Role of the tumor suppressor RASSF2 in regulation of MST1 kinase activity.
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.
Song
Hoogeun
H
Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 373-1 Guseong-dong, Yuseong-gu, Daejeon 305-701, Republic of Korea.
Oh
Sangphil
S
Oh
Hyun Jung
HJ
Lim
Dae-Sik
DS
D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D004789:Enzyme Activation; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000201:enzymology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D000099317:Hippo Kinases
D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D047908:Intracellular Signaling Peptides and Proteins; D048670:MAP Kinase Kinase 4; D017346:Protein Serine-Threonine Kinases; D025521:Tumor Suppressor Proteins; C499517:FOXO3 protein, human; C425300:RASSF2 protein, human; C095566:STK4 protein, human; D000099317:Hippo Kinases