The Ras Effector RASSF2 Controls the PAR-4 Tumor Suppressor

H Donninger, L Hesson, M Vos, K Beebe, L Gordon, D Sidransky, JW Liu, T Schlegel, S Payne, A Hartmann, Farida Latif, GJ Clark

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    23 Citations (Scopus)


    RASSF2 is a novel proapoptotic 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 we provide an explanation for the extraordinarily high frequency of RASSF2 inactivation we have observed in primary prostate tumors.
    Original languageEnglish
    Pages (from-to)2608-2620
    Number of pages13
    JournalMolecular and Cellular Biology
    Issue number11
    Publication statusPublished - 1 Jun 2010


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