Detail
Článek
Článek online
FT
Medvik - BMČ
  • Je něco špatně v tomto záznamu ?

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,

. 2018 ; 16 (10) : 1556-1567. [pub] 20180614

Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural, práce podpořená grantem, Research Support, U.S. Gov't, Non-P.H.S.

Perzistentní odkaz   https://www.medvik.cz/link/bmc19035186

Grantová podpora
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

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.

Citace poskytuje 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

Najít záznam

Citační ukazatele

Možnosti archivace