Hippo pathway-dependent and -independent roles of RASSF6.

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.