Regulation of Ras Localization by Acylation Enables a Mode of Intracellular Signal Propagation
Regulation of Ras Localization by Acylation Enables a Mode of Intracellular Signal Propagation
复制标题
DOI：
10.1126/scisignal.20001370
复制
发表时间：
2010-09-21
影响因子：
7.3
通讯作者：
Bastiaens, Philippe I. H.
中科院分区：
文献类型：
--
作者：
Lorentzen, Anna;Kinkhabwala, Ali;Bastiaens, Philippe I. H.
生长因子刺激在质膜上产生瞬时的H-RAS活性，但在高尔基体产生持续的活性。两个重叠的调控网络控制着划分的H-RAS活性：鸟苷二磷酸-鸟苷三磷酸循环和酰化循环，后者结构性地运输可以在细胞内膜间隔之间棕榈酰化的RAS亚型。这些网络解偶联后H-RAS活性的定量成像显示，H-RAS活性在质膜上受到调节，但在高尔基体不受调节。然而，在表皮生长因子刺激下，高尔基体的RAS活性表现出与质膜相似的脉冲状分布，但在初始刺激后仍保持较高水平。一个包括酰化循环和质膜H-RAS调节的隔室模型解释了高尔基体H-RAS活性的脉冲式分布，但暗示高尔基体持续的H-RAS活性需要在另一个隔室激活H-RAS，我们实验确定这个隔室是内质网。因此，除了维持RAS的局部化外，酰化循环还支持一种以前未知的信号传播形式，类似于无线电传输，它产生构成RAS的“载波”，在亚细胞间传输RAS活性。
Growth factor stimulation generates transient H-Ras activity at the plasma membrane but sustained activity at the Golgi. Two overlapping regulatory networks control compartmentalized H-Ras activity: the guanosine diphosphate-guanosine triphosphate cycle and the acylation cycle, which constitutively traffics Ras isoforms that can be palmitoylated between intracellular membrane compartments. Quantitative imaging of H-Ras activity after decoupling of these networks revealed regulation of H-Ras activity at the plasma membrane but not at the Golgi. Nevertheless, upon stimulation with epidermal growth factor, Ras activity at the Golgi displayed a pulse-like profile similar to that at the plasma membrane but also remained high after the initial stimulus. A compartmental model that included the acylation cycle and H-Ras regulation at the plasma membrane accounted for the pulse-like profile of H-Ras activity at the Golgi but implied that sustained H-Ras activity at the Golgi required H-Ras activation at an additional compartment, which we experimentally determined to be the endoplasmic reticulum. Thus, in addition to maintaining the localization of Ras, the acylation cycle underlies a previously unknown form of signal propagation similar to radio transmission in its generation of a constitutive Ras "carrier wave" that transmits Ras activity between subcellular compartments.