Rapamycin inhibits IGF-1 stimulated cell motility through PP2A pathway.
Rapamycin inhibits IGF-1 stimulated cell motility through PP2A pathway.
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DOI：
10.1371/journal.pone.0010578
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发表时间：
2010-05-11
期刊：
影响因子：
3.7
通讯作者：
Huang S
中科院分区：
文献类型：
--
作者：
Liu L;Chen L;Luo Y;Chen W;Zhou H;Xu B;Han X;Shen T;Huang S
丝氨酸/苏氨酸 (Ser/Thr) 蛋白磷酸酶 2A (PP2A) 被认为是哺乳动物雷帕霉素靶点 (mTOR) 信号通路的新成分。最近，我们证明 mTOR 部分通过 p70 S6 激酶 1 (S6K1) 和真核起始因子 4E (eIF4E) 结合蛋白 1 (4E-BP1) 途径调节细胞运动。关于 PP2A 在 mTOR 介导的细胞运动中的作用知之甚少。在这里，我们发现雷帕霉素抑制基础或胰岛素样生长因子 1 (IGF-1) 诱导的人尤文肉瘤 (Rh1) 和横纹肌肉瘤 (Rh30) 细胞的运动。用雷帕霉素处理细胞可激活 PP2A 活性，同时抑制 IGF-1 刺激 Erk1/2 的磷酸化。用 PD98059 抑制 Erk1/2 不会显着影响细胞的基础迁移率，但会显着抑制 IGF-1 诱导的细胞迁移率。此外，用冈田酸抑制 PP2A 显着减弱雷帕霉素对 IGF-1 刺激的 Erk1/2 磷酸化以及细胞运动的抑制作用。一致地，显性失活 PP2A 的表达赋予对 IGF-1 刺激的 Erk1/2 磷酸化和细胞运动的抵抗力。组成型活性 MKK1 的表达也减弱了雷帕霉素对 IGF-1 刺激的 Erk1/2 磷酸化和细胞运动的抑制作用。结果表明，雷帕霉素部分通过靶向 PP2A-Erk1/2 通路来抑制细胞运动。
Serine/threonine (Ser/Thr) protein phosphatase 2A (PP2A) has been implicated as a novel component of the mammalian target of rapamycin (mTOR) signaling pathway. Recently we have demonstrated that mTOR regulates cell motility in part through p70 S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1) pathways. Little is known about the role of PP2A in the mTOR-mediated cell motility. Here we show that rapamycin inhibited the basal or insulin-like growth factor 1 (IGF-1)-induced motility of human Ewing sarcoma (Rh1) and rhabdomyosarcoma (Rh30) cells. Treatment of the cells with rapamycin activated PP2A activity, and concurrently inhibited IGF-1 stimulated phosphorylation of Erk1/2. Inhibition of Erk1/2 with PD98059 did not significantly affect the basal mobility of the cells, but dramatically inhibited IGF-1-induced cell motility. Furthermore, inhibition of PP2A with okadaic acid significantly attenuated the inhibitory effect of rapamycin on IGF-1-stimulated phosphorylation of Erk1/2 as well as cell motility. Consistently, expression of dominant negative PP2A conferred resistance to IGF-1-stimulated phosphorylation of Erk1/2 and cell motility. Expression of constitutively active MKK1 also attenuated rapamycin inhibition of IGF-1-stimulated phosphorylation of Erk1/2 and cell motility. The results suggest that rapamycin inhibits cell motility, in part by targeting PP2A-Erk1/2 pathway.
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