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Dev Cell. 2015 Mar 9;32(5):640-51. doi: 10.1016/j.devcel.2015.01.011.

Cell density sensing alters TGF-β signaling in a cell-type-specific manner, independent from Hippo pathway activation.

Author information

1
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.
2
Thoracic Disease Research Unit, Departments of Biochemistry/Molecular Biology and Medicine, Mayo Clinic Cancer Center, Rochester, MN 55905, USA.
3
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.
4
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.

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.

PMID:
25758862
PMCID:
PMC4437188
DOI:
10.1016/j.devcel.2015.01.011
[Indexed for MEDLINE]
Free PMC Article

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