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Decisions, decisions: β-catenin chooses between adhesion and transcription

https://doi.org/10.1016/j.tcb.2005.03.002Get rights and content

β-catenin functions in both cell adhesion and transcription. Properly choosing between these functions is crucial for normal development, and the wrong choice can lead to cancer. Recent studies have revealed molecular switches that help dictate whether β-catenin interacts with adhesive or transcriptional complexes. Cara Gottardi and Barry Gumbiner identify Wnt-induced β-catenin conformational changes that favor assembly into transcription complexes, whereas α-catenin-associated β-catenin appears to favor adhesion. Furthermore, Felix Brembeck and colleagues reveal that phosphorylation dissociates β-catenin from adhesion complexes while enhancing BCL9-2 binding to promote transcription.

Introduction

Just as no man is an island, few proteins act alone. Proteins work together in multiprotein machines that in turn interact with one another, forming networks of cooperation and coordination. Different proteins have varying connectivity, and those that mediate many interactions act as network hubs. Just as major airports are crucial to transportation networks, protein interaction hubs are crucial to cell structure, signaling and physiology. Some hubs are relatively stable, using the same protein partners in different contexts, whereas other hubs are more versatile, assembling different multiprotein machines in different contexts [1]. Identifying how a hub protein selects its partners is essential for understanding the dynamics of protein interaction networks during normal processes and disease. Recent studies by Cara Gottardi and Barry Gumbiner [2], and Felix Brembeck and colleagues [3], have elucidated key mechanisms dictating the interaction decisions of the protein β-catenin.

Section snippets

Binding choices at the β-catenin protein interaction hub

β-catenin provided one of the first examples of a dynamic protein interaction hub (Figure 1a). In Drosophila, the pioneering work of Christiane Nüsslein-Volhard and Eric Wieschaus identified β-catenin as a key effector of Wnt (Wg) signaling [4]. In this role, it functions in the nucleus, linking T-cell factor (TCF) with other transcriptional regulators, including Legless (Bcl-9) and Pygopus, to activate transcription of Wnt target genes (reviewed in [5]). Meanwhile, Rolf Kemler, Masatoshi

β-catenin bends towards transcription, whereas α-catenin pushes for adhesion

Gottardi and Gumbiner's discovery [2] emerged from a simple set of protein-interaction tests. Using GST fusion proteins of the cadherin cytoplasmic tail (cad–GST) or TCF (TCF–GST), they discovered that, while β-catenin from untreated cells binds to both partners equally well, cytosolic β-catenin from cells exposed to Wnt signals preferentially binds to TCF. Remarkably, this interaction choice is not simply due to elevated β-catenin levels, as it is not observed for extracts from cells lacking

BCL9-2 and tyrosine phosphorylation weigh in for transcription

Gottardi and Gumbiner focused on the binding selectivity of cytoplasmic pools of β-catenin, which are normally quite small. Typically, most cellular β-catenin is associated with AJs. Thus, any activity capable of dissociating β-catenin from AJs could rapidly increase the level of free β-catenin available for transcription.

Brembeck and colleagues [3] investigated just such a mechanism, examining a role for tyrosine phosphorylation in the release of β-catenin from AJs and its recruitment into

Concluding remarks

The β-catenin protein interaction hub is highly regulated. Here, we focused on recently reported mechanisms that dictate whether β-catenin interacts with adhesion or transcription complexes. These include phosphorylation that releases β-catenin from AJs, two forms of cytoplasmic β-catenin with differential selectivity for adhesion and transcription complexes, and binding partners that sequester β-catenin in the nucleus. The challenge ahead is to define how β-catenin interaction decisions are

Acknowledgements

This work was supported by NIH grant R01GM47857 to M. Peifer. T. Harris was supported by postdoctoral fellowships from the Natural Sciences and Engineering Research Council of Canada and the Canadian Institutes of Health Research. M. Peifer was supported in part by the Welsh Distinguished Term Professorship. We thank D. Fox and J. Gates for critical reading of the manuscript.

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