Active epithelial Hippo signaling in idiopathic pulmonary fibrosis.

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  • Additional Information
    • Source:
      Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 101676073 Publication Model: Electronic Cited Medium: Internet ISSN: 2379-3708 (Electronic) Linking ISSN: 23793708 NLM ISO Abbreviation: JCI Insight Subsets: MEDLINE
    • Publication Information:
      Original Publication: Ann Arbor, Michigan : American Society for Clinical Investigation, [2016]-
    • Subject Terms:
      Signal Transduction*/drug effects; Adaptor Proteins, Signal Transducing/*metabolism ; Epithelial Cells/*metabolism ; Idiopathic Pulmonary Fibrosis/*metabolism ; Lung Diseases, Interstitial/*metabolism ; Phosphoproteins/*metabolism ; Protein Serine-Threonine Kinases/*metabolism; Adaptor Proteins, Signal Transducing/antagonists & inhibitors ; Carrier Proteins/metabolism ; Cell Culture Techniques ; Cell Differentiation ; Cell Movement ; Cell Proliferation ; Epithelial Cells/pathology ; Hepatocyte Growth Factor/metabolism ; Hippo Signaling Pathway ; Humans ; Idiopathic Pulmonary Fibrosis/pathology ; Lung/metabolism ; Lung/pathology ; Lung Diseases, Interstitial/pathology ; Membrane Proteins/metabolism ; Oncogene Protein v-akt/metabolism ; Organogenesis ; PTEN Phosphohydrolase/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphoproteins/antagonists & inhibitors ; Phosphorylation ; Proto-Oncogene Proteins/metabolism ; Ribosomal Protein S6 Kinases ; Serine-Threonine Kinase 3 ; Sirolimus/analogs & derivatives ; Sirolimus/pharmacology ; TOR Serine-Threonine Kinases/metabolism ; Transcription Factors ; Tumor Suppressor Proteins/metabolism ; Verteporfin/pharmacology ; YAP-Signaling Proteins
    • Abstract:
      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.
    • References:
      Dev Cell. 2015 Aug 10;34(3):283-96. (PMID: 26235047)
      Dev Biol. 2014 Feb 15;386(2):281-90. (PMID: 24384391)
      Elife. 2017 Mar 21;6:. (PMID: 28323616)
      Curr Top Dev Biol. 2017;123:181-228. (PMID: 28236967)
      J Cell Sci. 2014 Feb 15;127(Pt 4):709-17. (PMID: 24532814)
      Annu Rev Pathol. 2015;10:371-93. (PMID: 25621661)
      Curr Biol. 2010 Apr 13;20(7):657-62. (PMID: 20303269)
      Development. 2014 Apr;141(8):1614-26. (PMID: 24715453)
      PLoS One. 2013;8(3):e58658. (PMID: 23527003)
      N Engl J Med. 2001 Feb 22;344(8):573-9. (PMID: 11207353)
      Exp Eye Res. 2014 Jul;124:67-73. (PMID: 24837142)
      Am J Cancer Res. 2015 Dec 15;6(1):27-37. (PMID: 27073720)
      Thorax. 2011 Aug;66(8):651-7. (PMID: 21422041)
      Nat Cell Biol. 2014 Jan;16(1):108-17. (PMID: 24362629)
      Biochem Biophys Res Commun. 2014 Jan 17;443(3):917-23. (PMID: 24380865)
      Dev Cell. 2017 Oct 9;43(1):48-59.e5. (PMID: 29017029)
      Biochim Biophys Acta. 2013 Jul;1832(7):922-30. (PMID: 23219956)
      J Clin Invest. 2011 Jan;121(1):277-87. (PMID: 21135509)
      Front Pharmacol. 2014 Jan 10;4:173. (PMID: 24454287)
      Lancet. 2011 Dec 3;378(9807):1949-61. (PMID: 21719092)
      Med Klin (Munich). 2005 Mar 15;100(3):161-4. (PMID: 15966446)
      Am J Hum Genet. 2009 Jan;84(1):52-9. (PMID: 19100526)
