A negative-feedback loop regulating ERK1/2 activation and mediated by RasGPR2 phosphorylation.
A negative-feedback loop regulating ERK1/2 activation and mediated by RasGPR2 phosphorylation.
复制标题
调节 ERK1/2 激活并由 RasGPR2 磷酸化介导的负反馈环路。
DOI：
10.1016/j.bbrc.2016.04.100
复制
发表时间：
2016
影响因子：
3.1
通讯作者：
Sondek,John
中科院分区：
文献类型：
--
作者：
Ren,Jinqi;Cook,AaronA;Bergmeier,Wolfgang;Sondek,John
ERK 1和ERK-2（ERK 1/2）的动态调节是控制细胞增殖、分化和存活的精确信号转导所必需的。然而，调节ERK 1/2活化的潜在机制尚未完全了解。在这项研究中，我们表明，磷酸化的RasGRP 2，鸟嘌呤核苷酸交换因子（GEF），抑制其激活的小GTdR Rap 1，最终导致细胞中ERK 1/2的激活减少的能力。ERK 2磷酸化RasGRP 2的Ser 394位，位于与其自身抑制有关的连接区。这些研究将RasGRP 2鉴定为ERK 1/2的新型底物，并定义了调节BRaf-MEK-ERK信号级联的负反馈回路。这种负反馈回路决定了活性ERK 1/2的幅度和持续时间。
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.