Hippo Pathway–Dependent and –Independent Roles of RASSF6

RASSF6 is both an inhibitor and a promoter of apoptosis, and its proapoptotic activity is regulated by the mammalian kinase MST2, a Hippo homolog. Apoptosis, With or Without Hippo The Hippo signaling pathway, named after the kinase Hippo, limits organ size without affecting patterning, and the components of this pathway are conserved from Drosophila to mammals. Drosophila RASSF (Ras association domain family) not only inhibits Hippo signaling and thus counters Hippo-mediated apoptosis, but also exhibits tumor suppressor function. Of the 10 mammalian RASSF isoforms, the best-characterized isoform, RASSF1A, activates the mammalian homologs of Hippo (the MST kinases), which contrasts with the role of dRASSF. Ikeda et al. show that RASSF6 represents another twist in the RASSF protein family. RASSF6 and MST2 are mutual inhibitors: Activation of MST2 disrupted binding of RASSF6 to MST2, enabling MST2 to induce apoptosis through a process dependent on the Hippo pathway and allowing RASSF6 to mediate apoptosis through a Hippo-independent pathway. These results suggest that mammalian RASSF isoforms may have divergent functions and may link the Hippo pathway to other signal transduction cascades. 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.

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