Regulation of proapoptotic mammalian ste20-like kinase MST2 by the IGF1-Akt pathway.
Regulation of proapoptotic mammalian ste20-like kinase MST2 by the IGF1-Akt pathway.
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DOI：
10.1371/journal.pone.0009616
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发表时间：
2010-03-09
期刊：
影响因子：
3.7
通讯作者：
Cheng JQ
中科院分区：
文献类型：
--
作者：
Kim D;Shu S;Coppola MD;Kaneko S;Yuan ZQ;Cheng JQ
Hippo 是一种果蝇丝氨酸/苏氨酸激酶，可促进细胞凋亡并限制细胞生长和增殖。其哺乳动物同源物 MST2 已被证明发挥相似的作用，并通过激酶独立机制受到 Raf-1 的调节，并通过与 MST2 形成复合物受到 RASSF 家族蛋白的调节。然而，细胞存活信号对 MST2 的调节仍然很大程度上未知。使用免疫印迹、体外激酶和体内标记测定，我们表明 IGF1 通过磷脂酰肌醇 3-激酶 (PI3K)/Akt 途径抑制 DNA 损伤诱导的 MST2 裂解和激活。 Akt 在体外和体内磷酸化 MST2 高度保守的苏氨酸 117 残基，从而抑制 MST2 裂解、核易位、自磷酸化 - Thr180 和激酶活性。结果，MST2促凋亡和生长停滞功能显着降低。此外，在人类乳腺肿瘤中观察到 pMST2-T117/pAkt 和 pMST2-T180 之间呈负相关。我们的研究结果首次证明细胞外细胞生存信号 IGF1 调节 MST2，并且 Akt 是 MST2 的关键上游调节因子。
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. 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. 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.
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