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.


Sci. Signal., 29 September 2009
Vol. 2, Issue 90, p. ra59
[DOI: 10.1126/scisignal.2000300]


Hippo Pathway–Dependent and –Independent Roles of RASSF6

Mitsunobu Ikeda1*, Akira Kawata1*, Misa Nishikawa1*, Yuko Tateishi1,2*, Masato Yamaguchi1, Kentaro Nakagawa1, Susumu Hirabayashi1, Yijun Bao1, Shiho Hidaka1, Yukio Hirata2, and Yutaka Hata1,3{dagger}

1 Department of Medical Biochemistry, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
2 Department of Endocrinology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
3 Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.

* These authors contributed equally to this work.

Abstract: The Hippo pathway restricts cell growth and proliferation and promotes apoptosis to control organ size. The Drosophila melanogaster isoform of RASSF (Ras association domain family; dRASSF) antagonizes proapoptotic Hippo signaling by inhibiting the binding of the adaptor protein Salvador to the kinase Hippo. Paradoxically, however, dRASSF also functions as a tumor suppressor. In mammals, RASSF1A induces apoptosis by stimulating the mammalian Ste20–like kinases (MSTs) 1 and 2, which are Hippo homologs. Here, we characterize the interaction between MST2 and another mammalian RASSF isoform, RASSF6. When bound to MST2, RASSF6 inhibited MST2 activity to antagonize Hippo signaling. However, RASSF6 caused apoptosis when released from activated MST2 in a manner dependent on WW45, the mammalian Salvador homolog. Thus, RASSF6 antagonizes Hippo signaling and mediates apoptosis through a pathway that is parallel to the canonical Hippo pathway. Our findings suggest that activation of MST2 causes apoptosis through the Hippo pathway, as well as through a RASSF6-mediated pathway.

{dagger} To whom correspondence should be addressed. E-mail: yuhammch{at}

Citation: M. Ikeda, A. Kawata, M. Nishikawa, Y. Tateishi, M. Yamaguchi, K. Nakagawa, S. Hirabayashi, Y. Bao, S. Hidaka, Y. Hirata, Y. Hata, Hippo Pathway–Dependent and –Independent Roles of RASSF6. Sci. Signal. 2, ra59 (2009).

Read the Full Text

Screening with a Novel Cell-Based Assay for TAZ Activators Identifies a Compound That Enhances Myogenesis in C2C12 Cells and Facilitates Muscle Repair in a Muscle Injury Model.
Z. Yang, K. Nakagawa, A. Sarkar, J. Maruyama, H. Iwasa, Y. Bao, M. Ishigami-Yuasa, S. Ito, H. Kagechika, S. Hata, et al. (2014)
Mol. Cell. Biol. 34, 1607-1621
   Abstract »    Full Text »    PDF »
Protein Interaction Network of the Mammalian Hippo Pathway Reveals Mechanisms of Kinase-Phosphatase Interactions.
A. L. Couzens, J. D. R. Knight, M. J. Kean, G. Teo, A. Weiss, W. H. Dunham, Z.-Y. Lin, R. D. Bagshaw, F. Sicheri, T. Pawson, et al. (2013)
Science Signaling 6, rs15
   Abstract »    Full Text »    PDF »
The RASSF6 Tumor Suppressor Protein Regulates Apoptosis and the Cell Cycle via MDM2 Protein and p53 Protein.
H. Iwasa, T. Kudo, S. Maimaiti, M. Ikeda, J. Maruyama, K. Nakagawa, and Y. Hata (2013)
J. Biol. Chem. 288, 30320-30329
   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 »
Expression of RASSF6 in kidney and the implication of RASSF6 and the Hippo pathway in the sorbitol-induced apoptosis in renal proximal tubular epithelial cells.
K. Withanage, K. Nakagawa, M. Ikeda, H. Kurihara, T. Kudo, Z. Yang, A. Sakane, T. Sasaki, and Y. Hata (2012)
J. Biochem. 152, 111-119
   Abstract »    Full Text »    PDF »
The RASSF3 Candidate Tumor Suppressor Induces Apoptosis and G1-S Cell-Cycle Arrest via p53.
T. Kudo, M. Ikeda, M. Nishikawa, Z. Yang, K. Ohno, K. Nakagawa, and Y. Hata (2012)
Cancer Res. 72, 2901-2911
   Abstract »    Full Text »    PDF »
Lats2 kinase potentiates Snail1 activity by promoting nuclear retention upon phosphorylation.
K. Zhang, E. Rodriguez-Aznar, N. Yabuta, R. J. Owen, J. M. Mingot, H. Nojima, M. A. Nieto, and G. D. Longmore (2012)
EMBO J. 31, 29-43
   Abstract »    Full Text »    PDF »
A cell-based assay to screen stimulators of the Hippo pathway reveals the inhibitory effect of dobutamine on the YAP-dependent gene transcription.
Y. Bao, K. Nakagawa, Z. Yang, M. Ikeda, K. Withanage, M. Ishigami-Yuasa, Y. Okuno, S. Hata, H. Nishina, and Y. Hata (2011)
J. Biochem. 150, 199-208
   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 »
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 »
The Tumor Suppressor RASSF1A Prevents Dephosphorylation of the Mammalian STE20-like Kinases MST1 and MST2.
C. Guo, X. Zhang, and G. P. Pfeifer (2011)
J. Biol. Chem. 286, 6253-6261
   Abstract »    Full Text »    PDF »
Hippo signaling: growth control and beyond.
G. Halder and R. L. Johnson (2011)
Development 138, 9-22
   Abstract »    Full Text »    PDF »
Tumor Suppressor Ras Association Domain Family 5 (RASSF5/NORE1) Mediates Death Receptor Ligand-induced Apoptosis.
J. Park, S. I. Kang, S.-Y. Lee, X. F. Zhang, M. S. Kim, L. F. Beers, D.-S. Lim, J. Avruch, H.-S. Kim, and S. B. Lee (2010)
J. Biol. Chem. 285, 35029-35038
   Abstract »    Full Text »    PDF »
Mammalian Ste20-like Kinase (Mst2) Indirectly Supports Raf-1/ERK Pathway Activity via Maintenance of Protein Phosphatase-2A Catalytic Subunit Levels and Consequent Suppression of Inhibitory Raf-1 Phosphorylation.
G. K. Kilili and J. M. Kyriakis (2010)
J. Biol. Chem. 285, 15076-15087
   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