Cell Density Sensing Alters TGF-β Signaling in a Cell-Type-Specific Manner, Independent from Hippo Pathway Activation

Abstract

SUMMARY 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 β (TGF-β) responses, based on the ability of phospho-YAP/TAZ to sequester TGF-β-activated SMAD complexes in the cytoplasm. Herein, we provide evidence that epithelial cell polarization interferes with TGF-β signaling well upstream and independent of cytoplasmic YAP/TAZ. Rather, polarized basolateral presentation of TGF-β receptors I and II deprives apically delivered TGF-β of access to its receptors. Basolateral ligand delivery nonetheless remains entirely effective to induce TGF-β responses. These data demonstrate that cell-type-specific inhibition of TGF-β signaling by cell density is restricted to polarized epithelial cells and reflects the polarized distribution of TGF-β receptors, which thus affects SMAD activation irrespective of Hippo pathway activation.

Neogenin-YAP signaling in neocortical astrocytic differentiation

“…Our results suggest that YAP interaction with pSmad1 may be critical for maintaining pSmad1 protein stability. This view are in line with reports that YAP interacts with Smads in the nuclear to modulate BMP/ Smad1 or TGF/Smad2 signaling in HEK293 cells or Eph4 cells, [40][41][42][43] and that YAP-pSmad1/5/8 complex in the nuclei of HEK293 cells prevents p-Smad1/5/8 degradation by Smurf1. 40,43 These reports, combine with our results, demonstrate the importance of YAP regulation of BMP2/Smad1 signaling in various cell types.…”

A Balance between Secreted Inhibitors and Edge Sensing Controls Gastruloid Self-Organization

“…Recent studies about TGF-β signaling in epithelial cells have shown density-dependent TGF-β inhibition due to crosstalk with the HIPPO pathway (Varelas et al, 2010) or receptor localization to the baso-lateral surface of epithelia (Nallet-Staub et al, 2015). …”

EGF augments TGFβ-induced epithelial–mesenchymal transition by promoting SHP2 binding to GAB1

“…Such cell context-dependent effects could arise from perturbations to signaling processes regulating EMT that occur preferentially in specific cell lines. Indeed, previous work showed that high cell density can significantly impair TGFβ-induced SMAD nuclear localization in a cell line-dependent manner (Zieba et al, 2012;Nallet-Staub et al, 2015). An effect of cell density on EMT could be particularly important in vivo where epithelial cells are packed tightly in threedimensional structures.…”