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首页> 外文期刊>Cellular Signalling >The rapid activation of N-Ras by alpha-thrombin in fibroblasts is mediated by the specific G-protein G alpha(i2)-G beta(1)-G gamma(5) and occurs in lipid rafts
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The rapid activation of N-Ras by alpha-thrombin in fibroblasts is mediated by the specific G-protein G alpha(i2)-G beta(1)-G gamma(5) and occurs in lipid rafts

机译：N-Ras在成纤维细胞中被α-凝血酶快速激活是由特定的G蛋白G alpha（i2）-G beta（1）-G gamma（5）介导的，并发生在脂质筏中

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摘要

alpha-thrombin is a potent mitogen for fibroblasts and initiates a rapid signal transduction pathway leading to the activation of Ras and the stimulation of cell cycle progression. While the signaling events downstream of Ras have been studied in significant detail and appear well conserved across many species and cell types, the precise molecular events beginning with thrombin receptor activation and leading to the activation of Ras are not as well understood. In this study, we examined the immediate events in the rapid response to alpha-thrombin, in a single cell type, and found that an unexpected degree of specificity exists in the pathway linking alpha-thrombin to Ras activation. Specifically, although IIC9 cells express all three Ras isoforms, only N-Ras is rapidly activated by alpha-thrombin. Further, although several G alpha subunits associate with PAR1 and are released following stimulation, only G alpha(i2) couples to the rapid activation of Ras. Similarly, although IIC9 cells express many G beta and G gamma subunits, only a subset associates with G alpha(i2), and of those, only a single G beta gamma dinner, G beta(1)gamma(5), participates in the rapid activation of N-Ras. We then hypothesized that co-localization into membrane microdomains called lipid rafts, or caveolae, is at least partially responsible for this degree of specificity. Accordingly, we found that all components localize to lipid rafts and that disruption of caveolae abolishes the rapid activation of N-Ras by alpha-thrombin. We thus report the molecular elucidation of an extremely specific and rapid signal transduction pathway linking alpha-thrombin stimulation to the activation of Ras.
机译：α-凝血酶是成纤维细胞的有效促分裂原，它启动了快速的信号转导途径，导致Ras的激活和细胞周期进程的刺激。尽管已经对Ras下游的信号转导事件进行了详尽的研究，并且在许多物种和细胞类型中似乎都非常保守，但人们对由凝血酶受体激活开始并导致Ras激活的精确分子事件仍未完全了解。在这项研究中，我们检查了单个细胞类型中对α-凝血酶快速反应的近期事件，发现在将α-凝血酶与Ras激活连接的途径中存在出乎意料的特异性程度。具体而言，尽管IIC9细胞表达所有三种Ras亚型，但只有N-Ras被α-凝血酶快速激活。此外，尽管几个G alpha亚基与PAR1结合并在刺激后释放，但只有G alpha（i2）与Ras的快速激活偶联。同样，尽管IIC9细胞表达许多G beta和Gγ亚基，但只有一个子集与G alpha（i2）关联，其中只有一个G betaγ晚餐G beta（1）gamma（5）参与快速激活N-Ras。然后，我们假设共定位到称为脂质筏或小窝的膜微区中至少部分负责这种程度的特异性。因此，我们发现所有组分都定位于脂质筏，并且破坏小窝消除了α-凝血酶对N-Ras的快速活化。因此，我们报告了将α-凝血酶刺激与Ras激活相联系的极其特异和快速的信号转导途径的分子阐明。

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