Identification of a Ras GTPase-activating protein regulated by receptor-mediated Ca2+ oscillations
Identification of a Ras GTPase-activating protein regulated by receptor-mediated Ca2+ oscillations
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DOI：
10.1038/sj.emboj.7600197
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发表时间：
2004-04-21
期刊：
影响因子：
11.4
通讯作者：
Cullen, PJ
中科院分区：
文献类型：
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作者：
Walker, SA;Kupzig, S;Cullen, PJ
受体介导的细胞内游离钙（[Ca2+](i)）浓度的增加负责控制大量的生理过程，包括基因表达、分泌、收缩、增殖、神经信号传导和学习。[Ca2+](i)的增加通常以重复的Ca2+尖峰或振荡的形式发生。在电刺激或受体刺激的诱导下，这些重复的Ca2+尖峰随着受体刺激的幅度增加其频率，这一现象对于诱导选择性细胞功能至关重要。在这里，我们报告了RASAL的特征，RASAL是一种Ras gtpase激活蛋白，通过与质膜进行同步振荡关联来感知重复Ca2+峰值的频率。重要的是，我们发现只有在质膜结合期间RASAL才能灭活Ras信号。因此，RASAL感知复杂Ca2+信号的频率，并通过调节Ras的激活状态来解码它们。我们的数据提供了复杂Ca2+信号和Ras调节之间迄今未被认识的联系。
Receptor-mediated increases in the concentration of intracellular free calcium ([Ca2+](i)) are responsible for controlling a plethora of physiological processes including gene expression, secretion, contraction, proliferation, neural signalling, and learning. Increases in [Ca2+](i) often occur as repetitive Ca2+ spikes or oscillations. Induced by electrical or receptor stimuli, these repetitive Ca2+ spikes increase their frequency with the amplitude of the receptor stimuli, a phenomenon that appears critical for the induction of selective cellular functions. Here we report the characterisation of RASAL, a Ras GTPase-activating protein that senses the frequency of repetitive Ca2+ spikes by undergoing synchronous oscillatory associations with the plasma membrane. Importantly, we show that only during periods of plasma membrane association does RASAL inactivate Ras signalling. Thus, RASAL senses the frequency of complex Ca2+ signals, decoding them through a regulation of the activation state of Ras. Our data provide a hitherto unrecognised link between complex Ca2+ signals and the regulation of Ras.