Zyxin promotes colon cancer tumorigenesis in a mitotic phosphorylation-dependent manner and through CDK8-mediated YAP activation

被引：35
作者：
Zhou, Jiuli [1 ,2 ,3 ]
Zeng, Yongji [1 ,2 ,3 ]
Cui, Lian [4 ]
Chen, Xingcheng [1 ,2 ,3 ]
Stauffer, Seth [1 ,2 ,3 ]
Wang, Zhan [1 ,2 ]
Yu, Fang [5 ]
Lele, Subodh M. [3 ]
Talmon, Geoffrey A. [3 ]
Black, Adrian R. [1 ,2 ]
Chen, Yuanhong [1 ,2 ]
Dong, Jixin [1 ,2 ]
机构：
[1] Univ Nebraska Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA
[2] Univ Nebraska Med Ctr, Fred & Pamela Buffett Canc Ctr, Omaha, NE 68198 USA
[3] Univ Nebraska Med Ctr, Dept Pathol & Microbiol, Omaha, NE 68198 USA
[4] Tongji Univ, Sch Med, Shanghai Peoples Hosp 10, Dept Dermatol, Shanghai 200072, Peoples R China
[5] Univ Nebraska Med Ctr, Coll Publ Hlth, Dept Biostat, Omaha, NE 68198 USA
来源：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2018年 / 115卷 / 29期
基金：
美国国家卫生研究院;
关键词：
Zyxin; CDK8; Hippo-YAP pathway; mitosis; colon cancer; HIPPO PATHWAY; F-ACTIN; BETA-CATENIN; CDK1; PHOSPHORYLATION; CELL-PROLIFERATION; SIZE-CONTROL; ORGAN SIZE; CYCLIN D1; PROTEIN; GROWTH;
D O I：
10.1073/pnas.1800621115
中图分类号：
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号：
07 ; 0710 ; 09 ;
摘要：
Zyxin is a member of the focal adhesion complex and plays a critical role in actin filament polymerization and cell motility. Several recent studies showed that Zyxin is a positive regulator of Yki/YAP (Yes-associated protein) signaling. However, little is known about the mechanisms by which Zyxin itself is regulated and how Zyxin affects Hippo-YAP activity. We first showed that Zyxin is phosphorylated by CDK1 during mitosis. Depletion of Zyxin resulted in significantly impaired colon cancer cell proliferation, migration, anchorage-independent growth, and tumor formation in xenograft animal models. Mitotic phosphorylation is required for Zyxin activity in promoting growth. Zyxin regulates YAP activity through the colon cancer oncogene CDK8. CDK8 knockout phenocopied Zyxin knockdown in colon cancer cells, while ectopic expression of CDK8 substantially restored the tumorigenic defects of Zyxin-depletion cells. Mechanistically, we showed that CDK8 directly phosphorylated YAP and promoted its activation. Fully activated YAP is required to support the growth in CDK8-knockout colon cancer cells in vitro and in vivo. Together, these observations suggest that Zyxin promotes colon cancer tumorigenesis in a mitotic-phosphorylation-dependent manner and through CDK8-mediated YAP activation.
引用
收藏
页码：E6760 / E6769
页数：10
相关论文
共 64 条
  • [41] The Hippo Signaling Pathway in Development and Cancer
    Pan, Duojia
    [J]. DEVELOPMENTAL CELL, 2010, 19 (04) : 491 - 505
  • [42] LIM kinases: cofilin and beyond
    Prunier, Chloe
    Prudent, Renaud
    Kapur, Reuben
    Sadoul, Karin
    Lafanechere, Laurence
    [J]. ONCOTARGET, 2017, 8 (25) : 41749 - 41763
  • [43] Zyxin Links Fat Signaling to the Hippo Pathway
    Rauskolb, Cordelia
    Pan, Guohui
    Reddy, B. V. V. G.
    Oh, Hyangyee
    Irvine, Kenneth D.
    [J]. PLOS BIOLOGY, 2011, 9 (06)
  • [44] CDK8 kinase-An emerging target in targeted cancer therapy
    Rzymski, Tomasz
    Mikula, Michal
    Wiklik, Katarzyna
    Brzozka, Krzysztof
    [J]. BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS, 2015, 1854 (10): : 1617 - 1629
  • [45] SAKUMA T, 2014, SCI REP, V4
  • [46] Modulating F-actin organization induces organ growth by affecting the Hippo pathway
    Sansores-Garcia, Leticia
    Bossuyt, Wouter
    Wada, Ken-Ichi
    Yonemura, Shigenobu
    Tao, Chunyao
    Sasaki, Hiroshi
    Halder, Georg
    [J]. EMBO JOURNAL, 2011, 30 (12) : 2325 - 2335
  • [47] Hippo Coactivator YAP1 Upregulates SOX9 and Endows Esophageal Cancer Cells with Stem-like Properties
    Song, Shumei
    Ajani, Jaffer A.
    Honjo, Soichiro
    Maru, Dipen M.
    Chen, Qiongrong
    Scott, Ailing W.
    Heallen, Todd R.
    Xiao, Lianchun
    Hofstetter, Wayne L.
    Weston, Brian
    Lee, Jeffrey H.
    Wadhwa, Roopma
    Sudo, Kazuki
    Stroehlein, John R.
    Martin, James F.
    Hung, Mien-Chie
    Johnson, Randy L.
    [J]. CANCER RESEARCH, 2014, 74 (15) : 4170 - 4182
  • [48] CDK1-mediated mitotic phosphorylation of PBK is involved in cytokinesis and inhibits its oncogenic activity
    Stauffer, Seth
    Zeng, Yongji
    Zhou, Jiuli
    Chen, Xingcheng
    Chen, Yuanhong
    Dong, Jixin
    [J]. CELLULAR SIGNALLING, 2017, 39 : 74 - 83
  • [49] β-catenin regulates expression of cyclin D1 in colon carcinoma cells
    Tetsu, O
    McCormick, F
    [J]. NATURE, 1999, 398 (6726) : 422 - 426
  • [50] Rac1 activation controls nuclear localization of β-catenin during canonical Wnt signaling
    Wu, Ximei
    Tu, Xiaolin
    Joeng, Kyu Sang
    Hilton, Matthew J.
    Williams, David A.
    Long, Fanxin
    [J]. CELL, 2008, 133 (02) : 340 - 353
1234567