      Dis Model Mech. 2010 Sep-Oct;3(9-10):545-56. (PMID: 20699479)
      Dev Biol. 2013 May 1;377(1):1-8. (PMID: 23592229)
      Nat Cell Biol. 2012 Dec;14 (12 ):1322-9. (PMID: 23143395)
      Int J Immunopathol Pharmacol. 2012 Oct-Dec;25(4):989-1001. (PMID: 23298489)
      Dev Cell. 2014 Jul 28;30(2):151-65. (PMID: 25043474)
      PLoS One. 2014 Aug 27;9(8):e106155. (PMID: 25162417)
      Dev Cell. 2014 Jul 28;30(2):137-50. (PMID: 25043473)
      Sci Rep. 2017 Apr 21;7:46581. (PMID: 28429726)
      Eur Respir J. 2015 Jun;45(6):1717-27. (PMID: 25837031)
      J Mol Cell Biol. 2015 Feb;7(1):35-47. (PMID: 25480985)
      JCI Insight. 2016 Dec 8;1(20):e90558. (PMID: 27942595)
      Respirology. 2011 Jul;16(5):776-83. (PMID: 21362103)
      Pulm Med. 2011;2011:653524. (PMID: 21660239)
      Trends Cell Biol. 2015 Sep;25(9):499-513. (PMID: 26045258)
      Chest. 2002 Mar;121(3 Suppl):20S-21S. (PMID: 11893657)
      J Immunol. 2004 Aug 1;173(3):2099-108. (PMID: 15265946)
      Nat Cell Biol. 2011 Aug 01;13(8):877-83. (PMID: 21808241)
      Elife. 2018 Jan 10;7:null. (PMID: 29319504)
      Sci Rep. 2017 Aug 8;7(1):7602. (PMID: 28790340)
      Autoimmun Rev. 2014 Oct;13(10):1020-5. (PMID: 25182202)
      Onco Targets Ther. 2016 Aug 29;9:5371-81. (PMID: 27621651)
      Lab Invest. 2002 Oct;82(10):1335-45. (PMID: 12379768)
      Am J Physiol Cell Physiol. 2014 Jun 1;306(11):C987-96. (PMID: 24740535)
      Am J Physiol Lung Cell Mol Physiol. 2014 Jun 15;306(12):L1117-28. (PMID: 24793166)
      Am J Cancer Res. 2016 Dec 01;6(12 ):2816-2830. (PMID: 28042502)
      Annu Rev Med. 2013;64:265-76. (PMID: 23020878)
    • Grant Information:
      R56 HL123969 United States HL NHLBI NIH HHS; T32 HL007752 United States HL NHLBI NIH HHS; U01 HL110964 United States HL NHLBI NIH HHS; R01 HL131661 United States HL NHLBI NIH HHS; U01 HL122642 United States HL NHLBI NIH HHS
    • Contributed Indexing:
      Keywords: Cell Biology; Pulmonary surfactants; Pulmonology
    • Accession Number:
      0 (Adaptor Proteins, Signal Transducing)
      0 (Carrier Proteins)
      0 (Membrane Proteins)
      0 (Phosphoproteins)
      0 (Proto-Oncogene Proteins)
      0 (SCRIB protein, human)
      0 (Transcription Factors)
      0 (Tumor Suppressor Proteins)
      0 (VANGL1 protein, human)
      0 (YAP-Signaling Proteins)
      0 (YAP1 protein, human)
      0 (macrophage stimulating protein)
      0X9PA28K43 (Verteporfin)
      624KN6GM2T (temsirolimus)
      67256-21-7 (Hepatocyte Growth Factor)
      EC 2.7.1.1 (MTOR protein, human)
      EC 2.7.11.1 (Oncogene Protein v-akt)
      EC 2.7.11.1 (Protein Serine-Threonine Kinases)
      EC 2.7.11.1 (Ribosomal Protein S6 Kinases)
      EC 2.7.11.1 (STK3 protein, human)
      EC 2.7.11.1 (Serine-Threonine Kinase 3)
      EC 2.7.11.1 (TOR Serine-Threonine Kinases)
      EC 3.1.3.67 (PTEN Phosphohydrolase)
      EC 3.1.3.67 (PTEN protein, human)
      W36ZG6FT64 (Sirolimus)
    • Publication Date:
      Date Created: 20180323 Date Completed: 20191021 Latest Revision: 20211204
    • Publication Date:
      20231215
    • Accession Number:
      PMC5926907
    • Accession Number:
      10.1172/jci.insight.98738
    • Accession Number:
      29563341