[PDF][PDF] The Crumbs complex couples cell density sensing to Hippo-dependent control of the TGF-β-SMAD pathway

X Varelas, P Samavarchi-Tehrani, M Narimatsu… - Developmental cell, 2010 - cell.com
X Varelas, P Samavarchi-Tehrani, M Narimatsu, A Weiss, K Cockburn, BG Larsen, J Rossant
Developmental cell, 2010cell.com
The Hippo pathway senses cell density information to control tissue growth by regulating the
localization of the transcriptional regulators TAZ and YAP (TAZ/YAP). TAZ/YAP also regulate
TGF-β-SMAD signaling, but whether this role is linked to cell density sensing is unknown.
Here we demonstrate that TAZ/YAP dictate the localization of active SMAD complexes in
response to cell density-mediated formation of polarity complexes. In high-density cell
cultures, the Hippo pathway drives cytoplasmic localization of TAZ/YAP, which sequesters …
Summary
The Hippo pathway senses cell density information to control tissue growth by regulating the localization of the transcriptional regulators TAZ and YAP (TAZ/YAP). TAZ/YAP also regulate TGF-β-SMAD signaling, but whether this role is linked to cell density sensing is unknown. Here we demonstrate that TAZ/YAP dictate the localization of active SMAD complexes in response to cell density-mediated formation of polarity complexes. In high-density cell cultures, the Hippo pathway drives cytoplasmic localization of TAZ/YAP, which sequesters SMAD complexes, thereby suppressing TGF-β signaling. We show that during mouse embryogenesis, this is reflected by differences in TAZ/YAP localization, which define regions of active SMAD2/3 complexes. Interfering with TAZ/YAP phosphorylation drives nuclear accumulation of TAZ/YAP and SMAD2/3. Furthermore, we demonstrate that the Crumbs polarity complex interacts with TAZ/YAP, which relays cell density information by promoting TAZ/YAP phosphorylation, cytoplasmic retention, and suppressed TGF-β signaling. Accordingly, disruption of the Crumbs complex enhances TGF-β signaling and predisposes cells to TGF-β-mediated epithelial-to-mesenchymal transitions.
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