title: The Crumbs complex couples cell density sensing to Hippo-dependent control of the TGF-β-SMAD pathway.
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.
authors.affiliation: Center for Systems Biology, Mount Sinai Hospital, Toronto, ON, Canada.
authors.forename: Xaralabos
authors.initials: X
authors.lastname: Varelas
authors.forename: Payman
authors.initials: P
authors.lastname: Samavarchi-Tehrani
authors.forename: Masahiro
authors.initials: M
authors.lastname: Narimatsu
authors.forename: Alexander
authors.initials: A
authors.lastname: Weiss
authors.forename: Katie
authors.initials: K
authors.lastname: Cockburn
authors.forename: Brett G
authors.initials: BG
authors.lastname: Larsen
authors.forename: Janet
authors.initials: J
authors.lastname: Rossant
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Wrana
mesh_terms: D021581:Active Transport, Cell Nucleus; D000217:Acyltransferases; D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D000818:Animals; D001483:Base Sequence; D001755:Blastocyst / Q000378:metabolism; D002452:Cell Count; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D005260:Female; D055785:Gene Knockdown Techniques; D066298:In Vitro Techniques; D051379:Mice; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D011247:Pregnancy; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D051785:Smad Proteins / Q000502:physiology*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000502:physiology*; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C453730:Crb1 protein, mouse; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D051785:Smad Proteins; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D000217:Acyltransferases; C486363:tafazzin protein, mouse