Regulation of Proapoptotic Mammalian ste20–Like Kinase MST2 by the IGF1-Akt Pathway

PLoS One

Marc D. Coppola¹  Zeng-qiang Yuan¹  Donghwa Kim¹  Jin Q. Cheng¹  Shaokun Shu¹  Satoshi Kaneko¹ 

[1] Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States of America

关键词: Apoptosis;    Immunoprecipitation;    In vitro kinase assay;    Kinase inhibitors;    Antibodies;    Immunoblotting;    Phosphorylation;    Cell growth;   

DOI  :  10.1371/journal.pone.0009616

学科分类：医学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY