Pharmacological and Genetic Evaluation of Proposed Roles of Mitogen-activated Protein Kinase/Extracellular Signal-regulated Kinase Kinase (MEK), Extracellular Signal-regulated Kinase (ERK), and p90RSK in the Control of mTORC1 Protein Signaling by Phorbol Esters
Pharmacological and Genetic Evaluation of Proposed Roles of Mitogen-activated Protein Kinase/Extracellular Signal-regulated Kinase Kinase (MEK), Extracellular Signal-regulated Kinase (ERK), and p90RSK in the Control of mTORC1 Protein Signaling by Phorbol Esters
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DOI：
10.1074/jbc.m111.260794
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发表时间：
2011-08-05
影响因子：
4.8
通讯作者：
Proud, Christopher G.
中科院分区：
文献类型：
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作者：
Fonseca, Bruno D.;Alain, Tommy;Proud, Christopher G.
哺乳动物雷帕霉素靶蛋白复合物1（mTORC 1）将mRNA翻译、细胞生长和代谢的控制与多种刺激相联系。mTORC 1的不适当激活可导致癌症。佛波酯是天然存在的产品，作为有效的肿瘤促进剂。它们激活蛋白激酶C（PKC）的亚型并刺激致癌MEK/ERK信号级联。它们还激活mTORC 1信号传导。以前的工作表明，mTORC 1激活佛波醇酯PMA（佛波醇12-肉豆蔻酸酯13-乙酸酯）依赖于PKC，并可能涉及MEK。然而，它们激活mTORC 1的确切机制仍不清楚。最近的研究表明，ERK和ERK激活的90 kDa核糖体S6激酶（p90（RSK））通过磷酸化TSC 2（mTORC 1的调节因子）和/或mTORC 1组分raptor激活mTORC 1信号传导。然而，这些激酶和磷酸化事件中的每一个对于mTORC 1信号传导的激活的相对重要性是未知的。最近获得的MEK（PD 184352）和p90（RSK）（BI-D1870）抑制剂的特异性提高，使我们能够解决这些蛋白激酶在控制mTORC 1在各种人类和啮齿动物细胞类型的作用。同时，我们使用针对p90（RSK 1）和p90（RSK 2）的特异性shRNA进一步测试它们在调节mTORC 1信号传导中的作用。我们的数据表明，在所有测试的细胞类型中，p90（RSK）都被佛波醇酯激活mTORC 1信号。我们的数据还揭示了在不同细胞类型之间控制mTORC 1时对MEK/ERK的需求存在显著差异，这表明佛波醇酯和mTORC 1之间存在额外的信号连接，而不涉及MEK/ERK。这项研究提供了重要的信息，设计有效的策略，以打击过度激活的mTORC 1信号的致癌途径。
The mammalian target of rapamycin complex 1 (mTORC1) links the control of mRNA translation, cell growth, and metabolism to diverse stimuli. Inappropriate activation of mTORC1 can lead to cancer. Phorbol esters are naturally occurring products that act as potent tumor promoters. They activate isoforms of protein kinase C (PKCs) and stimulate the oncogenic MEK/ERK signaling cascade. They also activate mTORC1 signaling. Previous work indicated that mTORC1 activation by the phorbol ester PMA (phorbol 12-myristate 13-acetate) depends upon PKCs and may involve MEK. However, the precise mechanism(s) through which they activate mTORC1 remains unclear. Recent studies have implicated both the ERKs and the ERK-activated 90-kDa ribosomal S6 kinases (p90(RSK)) in activating mTORC1 signaling via phosphorylation of TSC2 (a regulator of mTORC1) and/or the mTORC1 component raptor. However, the relative importance of each of these kinases and phosphorylation events for the activation of mTORC1 signaling is unknown. The recent availability of MEK (PD184352) and p90(RSK) (BI-D1870) inhibitors of improved specificity allowed us to address the roles of these protein kinases in controlling mTORC1in a variety of human and rodent cell types. In parallel, we used specific shRNAs against p90(RSK1) and p90(RSK2) to further test their roles in regulating mTORC1 signaling. Our data indicate that p90(RSKs) are dispensable for the activation of mTORC1 signaling by phorbol esters in all cell types tested. Our data also reveal striking diversity in the requirements for MEK/ERK in the control of mTORC1 between different cell types, pointing to additional signaling connections between phorbol esters and mTORC1, which do not involve MEK/ERK. This study provides important information for the design of efficient strategies to combat the hyperactivation of mTORC1 signaling by oncogenic pathways.