Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Genes & Dev. 24 (21): 2383-2388

Copyright © 2010 by Cold Spring Harbor Laboratory Press.


The Hippo signaling pathway restricts the oncogenic potential of an intestinal regeneration program

Jing Cai1, Nailing Zhang1, Yonggang Zheng1, Roeland F. de Wilde2, Anirban Maitra2,, and Duojia Pan1,3

1 Department of Molecular Biology and Genetics, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;
2 Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA

Abstract: Although a developmental role for Hippo signaling in organ size control is well appreciated, how this pathway functions in tissue regeneration is largely unknown. Here we address this issue using a dextran sodium sulfate (DSS)-induced colonic regeneration model. We find that regenerating crypts express elevated Yes-associated protein (YAP) levels. Inactivation of YAP causes no obvious intestinal defects under normal homeostasis, but severely impairs DSS-induced intestinal regeneration. Conversely, hyperactivation of YAP results in widespread early-onset polyp formation following DSS treatment. Thus, the YAP oncoprotein must be exquisitely controlled in tissue regeneration to allow compensatory proliferation and prevent the intrinsic oncogenic potential of a tissue regeneration program.

Key Words: Hippo signaling • cancer • growth control • mouse • regeneration

Received for publication August 5, 2010. Accepted for publication September 14, 2010.

3 Corresponding author.

E-MAIL djpan{at}; FAX (410) 502-3177.

Article is online at

Supplemental material is available at

The Hippo pathway effectors TAZ and YAP in development, homeostasis and disease.
X. Varelas (2014)
Development 141, 1614-1626
   Abstract »    Full Text »    PDF »
Planarian yorkie/YAP functions to integrate adult stem cell proliferation, organ homeostasis and maintenance of axial patterning.
A. Y. T. Lin and B. J. Pearson (2014)
Development 141, 1197-1208
   Abstract »    Full Text »    PDF »
A temporal requirement for Hippo signaling in mammary gland differentiation, growth, and tumorigenesis.
Q. Chen, N. Zhang, R. S. Gray, H. Li, A. J. Ewald, C. A. Zahnow, and D. Pan (2014)
Genes & Dev. 28, 432-437
   Abstract »    Full Text »    PDF »
Hippo signaling disruption and Akt stimulation of ovarian follicles for infertility treatment.
K. Kawamura, Y. Cheng, N. Suzuki, M. Deguchi, Y. Sato, S. Takae, C.-h. Ho, N. Kawamura, M. Tamura, S. Hashimoto, et al. (2013)
PNAS 110, 17474-17479
   Abstract »    Full Text »    PDF »
The Hippo pathway acts via p53 and microRNAs to control proliferation and proapoptotic gene expression during tissue growth.
W. Zhang and S. M. Cohen (2013)
Biology Open 2, 822-828
   Abstract »    Full Text »    PDF »
YAP/TEAD-Mediated Transcription Controls Cellular Senescence.
Q. Xie, J. Chen, H. Feng, S. Peng, U. Adams, Y. Bai, L. Huang, J. Li, J. Huang, S. Meng, et al. (2013)
Cancer Res. 73, 3615-3624
   Abstract »    Full Text »    PDF »
cAMP/PKA signalling reinforces the LATS-YAP pathway to fully suppress YAP in response to actin cytoskeletal changes.
M. Kim, M. Kim, S. Lee, S. Kuninaka, H. Saya, H. Lee, S. Lee, and D.-S. Lim (2013)
EMBO J. 32, 1543-1555
   Abstract »    Full Text »    PDF »
The Hippo pathway: regulators and regulations.
F.-X. Yu and K.-L. Guan (2013)
Genes & Dev. 27, 355-371
   Abstract »    Full Text »    PDF »
Intersection of Hippo/YAP and Wnt/{beta}-catenin signaling pathways.
W. M. Konsavage Jr and G. S. Yochum (2013)
Acta Biochim Biophys Sin 45, 71-79
   Abstract »    Full Text »    PDF »
Hippo Signaling Regulates Pancreas Development through Inactivation of Yap.
N. M. George, C. E. Day, B. P. Boerner, R. L. Johnson, and N. E. Sarvetnick (2012)
Mol. Cell. Biol. 32, 5116-5128
   Abstract »    Full Text »    PDF »
Mammalian Sterile 20-like Kinase 1 Suppresses Lymphoma Development by Promoting Faithful Chromosome Segregation.
T.-S. Kim, D.-H. Lee, S. K. Kim, S. Y. Shin, E.-J. Seo, and D.-S. Lim (2012)
Cancer Res. 72, 5386-5395
   Abstract »    Full Text »    PDF »
Inducible progenitor-derived Wingless regulates adult midgut regeneration in Drosophila.
J. B. Cordero, R. K. Stefanatos, A. Scopelliti, M. Vidal, and O. J. Sansom (2012)
EMBO J. 31, 3901-3917
   Abstract »    Full Text »    PDF »
The Hippo pathway target, YAP, promotes metastasis through its TEAD-interaction domain.
J. M. Lamar, P. Stern, H. Liu, J. W. Schindler, Z.-G. Jiang, and R. O. Hynes (2012)
PNAS 109, E2441-E2450
   Abstract »    Full Text »    PDF »
The Role of Apoptosis-Induced Proliferation for Regeneration and Cancer.
H. D. Ryoo and A. Bergmann (2012)
Cold Spring Harb Perspect Biol 4, a008797
   Abstract »    Full Text »    PDF »
Quit your YAPing: a new target for cancer therapy.
B. Z. Stanger (2012)
Genes & Dev. 26, 1263-1267
   Abstract »    Full Text »    PDF »
Wnt/{beta}-Catenin Signaling Regulates Yes-associated Protein (YAP) Gene Expression in Colorectal Carcinoma Cells.
W. M. Konsavage Jr., S. L. Kyler, S. A. Rennoll, G. Jin, and G. S. Yochum (2012)
J. Biol. Chem. 287, 11730-11739
   Abstract »    Full Text »    PDF »
Mst1 and Mst2 protein kinases restrain intestinal stem cell proliferation and colonic tumorigenesis by inhibition of Yes-associated protein (Yap) overabundance.
D. Zhou, Y. Zhang, H. Wu, E. Barry, Y. Yin, E. Lawrence, D. Dawson, J. E. Willis, S. D. Markowitz, F. D. Camargo, et al. (2011)
PNAS 108, E1312-E1320
   Abstract »    Full Text »    PDF »
The growing role of the Hippo-NDR kinase signalling in neuronal development and disease.
K. Emoto (2011)
J. Biochem. 150, 133-141
   Abstract »    Full Text »    PDF »
The Human Adenocarcinoma-associated Gene, AGR2, Induces Expression of Amphiregulin through Hippo Pathway Co-activator YAP1 Activation.
A. Dong, A. Gupta, R. K. Pai, M. Tun, and A. W. Lowe (2011)
J. Biol. Chem. 286, 18301-18310
   Abstract »    Full Text »    PDF »
Mammalian Hippo pathway: from development to cancer and beyond.
Y. Bao, Y. Hata, M. Ikeda, and K. Withanage (2011)
J. Biochem. 149, 361-379
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882