The central role of β-catenin in Wnt signaling and the cadherin complex. β-Catenin exists in a cadherin-bound form that regulates adhesion; in a complex with axin, APC, and GSK-3β, where it is phosphorylated and targeted for degradation by β-TrCP; or in the nucleus with TCF/LEF transcription factors. Wnt signaling, proceeding through Frizzled and Arrow–LRP-5/6, activates Dishevelled (Dsh), which results in uncoupling β-catenin from the degradation pathway and its entry into the nucleus, where it interacts with TCF/LEF to control transcription. Wnt protein can also interact with the Derailed receptor to control axon path-finding. The Wnt pathway is also subject to extensive regulation and feedback control by extracellular factors that bind Wnt [Wnt inhibitory factor (WIF) and Frizzled-related protein (FRP)] or the coreceptor LRP (Dickkopf). The insert displays possible levels of interactions between Wnt signaling and cadherin-mediated adhesion (dotted lines) and the central role of β-catenin in both processes that are the focus of the review.

Structural and functional regulation of the cadherin-catenin complex by the balance of tyrosine kinase and phosphatase activities. Cadherin binds p120 and β-catenin, which in turn binds α-catenin. The integrity of this complex is negatively regulated by phosphorylation of β-catenin by receptor tyrosine kinases (RTKs) and cytoplasmic tyrosine kinases (Fer, Fyn, Yes, and Src), which phosphorylate (red arrows) specific tyrosine residues in β-catenin (Y654, Y142), which leads to dissociation of the cadherin-catenin complex. Integrity of the cadherin-catenin complex is positively regulated by β-catenin phosphorylation by casein kinase II, and dephosphorylation by protein tyrosine phosphatases that bind p120 and β-catenin (green arrows). Changes in the phosphorylation state of β-catenin (bottom) affect cell-cell adhesion, cell migration, and the level of signaling β-catenin.

Intersection of pathways controlling Wnt/β-catenin signaling and cadherin-mediated adhesion. Connections between cadherin and Wnt/β-catenin signaling pathways are based on studies in tissue culture cells and in tissues, and some involve manipulations of protein levels and expression patterns (for details, see text). All possible intersections between these pathways and their outcomes are represented together as a map, although individual pathways are likely to occur only in specific physiological contexts. Pathways that activate are indicated by solid green, pathways that reduce activity are indicated in solid red, and indirect consequences of pathway activation or inactivation are indicated by dotted lines.

Additional roles of Wnt signaling components, adhesion proteins, and APC. (A) Planar polarity in Drosophila is regulated by Frizzled signaling through Dsh, the small guanosine triphosphatase (GTPase) RhoA, and its downstream effector Rho-kinase (ROCK). Although it is not known whether this process is Wnt-dependent, it is controlled by nonclassical cadherin-like adhesion molecules of the Fat-Dachsous family, as well as by Flamingo. All these molecules contain cadherin repeats, that, in the case of Flamingo, are linked to a seven-transmembrane domain. The number of cadherin repeats displayed here is arbitrary. There are numerous additional components in planar polarity not discussed here (46). (B) In addition to a role in targeting β-catenin for degradation, APC also interacts with the plus-end of microtubules at the plasma membrane of migrating cells. Recent studies indicate that APC and microtubules orient the direction of cell migration through a signaling cascade from integrins that bind extracellular matrix; the small GTPase Cdc42; the PAR complex, which contains the scaffolding proteins Par3/Par 6 and an atypical protein kinase C; and serine/threonine kinase GSK-3β (50–52). (C) APC also localizes with the cadherin-catenin complex at the adherens junction (AJ), a major cell-cell adhesion complex with the tight junction (TJ) at the boundary between the apical and lateral membranes of polarized epithelial cells; E-APC may linkmicrotubules to the plasma membrane and may regulate the organization and function of the AJ (45, 53).