Glia maturation factor-γ is preferentially expressed in microvascular endothelial and inflammatory cells and modulates actin cytoskeleton reorganization
Glia maturation factor-γ is preferentially expressed in microvascular endothelial and inflammatory cells and modulates actin cytoskeleton reorganization
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DOI：
10.1161/01.res.0000237662.23539.0b
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发表时间：
2006-08-18
影响因子：
20.1
通讯作者：
Quertermous, Thomas
中科院分区：
文献类型：
--
作者：
Ikeda, Koji;Kundu, Ramendra K.;Quertermous, Thomas
肌动蛋白细胞骨架的重组是一个基本的过程肌动蛋白为基础的细胞功能，如胞质分裂，吞噬和趋化。因此，调节肌动蛋白细胞骨架重组是控制内皮细胞和炎症细胞功能以及治疗心血管疾病的有吸引力的方法。在这里，我们确定神经胶质成熟因子-γ（GMFG）作为一种新的因素，在肌动蛋白细胞骨架重组，并优先表达在微血管内皮细胞和炎症细胞。在小鼠胚胎发育过程中，GMFG主要表达于卵黄囊的血岛，在那里内皮细胞和造血细胞同时发育。在内皮细胞中，GMFG与F-肌动蛋白共定位于膜皱褶中，并通过肌动蛋白共沉降分析与F-肌动蛋白相关。有趣的是，GMFG在N-末端丝氨酸磷酸化，其磷酸化增强显性活性Rac 1和Cdc 42的共表达。此外，假磷酸化形式的GMFG（GMFG-S2 E）表现出更高的关联与F-肌动蛋白。稳定表达GMFG-S2 E显著增强HeLa细胞中刺激响应性板状伪足和随后的膜皱褶形成，推测是通过其与Arp 2/3复合物的相互作用。GMFG的表达增强肌动蛋白为基础的细胞功能，如迁移和管形成的内皮细胞。此外，我们发现，GMFG的表达显着增加，在心脏缺血/再灌注模型中，炎症和血管生成发生积极。总之，我们的研究结果定义了一个新的途径，在肌动蛋白为基础的细胞功能的调节。调节GMFG功能可能为调节心血管疾病的病理生理提供新的途径。
Actin cytoskeleton reorganization is a fundamental process for actin-based cellular functions such as cytokinesis, phagocytosis, and chemotaxis. Regulating actin cytoskeleton reorganization is therefore an attractive approach to control endothelial and inflammatory cells function and to treat cardiovascular diseases. Here, we identified glia maturation factor-gamma (GMFG) as a novel factor in actin cytoskeleton reorganization and is expressed preferentially in microvascular endothelial and inflammatory cells. During mouse embryogenesis, GMFG was expressed predominantly in blood islands of the yolk sac, where endothelial and hematopoietic cells develop simultaneously. In endothelial cells, GMFG was colocalized with F-actin in membrane ruffles and was associated with F-actin assessed by actin co-sedimentation assay. Interestingly, GMFG was phosphorylated at N-terminal serine, and its phosphorylation was enhanced by coexpression of dominant active Rac1 and Cdc42. Furthermore, a pseudophosphorylated form of GMFG (GMFG-S2E) demonstrated higher association with F-actin. Stable expression of GMFG-S2E remarkably enhanced stimulus-responsive lamellipodia and subsequent membrane ruffle formation in HeLa cells presumably through its interaction with Arp2/3 complex. Expression of GMFG enhanced actin-based cellular functions such as migration and tube-formation in endothelial cells. Moreover, we found that GMFG expression was significantly increased in a cardiac ischemia/reperfusion model where inflammation and angiogenesis take place actively. Taken together, our findings define a novel pathway in the regulation of actin-based cellular functions. Regulating GMFG function may provide a novel approach to modulate the pathophysiology of cardiovascular diseases.