Abstract
BackgroundHippo, 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 FindingsUsing 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/SignificanceOur findings demonstrate for the first time that extracellular cell survival signal IGF1 regulates MST2 and that Akt is a key upstream regulator of MST2.
Highlights
MST2 and its close homologue MST1 are members of the germinal center kinase group II (GCK II) family of mitogenactivated protein kinase (MAPK)–related kinases that includes the more distantly related kinases MST3, MST4, LOK, SOK, and SLK
In Drosophila, Hippo, a homolog of mammalian MST2, restricts cell growth and cell proliferation and promotes cell death by interaction with the tumor suppressors Salvador (Sav)/WW45 and Warts (Wts)/Lats1/Lats2, which result in inhibition of transcription and/or degradation of cyclin E and DIAPs [18,19], through phosphorylation of Yorkie, which is the Drosophila ortholog of the mammalian transcription co-activator yes-associated protein (YAP) [20]
Since MST2 is cleaved and activated upon apoptotic stimuli and is required for DNA damage-induced apoptosis in different types of cells, we initially examined if extracellular cell survival signal regulates MST2 cleavage and activation
Summary
MST2 and its close homologue MST1 are members of the germinal center kinase group II (GCK II) family of mitogenactivated protein kinase (MAPK)–related kinases that includes the more distantly related kinases MST3, MST4, LOK, SOK, and SLK. During the execution phase of apoptosis in mammalian cells induced by proapoptotic stimuli, MST1 and MST2 are activated by caspase cleavage and subsequently translocated to the nucleus. RASSF1A and RASSF5 activate NDR1, NDR2, and LATS1 to induce apoptosis [13,14,15,16]. These findings suggest that RASSF1A and RASSF5 stimulate MST signaling. RASSF6 caused apoptosis when released from activated MST2 in a manner dependent on WW45 [17]. 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. Regulation of MST2 by cell survival signal remains largely unknown
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