Beta-catenin versus the other armadillo catenins: assessing our current view of canonical Wnt signaling

Abstract

The prevailing view of canonical Wnt signaling emphasizes the role of beta-catenin acting downstream of Wnt activation to regulate transcriptional activity. However, emerging evidence indicates that other armadillo catenins in vertebrates, such as members of the p120 subfamily, convey parallel signals to the nucleus downstream of canonical Wnt pathway activation. Their study is thus needed to appreciate the networked mechanisms of canonical Wnt pathway transduction, especially as they may assist in generating the diversity of Wnt effects observed in development and disease. In this chapter, we outline evidence of direct canonical Wnt effects on p120 subfamily members in vertebrates and speculate upon these catenins' roles in conjunction with or aside from beta-catenin.

Figure 1. Catenins and canonical Wnt signaling. (color)

A. Canonical Wnt signaling inhibits the destruction complex (purple), preventing degradation of catenin proteins (red). Upon stabilization, catenin proteins may enter the nucleus to bind transcription factors (blue), regulating downstream gene expression. Canonical regulation of the p120- and plakophilin- catenin subfamilies is distinct from the non-canonical Wnt signaling trajectories (not shown). Dotted lines represent relationships that are currently uncertain. B. In Xenopus embryos, overexpression of Axin, a destruction complex component, reduces the levels of p120-catenin subfamily members. Beta-catenin is also destabilized by Axin (positive control) [6]. C. Members of all subfamilies of catenins localize to the nucleus in certain contexts [41].

Figure 2. The catenin superfamily and isoforms. (color)

A. Catenin proteins are characterized by an armadillo domain comprising 9 or 12 armadillo repeats. They are classified into three distinct subfamilies, the beta-catenin subfamily, the p120-catenin subfamily, and the plakophilin subfamily. B. The best characterized member of the p120 subfamily, p120-catenin, has numerous isoforms. These isoforms are generated by a combination of differential translational starts sites (e.g. Isoforms 1–4) and differential splice exons (e.g. exons A, B, and C in black). The isoforms vary in their regulation. For example, only the longest isoform of p120-catenin (Isoform 1) possesses a “destruction box” with conserved GSK3-beta (and CK1-alpha) phosphorylation sites at its N-terminus (*). Plakophilin isoforms arise through alternatively spliced exons. For example, plakophilin 2B has one additional exon (green) as compared with plakophilin 2A.

Figure 3. Cellular roles of catenins. (color)

Beta-catenin and p120-catenin have confirmed roles in Wnt signaling, although certain isoforms of all catenins (red) localize to the nucleus and may interact with transcription factors (blue). p120-catenin and plakophilin subfamily members (red) also regulate small-GTPases (Rac1, RhoA, Cdc42- yellow). All catenins associate with cadherins at junctional complexes (orange), with beta-catenin and p120 subfamily members residing exclusively at adherens junctions and plakophilins residing exclusively at desmosomes. Plakoglobin is present at both adherens and desmosomal junctions.