Yuan Z, Kim D, Shu S, Wu J, Guo J, Xiao L et al.. Phosphoinositide 3-kinase/Akt inhibits MST1-mediated pro-apoptotic signaling through phosphorylation of threonine 120. J Biol Chem 285: 3815-3824

National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Journal of Biological Chemistry (Impact Factor: 4.57). 11/2009; 285(6):3815-24. DOI: 10.1074/jbc.M109.059675
Source: PubMed


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-Thr183 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 Thr183. Phospho-MST1-Thr120 failed to activate downstream targets FOXO3a and JNK. Further, inverse correlation between pMST1-Thr120 and pMST1-Thr183 was observed in human ovarian tumors. These findings indicate that the phosphorylation of MST1-Thr120 by Akt could be a major mechanism of regulation of the Hippo/MST1 pathway by cell survival signaling.

Download full-text


Available from: Donghwa Kim, May 08, 2014
  • Source
    • "The mammalian Ste20-like kinase (MST) family is widely expressed in multiple tissues and consists of four members: MST1, MST2, MST3 and MST4 [29-34]. MST1 kinase was shown to be activated under multiple stress conditions, including oxidative stress [29] and activation of caspases [35,36]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Skeletal muscle undergoes rapid atrophy upon denervation and the underlying mechanisms are complicated. FOXO3a has been implicated as a major mediator of muscle atrophy, but how its subcellular location and activity is controlled during the pathogenesis of muscle atrophy remains largely unknown. MST1 (Mammalian Sterile 20-like kinase 1) is identified as a central component of the Hippo signaling pathway. MST1 has been shown to mediate phosphorylation of FOXO3a at Ser207. Whether this MST1-FOXO signaling cascade exerts any functional consequence on cellular homeostasis remains to be investigated. Result We identified that MST1 kinase was expressed widely in skeletal muscles and was dramatically up-regulated in fast- but not slow-dominant skeletal muscles immediately following denervation. The results of our histological and biochemical studies demonstrated that deletion of MST1 significantly attenuated denervation-induced skeletal muscle wasting and decreased expression of Atrogin-1 and LC3 genes in fast-dominant skeletal muscles from three- to five-month-old adult mice. Further studies indicated that MST1, but not MST2, remarkably increased FOXO3a phosphorylation level at Ser207 and promoted its nuclear translocation in atrophic fast-dominant muscles. Conclusions We have established that MST1 kinase plays an important role in regulating denervation-induced skeletal muscle atrophy. During the early stage of muscle atrophy, the up-regulated MST1 kinase promoted progression of neurogenic atrophy in fast-dominant skeletal muscles through activation of FOXO3a transcription factors.
    Full-text · Article · Feb 2013 · BMC Biology
  • Source
    • "The kinase activity of MST2 is partially required for stimulation of the SAV1-PPARγ interaction and stabilization and activation of PPARγ (Figure 1A, 3B, 5A, 6B). Several reports have shown that the catalytic activity of some protein kinases, such as PDK1 and MEK, is not required for the regulation of PPARγ activity by these kinases [28], [32]. MST2 as a protein kinase may work through two mechanisms: direct binding to PPARγ and phosphorylating PPARγ or its interacting co-activators or ubiquitin ligases. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The mammalian ste20 kinase (MST) signaling pathway plays an important role in the regulation of apoptosis and cell cycle control. We sought to understand the role of MST2 kinase and Salvador homolog 1 (SAV1), a scaffolding protein that functions in the MST pathway, in adipocyte differentiation. MST2 and MST1 stimulated the binding of SAV1 to peroxisome proliferator-activated receptor γ (PPARγ), a transcription factor that plays a key role in adipogenesis. The interaction of endogenous SAV1 and PPARγ was detected in differentiating 3T3-L1 adipocytes. This binding required the kinase activity of MST2 and was mediated by the WW domains of SAV1 and the PPYY motif of PPARγ. Overexpression of MST2 and SAV1 increased PPARγ levels by stabilizing the protein, and the knockdown of SAV1 resulted in a decrease of endogenous PPARγ protein in 3T3-L1 adipocytes. During the differentiation of 3T3-L1 cells into adipocytes, MST2 and SAV1 expression began to increase at 2 days when PPARγ expression also begins to increase. MST2 and SAV1 significantly increased PPARγ transactivation, and SAV1 was shown to be required for the activation of PPARγ by rosiglitazone. Finally, differentiation of 3T3-L1 cells was augmented by MST2 and SAV1 expression and inhibited by knockdown of MST1/2 or SAV1. These results suggest that PPARγ activation by the MST signaling pathway may be a novel regulatory mechanism of adipogenesis.
    Full-text · Article · Jan 2012 · PLoS ONE
  • Source
    • "MST1 and MST2 (mammalian STE-20 like kinase 1 and 2) are key components of the Hippo/MST1 tumor suppressor pathway [4], [5], and we have reported that MST1 mediates oxidative stress-induced neuronal cell death through phosphorylating FOXO3a at serine 207 [6]. Others and we also showed that PI3K/Akt and JNK regulate MST1 activation through protein interaction and phosphorylation during stress-induced cell death [7], [8], [9]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The Hippo/MST1 signaling pathway plays an important role in the regulation of cell proliferation and apoptosis. As a major downstream target of the Hippo/MST1 pathway, YAP2 (Yes-associated protein 2) functions as a transcriptional cofactor that has been implicated in many biological processes, including organ size control and cancer development. MST1/Lats kinase inhibits YAP2's nuclear accumulation and transcriptional activity through inducing the phosphorylation at serine 127 and the sequential association with 14-3-3 proteins. However, the dephosphorylation of YAP2 is not fully appreciated. In the present study, we demonstrate that PP1A (catalytic subunit of protein phosphatase-1) interacts with and dephosphorylates YAP2 in vitro and in vivo, and PP1A-mediated dephosphorylation induces the nuclear accumulation and transcriptional activation of YAP2. Inhibition of PP1 by okadiac acid (OA) increases the phosphorylation at serine 127 and cytoplasmic translocation of YAP2 proteins, thereby mitigating its transcription activity. PP1A expression enhances YAP2's pro-survival capability and YAP2 knockdown sensitizes ovarian cancer cells to cisplatin treatment. Our findings define a novel molecular mechanism that YAP2 is positively regulated by PP1-mediated dephosphorylation in the cell survival.
    Full-text · Article · Sep 2011 · PLoS ONE
Show more