Emerging Role for Epithelial Polarity Proteins of the Crumbs Family as Potential Tumor Suppressors

Figure 2

Functional relationship linking Crb proteins to the SWH pathway. (a) In Drosophila, nuclear Yki promotes cell proliferation and survival by modulating gene expression. Activation of the SWH pathway leads to the phosphorylation and cytoplasmic retention of Yki. Binding to the FERM domain protein Ex also prevents the nuclear translocation of Yki. Crb restricts Yki-dependent tissue hyperplasia by contributing to Ex localization and function. Overexpression of Crb leads to degradation of Ex, suggesting that Crb plays a crucial role in the fine-tuning of the SWH activity by activating Ex, while limiting its level. The table lists the components of the SWH pathway in Drosophila and mammals. (b) In mammalian cells, high cell density activates the SWH pathway, which contributes to contact-mediated inhibition of growth. Phosphorylation of YAP also results in cytoplasmic sequestration of SMAD proteins, thus limiting TGF-β responsiveness. CRB3 is important to couple cell density information to the SWH, perhaps through a homophilic interaction, leading to the suppression of TGF-β signaling and epithelial to mesenchymal transition.