Focus of Research:
University of Alberta
Co-Authors Payman Samavarchi-Tehrani, Masahiro Narimatsu, Alexander Weiss, Katie Cockburn, Brett G. Larsen, Janet Rossant, Jeffrey L. Wrana
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 TGFlive/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 TGFlive; 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 TGFlive signaling. Accordingly, disruption of the Crumbs complex enhances TGFlive; signaling and predisposes cells to TGFlive-mediated epithelial-to-mesenchymal transitions.
Dev Cell. 2010 Dec 14;19(6):831-44.