Statin-induced Ras activation integrates the phosphatidylinositol 3-kinase signal to Akt and MAPK for bone morphogenetic protein-2 expression in osteoblast differentiation
Statin-induced Ras activation integrates the phosphatidylinositol 3-kinase signal to Akt and MAPK for bone morphogenetic protein-2 expression in osteoblast differentiation
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DOI：
10.1074/jbc.m606706200
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发表时间：
2007-02-16
影响因子：
4.8
通讯作者：
Choudhury, Goutam Ghosh
中科院分区：
文献类型：
--
作者：
Ghosh-Choudhury, Nandini;Mandal, Chandi Charan;Choudhury, Goutam Ghosh
洛伐他汀通过增加骨形态发生蛋白-2 （BMP-2）表达促进成骨细胞分化。我们证明洛伐他汀刺激酪氨酸磷酸化磷脂酰肌醇3-激酶（PI3K）的p85调节亚基，导致其在成骨细胞中的激酶活性增加。抑制PI3K可改善成骨标志物碱性磷酸酶、I型胶原、骨桥蛋白和BMP-2的表达。显性阴性PI3K和PI3K信号抑制剂PTEN的表达显著减弱洛伐他汀诱导的BMP-2转录。Akt激酶也以pi3k依赖的方式被激活。然而，我们的数据表明参与了一个额外的信号通路。洛伐他汀诱导的Erk1/2活性有助于BMP-2转录。lovastatin对PI3K的抑制使Erk1/2活性降低，表明它们之间存在信号传递。作为这种串扰的机制，我们提供了洛伐他汀刺激Ras快速激活的第一个证据，Ras与质膜上的PI3K结合并激活，进而调节Akt和Erk1/2诱导BMP-2表达，促进成骨细胞分化。
Lovastatin promotes osteoblast differentiation by increasing bone morphogenetic protein-2 (BMP-2) expression. We demonstrate that lovastatin stimulates tyrosine phosphorylation of the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3K), leading to an increase in its kinase activity in osteoblast cells. Inhibition of PI3K ameliorated expression of the osteogenic markers alkaline phosphatase, type I collagen, osteopontin, and BMP-2. Expression of dominant-negative PI3K and PTEN, an inhibitor of PI3K signaling, significantly attenuated lovastatin-induced transcription of BMP-2. Akt kinase was also activated in a PI3K-dependent manner. However, our data suggest involvement of an additional signaling pathway. Lovastatin-induced Erk1/2 activity contributed to BMP-2 transcription. Inhibition of PI3K abrogated Erk1/2 activity in response to lovastatin, indicating the presence of a signal relay between them. We provide, as a mechanism of this cross-talk, the first evidence that lovastatin stimulates rapid activation of Ras, which associates with and activates PI3K in the plasma membrane, which in turn regulates Akt and Erk1/2 to induce BMP-2 expression for osteoblast differentiation.