論文

査読有り
2018年1月

Platelet-derived growth factor regulates YAP transcriptional activity via Src family kinase dependent tyrosine phosphorylation

JOURNAL OF CELLULAR BIOCHEMISTRY
  • Rory L. Smoot
  • ,
  • Nathan W. Werneburg
  • ,
  • Takaaki Sugihara
  • ,
  • Matthew C. Hernandez
  • ,
  • Lin Yang
  • ,
  • Christine Mehner
  • ,
  • Rondell P. Graham
  • ,
  • Steven F. Bronk
  • ,
  • Mark J. Truty
  • ,
  • Gregory J. Gores

119
1
開始ページ
824
終了ページ
836
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1002/jcb.26246
出版者・発行元
WILEY

The Hippo pathway effector YAP is implicated in the pathogenesis of cholangiocarcinoma (CCA). The Hippo pathway relies on signaling cross talk for its regulation. Given the importance of platelet derived growth factor receptor (PDGFR) signaling in CCA biology, our aim was to examine potential YAP regulation by PDGFR. We employed human and mouse CCA specimens and cell lines for these studies. Initially, we confirmed upregulation of PDGFR and PDGFR ligands in human and mouse CCA specimens and cell lines. YAP, a transcriptional co-activator, was localized to the nucleus in human CCA specimens and a cell line, as well as patient derived xenografts (PDX). PDGFR pharmacologic inhibition led to a redistribution of YAP from the nucleus to cytosol and downregulation of YAP target genes in a human CCA cell line. siRNA silencing of PDGFR- similarly downregulated YAP target genes. YAP activation (nuclear localization and target gene expression) was regulated by Src family kinases (SFKs) downstream of PDGFR. SFK activity resulted in phosphorylation of YAP on tyrosine(357) (YAP(Y357)). The importance of YAP(Y357) phosphorylation in regulating YAP activation was confirmed utilizing the SB-1 cell line, a mouse cell line expressing YAP S127A precluding canonical serine phosphorylation. PDGFR inhibition decreased cellular abundance of the survival protein Mcl-1, a known YAP target gene, and accordingly increased cell death in CCA cells in vitro and in vivo. These preclinical data demonstrate that a PDGFR-SFK cascade regulates YAP activation via tyrosine phosphorylation in CCA. Inhibiting this cascade may provide a viable therapeutic strategy for this human malignancy.

Web of Science ® 被引用回数 : 20

リンク情報
DOI
https://doi.org/10.1002/jcb.26246
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000416024300081&DestApp=WOS_CPL

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