Quantitative model of Ras-phosphoinositide 3-kinase signalling cross-talk based on co-operative molecular assembly
Quantitative model of Ras-phosphoinositide 3-kinase signalling cross-talk based on co-operative molecular assembly
复制标题
DOI：
10.1042/bj20051022
复制
发表时间：
2006-01-01
影响因子：
4.1
通讯作者：
Haugh, JM
中科院分区：
文献类型：
--
作者：
Kaur, H;Park, CS;Haugh, JM
在生长因子刺激的信号传导中，细胞表面受体将PI 3 K（磷酸肌醇3-激酶）和Ras特异性GEF（鸟嘌呤核苷酸交换因子）募集到质膜，在那里它们分别产生3 '-磷酸化磷酸肌醇脂质和Ras-GTP。作为通路网络的直接例子，Ras-GTP还招募并激活PI 3 K。为了完善Ras-PI 3 K串扰的机制并分析其定量意义，我们提供了一个理论模型，描述了涉及受体，PI 3 K和RasGTP的复合物的组装。虽然该模型提出了在两个步骤中形成三元受体-PI 3 K-Ras复合物的可能性，但它也包括受体-PI 3 K和Ras-PI 3 K相互作用是竞争性的可能性。为了支持这一分析，血小板源性生长因子刺激的成纤维细胞的实验表明，Ras明显增强了PI 3 K对受体的亲和力;在该模型的背景下，这表明确实形成了三元复合物，第二步通过膜定位和可能的变构效应大大增强。Ras对PI 3 K活化的明显贡献强烈依赖于相互作用分子的数量和结合亲和力，其在不同的细胞类型和刺激物中变化，因此该模型可用于预测PI 3 K信号传导对靶向Ras的干预敏感的条件。
In growth-factor-stimulated signal transduction, cell-surface receptors recruit PI3Ks (phosphoinositide 3-kinases) and Ras-specific GEFs (guanine nucleotide-exchange factors) to the plasma membrane, where they produce 3'-phosphorylated phosphoinositide lipids and Ras-GTP respectively. As a direct example of pathway networking, Ras-GTP also recruits and activates PI3Ks. To refine the mechanism of Ras-PI3K cross-talk and analyse its quantitative implications, we offer a theoretical model describing the assembly of complexes involving receptors, PI3K and RasGTP. While the model poses the possibility that a ternary receptor-PI3K-Ras complex forms in two steps, it also encompasses the possibility that receptor-PI3K and Ras-PI3K interactions are competitive. In support of this analysis, experiments with platelet-derived growth factor-stimulated fibroblasts revealed that Ras apparently enhances the affinity of PI3K for receptors; in the context of the model, this suggests that a ternary complex does indeed form, with the second step greatly enhanced through membrane localization and possibly allosteric effects. The apparent contribution of Ras to PI3K activation depends strongly on the quantities and binding affinities of the interacting molecules, which vary across different cell types and stimuli, and thus the model could be used to predict conditions under which PI3K signalling is sensitive to interventions targeting Ras.