Secretion of soluble vascular endothelial growth factor receptor 1 (sVEGFR1/sFlt1) requires Arf1, Arf6, and Rab11 GTPases.
Secretion of soluble vascular endothelial growth factor receptor 1 (sVEGFR1/sFlt1) requires Arf1, Arf6, and Rab11 GTPases.
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DOI：
10.1371/journal.pone.0044572
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Choudhury A
中科院分区：
文献类型：
--
作者：
Jung JJ;Tiwari A;Inamdar SM;Thomas CP;Goel A;Choudhury A
可溶形式的血管内皮生长因子受体 1 (sVEGFR-1/sFlt1) 是通过 FLT1 基因的选择性剪接产生的。内皮细胞分泌的 sFlt1 在血管萌芽和形态发生中起着重要作用。然而，sFlt1 分泌过多与先兆子痫和慢性肾病等疾病有关。迄今为止，人们对 sFlt1 分泌所涉及的分泌运输过程知之甚少。在本研究中，我们研究了 sFlt1 沿分泌途径运输的行程。为了了解 sFlt1 分泌的时间进程，用 [35S]-蛋氨酸和半胱氨酸对稳定表达 sFlt1 的内皮细胞进行代谢放射性标记。我们的结果表明，初始合成后，细胞外培养基中分泌的 [35S]-sFlt1 水平在 8 小时达到峰值。布雷菲德菌素 A (BFA) 是一种阻断内质网 (ER) 和高尔基复合体之间运输的药物，可抑制 sFlt1 的细胞外释放，表明 ER 至高尔基体以及高尔基体内 sFlt1 的运输对其分泌至关重要。此外，我们还发现，Arf1、Arf6 和 Rab11 的显性失活突变体形式的异位表达以及 siRNA 介导的这些 GTPases 的敲低会在常氧和缺氧条件下阻断 sFlt1 的分泌，表明这些小 GTPase 的作用。这项工作首次报道了参与 sFlt1 沿分泌途径运输的调节蛋白的作用，并可能为生理和病理条件下 sFlt-1 释放的调节提供见解和新的分子靶点。
The soluble form of vascular endothelial growth factor receptor 1 (sVEGFR-1/sFlt1) is generated by alternative splicing of the FLT1 gene. Secretion of sFlt1 from endothelial cells plays an important role in blood vessel sprouting and morphogenesis. However, excess sFlt1 secretion is associated with diseases such as preeclampsia and chronic kidney disease. To date, the secretory transport process involved in the secretion of sFlt1 is poorly understood. In the present study, we investigated the itinerary of sFlt1 trafficking along the secretory pathway. To understand the timecourse of sFlt1 secretion, endothelial cells stably expressing sFlt1 were metabolically radiolabeled with [35S]-methionine and cysteine. Our results indicate that after initial synthesis the levels of secreted [35S]-sFlt1 in the extracellular medium peaks at 8 hours. Treatment with brefeldin A (BFA), a drug which blocks trafficking between the endoplasmic reticulum (ER) and the Golgi complex, inhibited extracellular release of sFlt1 suggesting that ER to Golgi and intra-Golgi trafficking of sFlt1 are essential for its secretion. Furthermore, we show that ectopic expression of dominant-negative mutant forms of Arf1, Arf6, and Rab11 as well as siRNA-mediated knockdown of these GTPases block secretion of sFlt1 during normoxic and hypoxic conditions suggesting role for these small GTPases. This work is the first to report role of regulatory proteins involved in sFlt1 trafficking along the secretory pathway and may provide insights and new molecular targets for the modulation of sFlt-1 release during physiological and pathological conditions.
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DOI：
10.1083/jcb.200709114
发表时间：
2008-06-02
期刊：
The Journal of cell biology
影响因子：
--
作者：
Kappas NC;Zeng G;Chappell JC;Kearney JB;Hazarika S;Kallianos KG;Patterson C;Annex BH;Bautch VL
通讯作者：
Bautch VL
影响因子：
7.5
作者：
Chavrier, P;Goud, B
通讯作者：
Goud, B
Rab8 GTPase 选择性调节极化 Madin-Darby 犬肾细胞中 AP-1B 依赖性基底外侧转运。
影响因子：
7.8
作者：
Ang, AL;Fölsch, H;Koivisto, UM;Pypaert, M;Mellman, I
通讯作者：
Mellman, I
影响因子：
64.5
作者：
BALCH, WE;MCCAFFERY, JM;FARQUHAR, MG
通讯作者：
FARQUHAR, MG
影响因子：
2.4
作者：
Charnock-Jones, DS
通讯作者：
Charnock-Jones, DS