PMID- 28661054
OWN - NLM
STAT- MEDLINE
DCOM- 20180706
LR  - 20211204
IS  - 1097-4644 (Electronic)
IS  - 0730-2312 (Print)
IS  - 0730-2312 (Linking)
VI  - 119
IP  - 1
DP  - 2018 Jan
TI  - Platelet-derived growth factor regulates YAP transcriptional activity via Src 
      family kinase dependent tyrosine phosphorylation.
PG  - 824-836
LID - 10.1002/jcb.26246 [doi]
AB  - 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 PDGFRbeta 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-beta 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.
CI  - (c) 2017 Wiley Periodicals, Inc.
FAU - Smoot, Rory L
AU  - Smoot RL
AUID- ORCID: 0000-0001-8543-661X
AD  - Department of Surgery, Mayo Clinic College of Medicine and Science, Rochester, 
      Minnesota.
FAU - Werneburg, Nathan W
AU  - Werneburg NW
AD  - Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and 
      Science, Rochester, Minnesota.
FAU - Sugihara, Takaaki
AU  - Sugihara T
AD  - Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and 
      Science, Rochester, Minnesota.
FAU - Hernandez, Matthew C
AU  - Hernandez MC
AD  - Department of Surgery, Mayo Clinic College of Medicine and Science, Rochester, 
      Minnesota.
FAU - Yang, Lin
AU  - Yang L
AD  - Center for Individualized Medicine, Mayo Clinic College of Medicine and Science, 
      Rochester, Minnesota.
FAU - Mehner, Christine
AU  - Mehner C
AD  - Department of Biochemistry and Molecular Biology, Mayo Clinic Graduate School of 
      Biomedical Sciences, Jacksonville, Florida.
FAU - Graham, Rondell P
AU  - Graham RP
AD  - Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine 
      and Science, Rochester, Minnesota.
FAU - Bronk, Steven F
AU  - Bronk SF
AD  - Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and 
      Science, Rochester, Minnesota.
FAU - Truty, Mark J
AU  - Truty MJ
AD  - Department of Surgery, Mayo Clinic College of Medicine and Science, Rochester, 
      Minnesota.
FAU - Gores, Gregory J
AU  - Gores GJ
AD  - Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and 
      Science, Rochester, Minnesota.
LA  - eng
GR  - P30 DK084567/DK/NIDDK NIH HHS/United States
GR  - R01 DK059427/DK/NIDDK NIH HHS/United States
PT  - Journal Article
DEP - 20170803
PL  - United States
TA  - J Cell Biochem
JT  - Journal of cellular biochemistry
JID - 8205768
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Phosphoproteins)
RN  - 0 (Platelet-Derived Growth Factor)
RN  - 0 (Transcription Factors)
RN  - 0 (YAP-Signaling Proteins)
RN  - 0 (YAP1 protein, human)
RN  - EC 2.7.10.1 (PDGFRB protein, human)
RN  - EC 2.7.10.1 (Receptor, Platelet-Derived Growth Factor beta)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/*metabolism
MH  - Animals
MH  - Bile Duct Neoplasms/genetics/*metabolism
MH  - Cell Line, Tumor
MH  - Cell Nucleus/genetics/metabolism
MH  - Cholangiocarcinoma/genetics/*metabolism
MH  - Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - Mice
MH  - Neoplasm Transplantation
MH  - Phosphoproteins/*metabolism
MH  - Phosphorylation
MH  - Platelet-Derived Growth Factor/*metabolism
MH  - Receptor, Platelet-Derived Growth Factor beta/*metabolism
MH  - Signal Transduction
MH  - Transcription Factors
MH  - *Transcription, Genetic
MH  - Up-Regulation
MH  - YAP-Signaling Proteins
PMC - PMC5705491
MID - NIHMS897457
OTO - NOTNLM
OT  - Hippo
OT  - Src kinase family
OT  - cholangiocarcinoma
OT  - platelet derived growth factor
EDAT- 2017/07/01 06:00
MHDA- 2018/07/07 06:00
PMCR- 2019/01/01
CRDT- 2017/06/30 06:00
PHST- 2017/05/19 00:00 [received]
PHST- 2017/06/26 00:00 [accepted]
PHST- 2017/07/01 06:00 [pubmed]
PHST- 2018/07/07 06:00 [medline]
PHST- 2017/06/30 06:00 [entrez]
PHST- 2019/01/01 00:00 [pmc-release]
AID - 10.1002/jcb.26246 [doi]
PST - ppublish
SO  - J Cell Biochem. 2018 Jan;119(1):824-836. doi: 10.1002/jcb.26246. Epub 2017 Aug 3.