TAZ and YAP regulate the activity of SMAD transcription factors in response to TGFβ signalling by promoting their retention in the nucleus. Given that Hippo signalling induces the phosphorylation and cytoplasmic localization of TAZ and YAP upon increased cell density, Varelas et al. set out to address whether TAZ and YAP might also link cell density to control of SMADs. They first observed that, in mouse and human mammary cells, high cell density tightly correlated with cytoplasmic localization of TAZ and YAP, as well as SMAD2 and SMAD3. This cytoplasmic colocalization was also seen in early mouse embryos, at stages when cells were more compacted. Inhibition of TAZ and YAP phosphorylation resulted in their nuclear accumulation and enhanced SMAD2 and SMAD3 nuclear localization, and hence TGFβ signalling.
Next, the authors asked how cell density might be sensed by the Hippo pathway. They saw that the subcellular localization of TAZ, YAP, SMAD2 and SMAD3 was sensitive to the integrity of the cell–cell junctions that establish apical–basal cell polarity. From genetic studies of Drosophila melanogaster, the Crumbs apical polarity complex is known to act upstream of Hippo signalling and, consistent with this, the authors showed that TAZ and YAP bind to the Crumbs polarity complex. Furthermore, increased localization of the Crumbs complex to cell–cell junctions showed a close parallel with cytoplasmic TAZ, YAP and SMAD localization, and depletion of the Crumbs complex in high-density cell cultures led to nuclear accumulation of TAZ, YAP and SMADs, and increased responses to TGFβ. Interfering with the Crumbs complex also altered resistance of epithelial cells to TGFβ-mediated epithelial–mesenchymal transitions.
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