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

RESEARCH

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}tmd.ac.jp

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).

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