ERK and Akt signaling pathways function through parallel mechanisms to promote mTORC1 signaling
ERK and Akt signaling pathways function through parallel mechanisms to promote mTORC1 signaling
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DOI：
10.1152/ajpcell.00504.2010
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发表时间：
2011-05-01
影响因子：
5.5
通讯作者：
Kimball, Scot R.
中科院分区：
文献类型：
--
作者：
Winter, Jeremiah N.;Jefferson, Leonard S.;Kimball, Scot R.
Winter JN，Jefferson LS，Kimball SR. ERK和Akt信号通路通过平行机制发挥作用，以促进mTORC 1信号传导。美国生理学杂志细胞生理学300：C1172-C1180，2011年。首次发表于2011年2月2日; doi：10.1152/ajpcell.00504.2010。雷帕霉素的哺乳动物靶蛋白（mTOR）是一种蛋白激酶，当存在于称为mTOR复合物1（mTORC 1）的复合物中时，其充当生长和代谢的重要调节剂。复合物的活性通过多种上游信号传导途径调节，包括涉及Akt和细胞外调节激酶（ERK）的那些。先前的研究表明，Akt和ERK部分通过磷酸化GT3激活蛋白（GAP）（称为结节性硬化症复合物2（TSC 2））促进mTORC 1信号传导，该蛋白作为mTORC 1的上游抑制剂。在本研究中，我们扩展了早期的研究，表明Akt和ERK通路的激活以协同的方式促进mTORC 1信号传导。此外，我们提供的证据表明，Akt和ERK信号通路收敛于TSC 2，Akt磷酸化TSC 2上的残基不同于ERK磷酸化的残基。结果还表明，亮氨酸诱导的mTORC 1信号刺激通过与TSC 2和Akt和ERK信号通路不同的机制发生。总体而言，结果与Akt和ERK磷酸化TSC 2上的不同位点的模型一致，导致其GAP活性的更大抑制，因此与单独输入相比，mTORC 1信号转导的刺激放大。结果进一步表明，亮氨酸通过与TSC 2不同的机制来刺激mTORC 1信号传导。
Winter JN, Jefferson LS, Kimball SR. ERK and Akt signaling pathways function through parallel mechanisms to promote mTORC1 signaling. Am J Physiol Cell Physiol 300: C1172-C1180, 2011. First published February 2, 2011; doi:10.1152/ajpcell.00504.2010.-The mammalian target of rapamycin (mTOR) is a protein kinase that, when present in a complex referred to as mTOR complex 1 (mTORC1), acts as an important regulator of growth and metabolism. The activity of the complex is regulated through multiple upstream signaling pathways, including those involving Akt and the extracellular-regulated kinase (ERK). Previous studies have shown that, in part, Akt and ERK promote mTORC1 signaling through phosphorylation of a GTPase activator protein (GAP), referred to as tuberous sclerosis complex 2 (TSC2), that acts as an upstream inhibitor of mTORC1. In the present study we extend the earlier studies to show that activation of the Akt and ERK pathways acts in a synergistic manner to promote mTORC1 signaling. Moreover, we provide evidence that the Akt and ERK signaling pathways converge on TSC2, and that Akt phosphorylates residues on TSC2 distinct from those phosphorylated by ERK. The results also suggest that leucine-induced stimulation of mTORC1 signaling occurs through a mechanism distinct from TSC2 and the Akt and ERK signaling pathways. Overall, the results are consistent with a model in which Akt and ERK phosphorylate distinct sites on TSC2, leading to greater repression of its GAP activity, and consequently a magnified stimulation of mTORC1 signaling, when compared with either input alone. The results further suggest that leucine acts through a mechanism distinct from TSC2 to stimulate mTORC1 signaling.