Science 303(5663): 1483-1487

Convergence of Wnt, β-Catenin, and Cadherin Pathways

^{Department of Molecular and Cellular Physiology, Beckman Center for Molecular and Genetic Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.}

^{Howard Hughes Medical Institute, Beckman Center for Molecular and Genetic Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.}

^{Department of Developmental Biology, Beckman Center for Molecular and Genetic Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.}

^{To whom correspondence should be addressed.}ude.drofnats@noslenjw

Abstract

The specification and proper arrangements of new cell types during tissue differentiation require the coordinated regulation of gene expression and precise interactions between neighboring cells. Of the many growth factors involved in these events, Wnts are particularly interesting regulators, because a key component of their signaling pathway, β-catenin, also functions as a component of the cadherin complex, which controls cell-cell adhesion and influences cell migration. Here, we assemble evidence of possible interrelations between Wnt and other growth factor signaling, β-catenin functions, and cadherin-mediated adhesion.

Abstract

During embryogenesis, cells often acquire new identities as they migrate to new locations (1). Many of these morphogenetic changes are induced by extracellular ligands and their receptors (1–4). An important problem is to identify the signaling pathways that coordinate changes in gene expression with dynamic changes in cell adhesion and migration. Deregulation of these pathways is likely to lead to alterations in cell fate, adhesion, and migration, hallmarks of diseases such as cancer.

Although several growth factors are known to affect both gene expression and cell migration (3), recent focus has been on the Wnt signaling pathway. Wnts are powerful regulators of cell proliferation and differentiation, and their signaling pathway involves proteins that directly participate in both gene transcription and cell adhesion. The central player is β-catenin, which is a transcription cofactor with T cell factor/lymphoid enhancer factor TCF/LEF in the Wnt pathway (2) and a structural adaptor protein linking cadherins to the actin cytoskeleton in cell-cell adhesion (5). This review explores intriguing connections between Wnt and other growth factor signals, β-catenin distribution, and cadherin-mediated cell adhesion (Fig. 1, inset).

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Fig. 1

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.

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