Active epithelial Hippo signaling in idiopathic pulmonary fibrosis

JCI Insight. 2018 Mar 22;3(6):e98738. doi: 10.1172/jci.insight.98738.


Hippo/YAP signaling plays pleiotropic roles in the regulation of cell proliferation and differentiation during organogenesis and tissue repair. Herein we demonstrate increased YAP activity in respiratory epithelial cells in lungs of patients with idiopathic pulmonary fibrosis (IPF), a common, lethal form of interstitial lung disease (ILD). Immunofluorescence staining in IPF epithelial cells demonstrated increased nuclear YAP and loss of MST1/2. Bioinformatic analyses of epithelial cell RNA profiles predicted increased activity of YAP and increased canonical mTOR/PI3K/AKT signaling in IPF. Phospho-S6 (p-S6) and p-PTEN were increased in IPF epithelial cells, consistent with activation of mTOR signaling. Expression of YAP (S127A), a constitutively active form of YAP, in human bronchial epithelial cells (HBEC3s) increased p-S6 and p-PI3K, cell proliferation and migration, processes that were inhibited by the YAP-TEAD inhibitor verteporfin. Activation of p-S6 was required for enhancing and stabilizing YAP, and the p-S6 inhibitor temsirolimus blocked nuclear YAP localization and suppressed expression of YAP target genes CTGF, AXL, and AJUBA (JUB). YAP and mTOR/p-S6 signaling pathways interact to induce cell proliferation and migration, and inhibit epithelial cell differentiation that may contribute to the pathogenesis of IPF.

Keywords: Cell Biology; Pulmonary surfactants; Pulmonology.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / antagonists & inhibitors
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Carrier Proteins / metabolism
  • Cell Culture Techniques
  • Cell Differentiation
  • Cell Movement
  • Cell Proliferation
  • Epithelial Cells / metabolism*
  • Epithelial Cells / pathology
  • Hepatocyte Growth Factor / metabolism
  • Hippo Signaling Pathway
  • Humans
  • Idiopathic Pulmonary Fibrosis / metabolism*
  • Idiopathic Pulmonary Fibrosis / pathology
  • Lung / metabolism
  • Lung / pathology
  • Lung Diseases, Interstitial / metabolism*
  • Lung Diseases, Interstitial / pathology
  • Membrane Proteins / metabolism
  • Oncogene Protein v-akt / metabolism
  • Organogenesis
  • PTEN Phosphohydrolase / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoproteins / antagonists & inhibitors
  • Phosphoproteins / metabolism*
  • Phosphorylation
  • Protein Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / metabolism
  • Ribosomal Protein S6 Kinases
  • Serine-Threonine Kinase 3
  • Signal Transduction* / drug effects
  • Sirolimus / analogs & derivatives
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases / metabolism
  • Transcription Factors
  • Tumor Suppressor Proteins / metabolism
  • Verteporfin / pharmacology
  • YAP-Signaling Proteins


  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • Membrane Proteins
  • Phosphoproteins
  • Proto-Oncogene Proteins
  • SCRIB protein, human
  • Transcription Factors
  • Tumor Suppressor Proteins
  • VANGL1 protein, human
  • YAP-Signaling Proteins
  • YAP1 protein, human
  • macrophage stimulating protein
  • Verteporfin
  • temsirolimus
  • Hepatocyte Growth Factor
  • MTOR protein, human
  • Oncogene Protein v-akt
  • Protein Serine-Threonine Kinases
  • Ribosomal Protein S6 Kinases
  • STK3 protein, human
  • Serine-Threonine Kinase 3
  • TOR Serine-Threonine Kinases
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Sirolimus