近日,來自美國的華人科學家Weilan Ye在國際著名期刊nature在線發(fā)表了他們的最新研究進展,他們發(fā)現了影響內皮細胞遷移的一條新的信號通路,該發(fā)現對于調控腫瘤等疾病中病理性血管生成具有重要意義。
細胞遷移是一個循序漸進的過程,需要多種分子機制協(xié)同作用才能完成。研究人員利用siRNA和化學抑制劑進行了體外篩選,發(fā)現MAP4K4-moesin-talin-β1-integrin這條分子通路能夠有效促進內皮細胞遷移過程中的質膜縮回。MAP4K4缺失會降低細胞質膜的動態(tài)性,延緩內皮細胞遷移進程,同時損傷血管生成過程。在行進中的內皮細胞里,MAP4K4能夠在縮回的細胞質膜黏著斑去組裝位置對moesin進行磷酸化。
研究人員通過異位顯性分析發(fā)現moesin作為MAP4K4的下游蛋白,能夠通過與talin競爭性結合β1-integrin胞內結構域抑制integrin正常功能。因此,moesin缺失或MAP4K4缺失會降低內皮細胞黏著部位的去組裝速率。除此之外,阻斷α5β1-integrin能夠逆轉MAP4K4缺失導致的質膜縮回缺陷。
這項研究揭示了影響內皮細胞遷移的一條新的信號通路,同時表明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或許可成為一個潛在的藥物靶點。
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.
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