近日，来自美国的华人科学家Weilan Ye在国际著名期刊nature在线发表了他们的最新研究进展，他们发现了影响内皮细胞迁移的一条新的信号通路，该发现对于调控肿瘤等疾病中病理性血管生成具有重要意义。

    细胞迁移是一个循序渐进的过程，需要多种分子机制协同作用才能完成。研究人员利用siRNA和化学抑制剂进行了体外筛选，发现MAP4K4-moesin-talin-β1-integrin这条分子通路能够有效促进内皮细胞迁移过程中的质膜缩回。MAP4K4缺失会降低细胞质膜的动态性，延缓内皮细胞迁移进程，同时损伤血管生成过程。在行进中的内皮细胞里，MAP4K4能够在缩回的细胞质膜黏着斑去组装位置对moesin进行磷酸化。

    研究人员通过异位显性分析发现moesin作为MAP4K4的下游蛋白，能够通过与talin竞争性结合β1-integrin胞内结构域抑制integrin正常功能。因此，moesin缺失或MAP4K4缺失会降低内皮细胞黏着部位的去组装速率。除此之外，阻断α5β1-integrin能够逆转MAP4K4缺失导致的质膜缩回缺陷。

    这项研究揭示了影响内皮细胞迁移的一条新的信号通路，同时表明MAP4K4功能缺失可以抑制疾病模型中的病理性血管生成，提示人们MAP4K4或许可成为一个潜在的药物靶点。

    doi:10.1038/nature14323

    MAP4K4 regulates integrin-FERM binding to control endothelial cell motilityPhilip Vitorino,Stacey Yeung,Ailey Crow,Jesse Bakke,Tanya Smyczek,Kristina West, Erin McNamara,Jeffrey Eastham-Anderson,Stephen Gould,Seth F.Harris,Chudi Ndubaku& Weilan YeCell 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 **yses 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.