-
Something wrong with this record ?
YAP Tyrosine Phosphorylation and Nuclear Localization in Cholangiocarcinoma Cells Are Regulated by LCK and Independent of LATS Activity
T. Sugihara, NW. Werneburg, MC. Hernandez, L. Yang, A. Kabashima, P. Hirsova, L. Yohanathan, C. Sosa, MJ. Truty, G. Vasmatzis, GJ. Gores, RL. Smoot,
Language English Country United States
Document type Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.
Grant support
P30 CA015083
NCI NIH HHS - United States
P30 DK084567
NIDDK NIH HHS - United States
R01 DK059427
NIDDK NIH HHS - United States
R03 CA171017
NCI NIH HHS - United States
NLK
Free Medical Journals
from 2002 to 1 year ago
Open Access Digital Library
from 2002-11-01
Open Access Digital Library
from 2002-11-01
- MeSH
- Adaptor Proteins, Signal Transducing genetics MeSH
- Cell Nucleus drug effects MeSH
- Cholangiocarcinoma drug therapy genetics pathology MeSH
- Cytoplasm drug effects MeSH
- Dasatinib administration & dosage MeSH
- Phosphoproteins genetics MeSH
- Phosphorylation drug effects MeSH
- Humans MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Cell Proliferation drug effects MeSH
- Protein Serine-Threonine Kinases genetics MeSH
- Gene Expression Regulation, Neoplastic drug effects MeSH
- Signal Transduction drug effects MeSH
- src-Family Kinases antagonists & inhibitors genetics MeSH
- Tyrosine genetics MeSH
- Lymphocyte Specific Protein Tyrosine Kinase p56(lck) genetics MeSH
- Xenograft Model Antitumor Assays MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
The Hippo pathway effector, Yes-associated protein (YAP), is a transcriptional coactivator implicated in cholangiocarcinoma (CCA) pathogenesis. YAP is known to be regulated by a serine/threonine kinase relay module (MST1/2-LATS1/2) culminating in phosphorylation of YAP at Serine 127 and cytoplasmic sequestration. However, YAP also undergoes tyrosine phosphorylation, and the role of tyrosine phosphorylation in YAP regulation remains unclear. Herein, YAP regulation by tyrosine phosphorylation was examined in human and mouse CCA cells, as well as patient-derived xenograft (PDX) models. YAP was phosphorylated on tyrosine 357 (Y357) in CCA cell lines and PDX models. SRC family kinase (SFK) inhibition with dasatinib resulted in loss of YAPY357 phosphorylation, promoted its translocation from the nucleus to the cytoplasm, and reduced YAP target gene expression, including cell lines expressing a LATS1/2-resistant YAP mutant in which all serine residues were mutated to alanine. Consistent with these observations, precluding YAPY357 phosphorylation by site-directed mutagenesis (YAPY357F) excluded YAP from the nucleus. Targeted siRNA experiments identified LCK as the SFK that most potently mediated YAPY357 phosphorylation. Likewise, inducible CRISPR/Cas9-targeted LCK deletion decreased YAPY357 phosphorylation and its nuclear localization. The importance of LCK in CCA biology was demonstrated by clinical observations suggesting LCK expression levels were associated with early tumor recurrence following resection of CCA. Finally, dasatinib displayed therapeutic efficacy in PDX models. Mol Cancer Res; 16(10); 1556-67. ©2018 AACR.
Center for Individualized Medicine Mayo Clinic College of Medicine and Science Rochester Minnesota
Department of Surgery Mayo Clinic College of Medicine and Science Rochester Minnesota
References provided by Crossref.org
- 000
- 00000naa a2200000 a 4500
- 001
- bmc19035186
- 003
- CZ-PrNML
- 005
- 20191015121322.0
- 007
- ta
- 008
- 191007s2018 xxu f 000 0|eng||
- 009
- AR
- 024 7_
- $a 10.1158/1541-7786.MCR-18-0158 $2 doi
- 035 __
- $a (PubMed)29903769
- 040 __
- $a ABA008 $b cze $d ABA008 $e AACR2
- 041 0_
- $a eng
- 044 __
- $a xxu
- 100 1_
- $a Sugihara, Takaaki $u Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota.
- 245 10
- $a YAP Tyrosine Phosphorylation and Nuclear Localization in Cholangiocarcinoma Cells Are Regulated by LCK and Independent of LATS Activity / $c T. Sugihara, NW. Werneburg, MC. Hernandez, L. Yang, A. Kabashima, P. Hirsova, L. Yohanathan, C. Sosa, MJ. Truty, G. Vasmatzis, GJ. Gores, RL. Smoot,
- 520 9_
- $a The Hippo pathway effector, Yes-associated protein (YAP), is a transcriptional coactivator implicated in cholangiocarcinoma (CCA) pathogenesis. YAP is known to be regulated by a serine/threonine kinase relay module (MST1/2-LATS1/2) culminating in phosphorylation of YAP at Serine 127 and cytoplasmic sequestration. However, YAP also undergoes tyrosine phosphorylation, and the role of tyrosine phosphorylation in YAP regulation remains unclear. Herein, YAP regulation by tyrosine phosphorylation was examined in human and mouse CCA cells, as well as patient-derived xenograft (PDX) models. YAP was phosphorylated on tyrosine 357 (Y357) in CCA cell lines and PDX models. SRC family kinase (SFK) inhibition with dasatinib resulted in loss of YAPY357 phosphorylation, promoted its translocation from the nucleus to the cytoplasm, and reduced YAP target gene expression, including cell lines expressing a LATS1/2-resistant YAP mutant in which all serine residues were mutated to alanine. Consistent with these observations, precluding YAPY357 phosphorylation by site-directed mutagenesis (YAPY357F) excluded YAP from the nucleus. Targeted siRNA experiments identified LCK as the SFK that most potently mediated YAPY357 phosphorylation. Likewise, inducible CRISPR/Cas9-targeted LCK deletion decreased YAPY357 phosphorylation and its nuclear localization. The importance of LCK in CCA biology was demonstrated by clinical observations suggesting LCK expression levels were associated with early tumor recurrence following resection of CCA. Finally, dasatinib displayed therapeutic efficacy in PDX models. Mol Cancer Res; 16(10); 1556-67. ©2018 AACR.
