Phosphoinositide 3-Kinase/Akt Inhibits MST1-Mediated Pro-apoptotic Signaling through Phosphorylation of Threonine 120

Zengqiang Yuan,Donghwa Kim,Shaokun Shu,Junbing Wu,Jianping Guo,Lei Xiao,Satoshi Kaneko,Domenico Coppola,Jin Q Cheng

doi:10.1074/jbc.m109.059675

Abstract

The protein kinase mammalian sterile 20-like kinase 1 (MST1) is a mammalian homologue of the Drosophila hippo and plays a critical role in regulation of programmed cell death. MST1 exerts pro-apoptotic function through cleavage, autophosphorylation-Thr(183) and subsequent translocation to the nucleus where it phosphorylates a number of molecules, including LATS1/2, FOXO, JNK, and histone H2B. Here, we show that the cleavage of MST1 is inhibited by the phosphatidylinositol 3-kinase/Akt pathway. Akt interacts with MST1 and phosphorylates a highly conserved residue threonine 120 of MST1, which leads to inhibition of its kinase activity and nuclear translocation as well as the autophosphorylation of Thr(183). Phospho-MST1-Thr(120) failed to activate downstream targets FOXO3a and JNK. Further, inverse correlation between pMST1-Thr(120) and pMST1-Thr(183) was observed in human ovarian tumors. These findings indicate that the phosphorylation of MST1-Thr(120) by Akt could be a major mechanism of regulation of the Hippo/MST1 pathway by cell survival signaling.

Highlights

Mammalian sterile 20-like kinase 1 (MST1) exerts pro-apoptotic function through cleavage, auto- amide as well as heat shock and arsenite
MST1 has been implicated in the control of ylates a highly conserved residue threonine 120 of MST1, which cell death via phosphorylation of FOXO3a-Ser207 and the corleads to inhibition of its kinase activity and nuclear transloca- responding site of FOXO1-Ser212 [7, 8]
PI3K/Akt pathway [29], we further demonstrated that IGF-1-inhibited MST1 cleavage was abrogated with PI3K inhibitor, LY294002

Summary

Introduction

MST1 exerts pro-apoptotic function through cleavage, auto- amide as well as heat shock and arsenite. Mammalian sterile 20-like kinase 1 (MST1) contains an Ste20-related kinase catalytic domain in the N-terminal region followed by a non-catalytic tail, which contains a successively autoinhibitory domain, a dimerization domain, two nuclear export sequences, and a nuclear localization signal [1]. It has phosphorylation of Yorkie, the Drosophila ortholog of the mammalian transcription co-activator yes-associated protein [12]. Accumulating evidence indicates that PI3K/Akt signaling is a major cell survival pathway It suppresses apoptosis through regulation of a number of molecules [15]. Several pro-apoptotic and anti-apoptotic proteins are phosphorylated by Akt, including ASK1

Methods

Conclusion