GEFs: Dual regulation of Rac1 signaling.
GEFs: Dual regulation of Rac1 signaling.
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DOI：
10.1080/21541248.2016.1202635
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发表时间：
2017-04-03
期刊：
影响因子：
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通讯作者：
Malliri A
中科院分区：
文献类型：
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作者：
Marei H;Malliri A
GEF 在调节 Rac1 信号传导中发挥着关键作用。它们充当信号节点，将上游信号转换为下游 Rac1 驱动的细胞响应。通过与膜结合的 Rac1 结合，GEF 促进 GDP 与 GTP 的交换，从而激活 Rac1。结果，Rac1 经历构象变化，介导其与下游效应器的相互作用，将 Rac1 与多种生理和病理过程联系起来。有趣的是，至少有 20 个 GEF 参与 Rac1 激活，这表明除了促进 GDP 与 GTP 的交换外，GEF 在调节 Rac1 信号传导方面还发挥着更复杂的作用。事实上，越来越多的证据表明 GEF 可以指导 Rac1 驱动的信号级联的特异性，尽管其潜在机制尚不明确。最近，通过进行比较研究，我们强调了 2 个 Rac 特异性 GEF（Tiam1 和 P-Rex1）在决定 Rac1 下游生物学结果中的作用。重要的是，进一步的蛋白质组学分析发现，两个 GEF 在调节 Rac1 相互作用组方面具有与 GEF 活性无关的功能，从而刺激 GEF 特异性信号级联。在这里，我们概述了我们最近的发现，并讨论了 GEF 作为 Rac1 信号传导主要调节因子的作用，特别关注 Rac1 激活后 GEF 介导的细胞迁移调节。
GEFs play a critical role in regulating Rac1 signaling. They serve as signaling nodes converting upstream signals into downstream Rac1-driven cellular responses. Through associating with membrane-bound Rac1, GEFs facilitate the exchange of GDP for GTP, thereby activating Rac1. As a result, Rac1 undergoes conformational changes that mediate its interaction with downstream effectors, linking Rac1 to a multitude of physiological and pathological processes. Interestingly, there are at least 20 GEFs involved in Rac1 activation, suggesting a more complex role of GEFs in regulating Rac1 signaling apart from promoting the exchange of GDP for GTP. Indeed, accumulating evidence implicates GEFs in directing the specificity of Rac1-driven signaling cascades, although the underlying mechanisms were poorly defined. Recently, through conducting a comparative study, we highlighted the role of 2 Rac-specific GEFs, Tiam1 and P-Rex1, in dictating the biological outcome downstream of Rac1. Importantly, further proteomic analysis uncovered a GEF activity-independent function for both GEFs in modulating the Rac1 interactome, which results in the stimulation of GEF-specific signaling cascades. Here, we provide an overview of our recent findings and discuss the role of GEFs as master regulators of Rac1 signaling with a particular focus on GEF-mediated modulation of cell migration following Rac1 activation.