Molecular mechanisms underlying TGF-ß/Hippo signaling crosstalks - Role of baso-apical epithelial cell polarity.

The ubiquitous distribution of both Hippo and TGF-ß signaling cascade components and their critical implication in tissue homeostasis and disease has led to the discovery of a remarkable slew of interesting and unique features regarding their functional crosstalks. Upstream cellular cues regulating the Hippo pathway, including cell-cell contacts and apico-basal cell polarity have been well characterized. Herein, we provide an overview of the published models of compartmentalized signaling crosstalk mechanisms between Hippo signaling and the TGF-ß/SMAD pathway. How cell polarity impacts the interaction between the two pathways is discussed, together with the specifics of cytoplasmic and nuclear events implicating SMADs and YAP/TAZ, leading to contextual regulation of target gene expression.

Cell density sensing alters TGF-ß signaling in a cell-type-specific manner, independent from Hippo pathway activation.

Cell-cell contacts inhibit cell growth and proliferation in part by activating the Hippo pathway that drives the phosphorylation and nuclear exclusion of the transcriptional coactivators YAP and TAZ. Cell density and Hippo signaling have also been reported to block transforming growth factor ß (TGF-ß) responses, based on the ability of phospho-YAP/TAZ to sequester TGF-ß-activated SMAD complexes in the cytoplasm. Herein, we provide evidence that epithelial cell polarization interferes with TGF-ß signaling well upstream and independent of cytoplasmic YAP/TAZ. Rather, polarized basolateral presentation of TGF-ß receptors I and II deprives apically delivered TGF-ß of access to its receptors. Basolateral ligand delivery nonetheless remains entirely effective to induce TGF-ß responses. These data demonstrate that cell-type-specific inhibition of TGF-ß signaling by cell density is restricted to polarized epithelial cells and reflects the polarized distribution of TGF-ß receptors, which thus affects SMAD activation irrespective of Hippo pathway activation.