Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control

  1. Bin Zhao1,2,10,
  2. Xiaomu Wei3,
  3. Weiquan Li1,
  4. Ryan S. Udan4,5,
  5. Qian Yang1,2,
  6. Joungmok Kim1,10,
  7. Joe Xie1,
  8. Tsuneo Ikenoue1,
  9. Jindan Yu6,
  10. Li Li2,10,
  11. Pan Zheng6,7,
  12. Keqiang Ye8,
  13. Arul Chinnaiyan6,
  14. Georg Halder4,5,
  15. Zhi-Chun Lai3, and
  16. Kun-Liang Guan1,2,9,10,11
  1. 1 Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA;
  2. 2 Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA;
  3. 3 Department of Biology and Intercollege Graduate Program in Genetics, The Pennsylvania State University, University Park, Pennsylvania 16802, USA;
  4. 4 Program in Developmental Biology, Baylor College of Medicine, Houston, Texas, 77030, USA;
  5. 5 Department of Biochemistry and Molecular Biology, M.D. Anderson Cancer Center, Houston, Texas 77030, USA;
  6. 6 Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA;
  7. 7 Department of Surgery, University of Michigan, Ann Arbor, Michigan 48109, USA;
  8. 8 Department of Pathology, Emory University School of Medicine, Atlanta, Georgia 30322, USA;
  9. 9 Institute of Gerontology, University of Michigan, Ann Arbor, Michigan 48109, USA

Abstract

The Hippo pathway plays a key role in organ size control by regulating cell proliferation and apoptosis in Drosophila. Although recent genetic studies have shown that the Hippo pathway is regulated by the NF2 and Fat tumor suppressors, the physiological regulations of this pathway are unknown. Here we show that in mammalian cells, the transcription coactivator YAP (Yes-associated protein), is inhibited by cell density via the Hippo pathway. Phosphorylation by the Lats tumor suppressor kinase leads to cytoplasmic translocation and inactivation of the YAP oncoprotein. Furthermore, attenuation of this phosphorylation of YAP or Yorkie (Yki), the Drosophila homolog of YAP, potentiates their growth-promoting function in vivo. Moreover, YAP overexpression regulates gene expression in a manner opposite to cell density, and is able to overcome cell contact inhibition. Inhibition of YAP function restores contact inhibition in a human cancer cell line bearing deletion of Salvador (Sav), a Hippo pathway component. Interestingly, we observed that YAP protein is elevated and nuclear localized in some human liver and prostate cancers. Our observations demonstrate that YAP plays a key role in the Hippo pathway to control cell proliferation in response to cell contact.

Keywords

Footnotes

  • 10 Present address: Department of Pharmacology and Moores Cancer Center, University of California at San Diego, La Jolla, CA 92093, USA.

  • 11 Corresponding author.

    11 E-MAIL kunliang{at}umich.edu; FAX (734) 647-9702.

  • Supplemental material is available at http://www.genesdev.org.

  • Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1602907

    • Received August 9, 2007.
    • Accepted September 14, 2007.
| Table of Contents

Life Science Alliance