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Nature:MAP4K4对血管生成的调控

摘要 : 细胞迁移在胚胎发生、炎症和血管生成等重要生物过程中至关重要,但细胞运动机制的很多方面仍有待在分子层面上确定。在这项研究中,Weilan Ye及同事识别出调控内皮细胞运动的一个以前不知道的通道。

 细胞迁移在胚胎发生、炎症和血管生成等重要生物过程中至关重要,但细胞运动机制的很多方面仍有待在分子层面上确定。在这项研究中,Weilan Ye及同事识别出调控内皮细胞运动的一个以前不知道的通道。

利用化学和RNA筛选,他们发现,MAP4K4的一种选择性抑制剂在血管发生期间能改变内皮细胞的萌芽形态。该抑制剂造成内皮细胞积累长而细的亚细胞突出结构,说明未能将这些突出结构缩回。作者显示,MAP4K4会将膜突蛋白磷酸化,后者通过使β1-integrin失活来调控粘着斑(focal adhesions)的分解;他们还发现,这一 “MAP4K4-膜突蛋白-β1-integrin”通道在正常的和病理性的血管生成中都起一定作用。

原文链接:MAP4K4 regulates integrin-FERM binding to control endothelial cell motility

Cell migration is a stepwise process that coordinates multiple molecular machineries. Using in vitroangiogenesis screens with short interfering RNA and chemical inhibitors, we define here a MAP4K4–moesin–talin–β1-integrin molecular pathway that promotes efficient plasma membrane retraction during endothelial cell migration. Loss of MAP4K4 decreased membrane dynamics, slowed endothelial cell migration, and impaired angiogenesis in vitro and in vivo. In migrating endothelial cells, MAP4K4 phosphorylates moesin in retracting membranes at sites of focal adhesion disassembly. Epistasis analyses indicated that moesin functions downstream of MAP4K4 to inactivate integrin by competing with talin for binding to β1-integrin intracellular domain. Consequently, loss of moesin (encoded by the MSN gene) or MAP4K4 reduced adhesion disassembly rate in endothelial cells. Additionally, α5β1-integrin blockade reversed the membrane retraction defects associated with loss of Map4k4 in vitro and in vivo. Our study uncovers a novel aspect of endothelial cell migration. Finally, loss of MAP4K4 function suppressed pathological angiogenesis in disease models, identifying MAP4K4 as a potential therapeutic target.

对应Nature杂志: 2015年03月26日Nature杂志精选

来源: Nature 浏览次数:11

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