近日，來(lái)自美國(guó)的華人科學(xué)家Weilan Ye在國(guó)際著名期刊nature在線發(fā)表了他們的最新研究進(jìn)展，他們發(fā)現(xiàn)了影響內(nèi)皮細(xì)胞遷移的一條新的信號(hào)通路，該發(fā)現(xiàn)對(duì)于調(diào)控腫瘤等疾病中病理性血管生成具有重要意義。

    細(xì)胞遷移是一個(gè)循序漸進(jìn)的過(guò)程，需要多種分子機(jī)制協(xié)同作用才能完成。研究人員利用siRNA和化學(xué)抑制劑進(jìn)行了體外篩選，發(fā)現(xiàn)MAP4K4-moesin-talin-β1-integrin這條分子通路能夠有效促進(jìn)內(nèi)皮細(xì)胞遷移過(guò)程中的質(zhì)膜縮回。MAP4K4缺失會(huì)降低細(xì)胞質(zhì)膜的動(dòng)態(tài)性，延緩內(nèi)皮細(xì)胞遷移進(jìn)程，同時(shí)損傷血管生成過(guò)程。在行進(jìn)中的內(nèi)皮細(xì)胞里，MAP4K4能夠在縮回的細(xì)胞質(zhì)膜黏著斑去組裝位置對(duì)moesin進(jìn)行磷酸化。

    研究人員通過(guò)異位顯性分析發(fā)現(xiàn)moesin作為MAP4K4的下游蛋白，能夠通過(guò)與talin競(jìng)爭(zhēng)性結(jié)合β1-integrin胞內(nèi)結(jié)構(gòu)域抑制integrin正常功能。因此，moesin缺失或MAP4K4缺失會(huì)降低內(nèi)皮細(xì)胞黏著部位的去組裝速率。除此之外，阻斷α5β1-integrin能夠逆轉(zhuǎn)MAP4K4缺失導(dǎo)致的質(zhì)膜縮回缺陷。

    這項(xiàng)研究揭示了影響內(nèi)皮細(xì)胞遷移的一條新的信號(hào)通路，同時(shí)表明MAP4K4功能缺失可以抑制疾病模型中的病理性血管生成，提示人們MAP4K4或許可成為一個(gè)潛在的藥物靶點(diǎn)。

    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.