Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
PLoS One. 2010 Mar 9;5(3):e9616. doi: 10.1371/journal.pone.0009616.
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.
METHODOLOGY/PRINCIPAL FINDINGS: 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/SIGNIFICANCE: 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.
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 已被证明具有相似的作用，并且通过 Raf-1 以激酶非依赖性机制和通过与 MST2 形成复合物的 RASSF 家族蛋白来调节。然而，细胞存活信号对 MST2 的调节在很大程度上仍然未知。
方法/主要发现：通过免疫印迹、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 切割和激活。Akt 在体外和体内磷酸化 MST2 的高度保守的苏氨酸-117 残基，导致 MST2 切割、核易位、自身磷酸化-Thr180 和激酶活性的抑制。结果，MST2 的促凋亡和生长抑制功能显著降低。此外，在人乳腺癌肿瘤中观察到 pMST2-T117/pAkt 和 pMST2-T180 之间的负相关。
结论/意义：我们的研究结果首次表明，细胞外存活信号 IGF1 调节 MST2，并且 Akt 是 MST2 的关键上游调节剂。
