Trends in Cell Biology
Research FocusDecisions, decisions: β-catenin chooses between adhesion and 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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2016, Biochimica et Biophysica Acta - Molecular Cell ResearchCitation Excerpt :Wnt/β-catenin signaling plays critical roles in many biological processes, including stem cell maintenance, embryonic development, and cell destination [1,2]. There are two pools of β-catenin within the cell which are required for two principal roles that include its involvement in cell-cell adhesion junction at the membrane and its transcriptional functions in nucleus [3–6]. As a component of adhesion junction, β-catenin interacts with E-cadherin and α-catenin [7,8].