Regulation of proapoptotic mammalian ste20-like kinase MST2 by the IGF1-Akt pathway.
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.


RESULTS
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
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.
Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
Donghwa
D
Kim
Shaokun
S
Shu
Marc D
MD
Coppola
Satoshi
S
Kaneko
Zeng-Qiang
ZQ
Yuan
Jin Q
JQ
Cheng
D021581:Active Transport, Cell Nucleus; D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology; D019556:COS Cells; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002460:Cell Line; D002522:Chlorocebus aethiops; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D000090742:Serine-Threonine Kinase 3; D015398:Signal Transduction; D000099317:Hippo Kinases
D053148:Caspase 3; D053179:Caspase 7; D007334:Insulin-Like Growth Factor I; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000090742:Serine-Threonine Kinase 3; C097835:STK3 protein, human; D000099317:Hippo Kinases