeared to either stabilize (Zhang et al., 1998) or destabilize ␤-catenin (Kang et al., 1999). Remarkably , clinical PS mutations that cause Alzheimer's disease also affected …