regulation of proapoptotic mammalian ste20–like kinase mst2 by the igf1-akt pathway监管proapoptotic哺乳动物ste20-like激酶mst2 igf1-akt通路.pdfVIP

Regulation of Proapoptotic Mammalian ste20–Like Kinase MST2 by the IGF1-Akt Pathway Donghwa Kim, Shaokun Shu, Marc D. Coppola, Satoshi Kaneko¤a, Zeng-qiang Yuan¤b, Jin Q. Cheng* Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States of America Abstract Background: Hippo, a Drosophila serine/threonine kinase, promotes apoptosis and restricts cell growth and proliferation. Its mammalian homolog MST2 has been shown to play similar role and be regulated by Raf-1 via a kinase-independent mechanism and by RASSF family proteins through forming complex with MST2. However, regulation of MST2 by cell survival signal remains largely unknown. Methodology/Principal Findings: Using immunoblotting, in vitro kinase and in vivo labeling assays, we show that IGF1 inhibits MST2 cleavage and activation induced by DNA damage through the phosphatidylinosotol 3-kinase (PI3K)/Akt pathway. Akt phosphorylates a highly conserved threonine-117 residue of MST2 in vitro and in vivo, which leads to inhibition of MST2 cleavage, nuclear translocation, autophosphorylation-Thr180 and kinase activity. As a result, MST2 proapoptotic and growth arrest function was significantly reduced. Further, inverse correlation between pMST2-T117/pAkt and pMST2-T180 was observed in human breast tumors. Conclusions/Significance: Our findings demonstrate for the first time that extracellular cell survival signal IGF1 regulates MST2 and that Akt is a key upstream regulator of MST2. Citation: Kim D, Shu S, Coppola MD, Kaneko S, Yuan Z-q, et al. (2010) Regulation of Proapoptotic Mammalian ste20–Like Kinase MST2 by the IGF1-Akt Pathway. PLoS ONE 5(3): e9616. doi:10.1371/journal.pone.0009616 Editor: Andreas Bergmann, University of Texas MD Anderson Cancer Center, United Stat