title: Cell density sensing alters TGF-β signaling in a cell-type-specific manner, independent from Hippo pathway activation.
abstract: 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.
authors.affiliation: Institut Curie, Centre de Recherche, Team "TGF-β and Oncogenesis," Equipe Labellisée Ligue Contre le Cancer, 91400 Orsay, France; INSERM U1021, 91400 Orsay, France; CNRS UMR 3347, 91400 Orsay, France; Université Paris XI, 91400 Orsay, France.
authors.forename: Flore
authors.initials: F
authors.lastname: Nallet-Staub
authors.affiliation: Thoracic Disease Research Unit, Departments of Biochemistry/Molecular Biology and Medicine, Mayo Clinic Cancer Center, Rochester, MN 55905, USA.
authors.forename: Xueqian
authors.initials: X
authors.lastname: Yin
authors.affiliation: Institut Curie, Centre de Recherche, Team "TGF-β and Oncogenesis," Equipe Labellisée Ligue Contre le Cancer, 91400 Orsay, France; INSERM U1021, 91400 Orsay, France; CNRS UMR 3347, 91400 Orsay, France; Université Paris XI, 91400 Orsay, France.
authors.forename: Cristèle
authors.initials: C
authors.lastname: Gilbert
authors.affiliation: Institut Curie, Centre de Recherche, Team "TGF-β and Oncogenesis," Equipe Labellisée Ligue Contre le Cancer, 91400 Orsay, France; INSERM U1021, 91400 Orsay, France; CNRS UMR 3347, 91400 Orsay, France; Université Paris XI, 91400 Orsay, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Marsaud
authors.affiliation: Institut Curie, Centre de Recherche, Team "TGF-β and Oncogenesis," Equipe Labellisée Ligue Contre le Cancer, 91400 Orsay, France; INSERM U1021, 91400 Orsay, France; CNRS UMR 3347, 91400 Orsay, France; Université Paris XI, 91400 Orsay, France.
authors.forename: Saber
authors.initials: S
authors.lastname: Ben Mimoun
authors.affiliation: Institut Curie, Centre de Recherche, Team "TGF-β and Oncogenesis," Equipe Labellisée Ligue Contre le Cancer, 91400 Orsay, France; INSERM U1021, 91400 Orsay, France; CNRS UMR 3347, 91400 Orsay, France; Université Paris XI, 91400 Orsay, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Javelaud
authors.affiliation: Thoracic Disease Research Unit, Departments of Biochemistry/Molecular Biology and Medicine, Mayo Clinic Cancer Center, Rochester, MN 55905, USA. Electronic address: leof.edward@mayo.edu.
authors.forename: Edward B
authors.initials: EB
authors.lastname: Leof
authors.affiliation: Institut Curie, Centre de Recherche, Team "TGF-β and Oncogenesis," Equipe Labellisée Ligue Contre le Cancer, 91400 Orsay, France; INSERM U1021, 91400 Orsay, France; CNRS UMR 3347, 91400 Orsay, France; Université Paris XI, 91400 Orsay, France. Electronic address: alain.mauviel@curie.fr.
authors.forename: Alain
authors.initials: A
authors.lastname: Mauviel
mesh_terms: D000217:Acyltransferases; D015153:Blotting, Western; D002452:Cell Count; D018797:Cell Cycle Proteins; D049109:Cell Proliferation; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D000090683:Hippo Signaling Pathway; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C456659:YY1AP1 protein, human; D000217:Acyltransferases; C108675:TAFAZZIN protein, human; D017346:Protein Serine-Threonine Kinases