Running title RASSF2 AND PAR-4

RASSF2 is a novel pro-apoptotic effector of K-Ras. Inhibition of RASSF2 expression enhances the transforming effects of K-Ras and epigenetic inactivation of RASSF2 is frequently detected in mutant Ras containing primary tumors. Thus, RASSF2 is implicated as a tumor suppressor whose inactivation facilitates transformation by disconnecting apoptotic responses from Ras. The mechanism of action of RASSF2 is not known. Here we show that RASSF2 forms a direct and endogenous complex with the Prostate Apoptosis Response Protein 4 (PAR-4) tumor suppressor. This interaction is regulated by K-Ras and is essential for the full apoptotic effects of PAR-4. RASSF2 is primarily a nuclear protein and shuttling of PAR-4 from the cytoplasm to the nucleus is essential for its function. We show that RASSF2 modulates the nuclear translocation of PAR-4 in prostate tumor cells, providing a mechanism for its biological effects. Thus we identify the first tumor suppressor signaling pathway emanating from RASSF2, we identify a novel mode of action of a RASSF protein and provide an explanation for the extraordinarily hig