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

Dev Cell. 2010 Dec 14;19(6):831-44. doi: 10.1016/j.devcel.2010.11.012.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Adaptor Proteins, Signal Transducing / antagonists & inhibitors
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / physiology
  • Animals
  • Base Sequence
  • Blastocyst / metabolism
  • Cell Count
  • Cell Cycle Proteins
  • Cells, Cultured
  • Female
  • Gene Knockdown Techniques
  • In Vitro Techniques
  • Mice
  • Nerve Tissue Proteins / deficiency
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / physiology*
  • Phosphoproteins / antagonists & inhibitors
  • Phosphoproteins / genetics
  • Phosphoproteins / physiology
  • Pregnancy
  • RNA, Small Interfering / genetics
  • Signal Transduction
  • Smad Proteins / physiology*
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / genetics
  • Transcription Factors / physiology
  • Transforming Growth Factor beta / physiology*

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Crb1 protein, mouse
  • Nerve Tissue Proteins
  • Phosphoproteins
  • RNA, Small Interfering
  • Smad Proteins
  • Taz protein, mouse
  • Transcription Factors
  • Transforming Growth Factor beta
  • Yap protein, mouse