- 650 _2
- $a adaptorové proteiny signální transdukční $x genetika $7 D048868
- 650 _2
- $a zvířata $7 D000818
- 650 _2
- $a nádorové buněčné linie $7 D045744
- 650 _2
- $a buněčné jádro $x účinky léků $7 D002467
- 650 _2
- $a proliferace buněk $x účinky léků $7 D049109
- 650 _2
- $a cholangiokarcinom $x farmakoterapie $x genetika $x patologie $7 D018281
- 650 _2
- $a cytoplazma $x účinky léků $7 D003593
- 650 _2
- $a dasatinib $x aplikace a dávkování $7 D000069439
- 650 _2
- $a regulace genové exprese u nádorů $x účinky léků $7 D015972
- 650 _2
- $a lidé $7 D006801
- 650 _2
- $a tyrosinkinasa p56(lck), specifická pro lymfocyty $x genetika $7 D019860
- 650 _2
- $a myši $7 D051379
- 650 _2
- $a fosfoproteiny $x genetika $7 D010750
- 650 _2
- $a fosforylace $x účinky léků $7 D010766
- 650 _2
- $a protein-serin-threoninkinasy $x genetika $7 D017346
- 650 _2
- $a signální transdukce $x účinky léků $7 D015398
- 650 _2
- $a tyrosin $x genetika $7 D014443
- 650 _2
- $a xenogenní modely - testy protinádorové aktivity $7 D023041
- 650 _2
- $a skupina kinas odvozených od src-genu $x antagonisté a inhibitory $x genetika $7 D019061
- 655 _2
- $a časopisecké články $7 D016428
- 655 _2
- $a Research Support, N.I.H., Extramural $7 D052061
- 655 _2
- $a práce podpořená grantem $7 D013485
- 655 _2
- $a Research Support, U.S. Gov't, Non-P.H.S. $7 D013486
- 700 1_
- $a Werneburg, Nathan W $u Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota.
- 700 1_
- $a Hernandez, Matthew C $u Department of Surgery, Mayo Clinic College of Medicine and Science, Rochester, Minnesota.
- 700 1_
- $a Yang, Lin $u Center for Individualized Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota.
- 700 1_
- $a Kabashima, Ayano $u Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota.
- 700 1_
- $a Hirsova, Petra $u Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota. Institute of Clinical Biochemistry and Diagnostics, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic.
- 700 1_
- $a Yohanathan, Lavanya $u Department of Surgery, Mayo Clinic College of Medicine and Science, Rochester, Minnesota.
- 700 1_
- $a Sosa, Carlos $u Division of Health Sciences Research, Biomedical Statistics and Informatics, Mayo Clinic College of Medicine and Science, Rochester, Minnesota.
- 700 1_
- $a Truty, Mark J $u Department of Surgery, Mayo Clinic College of Medicine and Science, Rochester, Minnesota.
- 700 1_
- $a Vasmatzis, George $u Department of Laboratory Medicine and Pathology, Molecular Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota.
- 700 1_
- $a Gores, Gregory J $u Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota.
- 700 1_
- $a Smoot, Rory L $u Department of Surgery, Mayo Clinic College of Medicine and Science, Rochester, Minnesota. smoot.rory@mayo.edu.
- 773 0_
- $w MED00007101 $t Molecular cancer research : MCR $x 1557-3125 $g Roč. 16, č. 10 (2018), s. 1556-1567
- 856 41
- $u https://pubmed.ncbi.nlm.nih.gov/29903769 $y Pubmed
- 910 __
- $a ABA008 $b sig $c sign $y a $z 0
- 990 __
- $a 20191007 $b ABA008
- 991 __
- $a 20191015121748 $b ABA008
- 999 __
- $a ok $b bmc $g 1451846 $s 1073736
- BAS __
- $a 3
- BAS __
- $a PreBMC
- BMC __
- $a 2018 $b 16 $c 10 $d 1556-1567 $e 20180614 $i 1557-3125 $m Molecular cancer research $n Mol Cancer Res $x MED00007101
- GRA __
- $a P30 CA015083 $p NCI NIH HHS $2 United States
- GRA __
- $a P30 DK084567 $p NIDDK NIH HHS $2 United States
- GRA __
- $a R01 DK059427 $p NIDDK NIH HHS $2 United States
- GRA __
- $a R03 CA171017 $p NCI NIH HHS $2 United States
- LZP __
- $a Pubmed-20191007