Delayed onset of positive feedback activation of Rab5 by Rabex-5 and Rabaptin-5 in endocytosis.
Delayed onset of positive feedback activation of Rab5 by Rabex-5 and Rabaptin-5 in endocytosis.
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胞吞作用中 Rabex-5 和 Rabaptin-5 对 Rab5 的正反馈激活延迟发生。
DOI：
10.1371/journal.pone.0009226
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发表时间：
2010-02-16
期刊：
影响因子：
3.7
通讯作者：
Li, Guangpu
中科院分区：
文献类型：
--
作者：
Zhu, Huaiping;Qian, Hong;Li, Guangpu
Rabex-5是特异性激活Rab 5的鸟嘌呤核苷酸交换因子（GEF），即，通过两种不同的途径将Rab 5-GDP转化为Rab 5-GTP，以促进内体融合和内吞作用。直接途径涉及通过早期内体靶向（EET）结构域靶向膜的膜相关Rabex-5库。另一方面，间接途径涉及Rabex-5/Rabaptin-5复合物的胞质池。该复合物通过Rabaptin-5与Rab 5-GTP的结合被募集到膜上，这表明了正反馈机制。这两种途径在细胞中Rab 5激活的关系尚不清楚。我们通过细胞中的数学建模和动力学分析来剖析每个途径对Rab 5激活的相对贡献。这些研究表明，间接途径构成了将Rab 5-GDP转化为内体膜上的Rab 5-GTP的正反馈环，并允许通过细胞中Rab 5和Rabex-5的水平灵敏地调节内体融合活性。然而，这种正反馈效应的开始包含一个阈值，该阈值需要细胞中Rab 5或Rabex-5的内源性水平以上。我们称这种新现象为“延迟反应”。直接途径的存在通过增加Rab 5-GTP的基础水平来减少延迟，从而促进Rabex-5/Rabaptin-5介导的正反馈环的功能。我们的数据支持这个数学模型。在模型的指导下，数据揭示了细胞中Rabex-5/Rabaptin-5/Rab 5-GTP相互作用的亲和力，其与间接正反馈途径开始的Rabex-5浓度定量相关。直接途径的存在和Rab 5浓度的增加可以降低正反馈回路开始所需的Rabex-5浓度。因此，直接和间接途径在早期内体融合的调节中合作。
Rabex-5 is a guanine nucleotide exchange factor (GEF) that specifically activates Rab5, i.e., converting Rab5-GDP to Rab5-GTP, through two distinct pathways to promote endosome fusion and endocytosis. The direct pathway involves a pool of membrane-associated Rabex-5 that targets to the membrane via an early endosomal targeting (EET) domain. The indirect pathway, on the other hand, involves a cytosolic pool of Rabex-5/Rabaptin-5 complex. The complex is recruited to the membrane via Rabaptin-5 binding to Rab5-GTP, suggesting a positive feedback mechanism. The relationship of these two pathways for Rab5 activation in the cell is unclear. We dissect the relative contribution of each pathway to Rab5 activation via mathematical modeling and kinetic analysis in the cell. These studies show that the indirect pathway constitutes a positive feedback loop for converting Rab5-GDP to Rab5-GTP on the endosomal membrane and allows sensitive regulation of endosome fusion activity by the levels of Rab5 and Rabex-5 in the cell. The onset of this positive feedback effect, however, contains a threshold, which requires above endogenous levels of Rab5 or Rabex-5 in the cell. We term this novel phenomenon “delayed response”. The presence of the direct pathway reduces the delay by increasing the basal level of Rab5-GTP, thus facilitates the function of the Rabex-5/Rabaptin-5-mediated positive feedback loop. Our data support the mathematical model. With the model's guidance, the data reveal the affinity of Rabex-5/Rabaptin-5/Rab5-GTP interaction in the cell, which is quantitatively related to the Rabex-5 concentration for the onset of the indirect positive feedback pathway. The presence of the direct pathway and increased Rab5 concentration can reduce the Rabex-5 concentration required for the onset of the positive feedback loop. Thus the direct and indirect pathways cooperate in the regulation of early endosome fusion.
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影响因子：
64.5
作者：
Horiuchi, H;Lippe, R;Zerial, M
通讯作者：
Zerial, M
影响因子：
4.1
作者：
Li, GP;Liang, ZM
通讯作者：
Liang, ZM
影响因子：
16.8
作者：
Zhu, GY;Zhai, P;Zhang, XJC
通讯作者：
Zhang, XJC
DOI：
10.2165/00129784-200505010-00002
发表时间：
2005-01-01
期刊：
American journal of cardiovascular drugs : drugs, devices, and other interventions
影响因子：
--
作者：
Hassler, Christopher;Burnier, Michel
通讯作者：
Burnier, Michel
影响因子：
3.3
作者：
Liu, Jay;Lamb, Darija;Li, Guangpu
通讯作者：
Li, Guangpu