The tumor suppressor, RASSF2 (Ras association domain family 2), is frequently downregulated in a number of cancers Although exogenously expressed RASSF2 induces apoptotic cell death, the precise roles of RASSF2 under pro-apoptotic conditions remain largely unknown Here. we demonstrate that MST1 (mammalian sterile 20-like kinase 1) regulates RASSF2 protein stability Knockdown of MST1 in cancer cells markedly destabilizes RASSF2, and Mst1-deficient mice show reduced Rassf2 protein levels in several organs. Conversely. RASSF2 activates MsT1 kinase activity through formation of a RASSF2-MST1 complex, which inhibits the MST-FOXO3 signaling pathway RASSF2 also engages the JNK pathway and induces apoptosis in an MST1-independent manner. Collectively, these findings indicate that MST1 is a major determinant of RASSF2 protein stability. and suggest that RASSF2 acts in a complex manner that extends beyond simple protein-protein association to play an important role in MST1 regulation (C) 2009 Published by Elsevier Inc