一个由RasGPR2磷酸化介导的调节ERK1/2激活的负反馈回路。
A negative-feedback loop regulating ERK1/2 activation and mediated by RasGPR2 phosphorylation.
作者信息
Ren Jinqi, Cook Aaron A, Bergmeier Wolfgang, Sondek John
机构信息
Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599.
Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599.
出版信息
Biochem Biophys Res Commun. 2016 May 20;474(1):193-198. doi: 10.1016/j.bbrc.2016.04.100. Epub 2016 Apr 21.
Abstract
The dynamic regulation of ERK1 and -2 (ERK1/2) is required for precise signal transduction controlling cell proliferation, differentiation, and survival. However, the underlying mechanisms regulating the activation of ERK1/2 are not completely understood. In this study, we show that phosphorylation of RasGRP2, a guanine nucleotide exchange factor (GEF), inhibits its ability to activate the small GTPase Rap1 that ultimately leads to decreased activation of ERK1/2 in cells. ERK2 phosphorylates RasGRP2 at Ser394 located in the linker region implicated in its autoinhibition. These studies identify RasGRP2 as a novel substrate of ERK1/2 and define a negative-feedback loop that regulates the BRaf-MEK-ERK signaling cascade. This negative-feedback loop determines the amplitude and duration of active ERK1/2.
摘要
细胞外信号调节激酶1和2（ERK1/2）的动态调节对于精确控制细胞增殖、分化和存活的信号转导至关重要。然而，调节ERK1/2激活的潜在机制尚未完全明确。在本研究中，我们发现鸟嘌呤核苷酸交换因子（GEF）RasGRP2的磷酸化抑制了其激活小GTP酶Rap1的能力，最终导致细胞中ERK1/2的激活减少。ERK2在位于其自身抑制相关连接区域的Ser394位点使RasGRP2磷酸化。这些研究确定RasGRP2为ERK1/2的一种新底物，并定义了一个调节BRAF-MEK-ERK信号级联反应的负反馈环。这个负反馈环决定了活性ERK1/2的幅度和持续时间。
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本文引用的文献
1
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Neuron. 2016 Feb 3;89(3):550-65. doi: 10.1016/j.neuron.2015.12.019. Epub 2016 Jan 21.
2
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Proc Natl Acad Sci U S A. 2015 Jan 6;112(1):148-53. doi: 10.1073/pnas.1412089112. Epub 2014 Dec 22.
3
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Cell Rep. 2014 Sep 11;8(5):1583-94. doi: 10.1016/j.celrep.2014.07.036. Epub 2014 Aug 21.
4
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5
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6
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7
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Mol Cell Proteomics. 2012 Dec;11(12):1640-51. doi: 10.1074/mcp.M112.019091. Epub 2012 Aug 30.
10
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