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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Abl-interactor-1 (Abi1) has a role in cardiovascular and placental development and is a binding partner of the α4 integrin
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Abl-interactor-1 (Abi1) has a role in cardiovascular and placental development and is a binding partner of the α4 integrin

机译：Abl-interactor-1（Abi1）在心血管和胎盘发育中起作用，并且是α4整联蛋白的结合伴侣

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Dynamic signals linking the actin cytoskeleton and cell adhesion receptors are essential for morphogenesis during development and normal tissue homeostasis. Abi1 is a central regulator of actin polymerization through interactions with multiple protein complexes. However, the in vivo role of Abi1 remains to be defined. The α4 integrin adhesion receptor is associated with enhanced protrusive activity and regulation of directional cell migration. Among integrin subunits, α4 exhibits unique properties in that it predominantly accumulates at the leading edge of migrating cells; however, the pathways that link the actin-regulatory machinery to α4 at the leading edge have remained elusive. We generated Abi1 KO mice and found that loss of Abi1 phenocopies KO of α4. Mice lacking Abi1 or a4 exhibit midgestational lethality with abnormalities in placental and cardiovascular development. Notably, purified Abi1 protein binds directly to the α4 cytoplasmic tail and endogenous Abi1 colocalizes with phosphorylated α4 at the leading edge of spreading cells. Moreover, Abi1-deficient cells expressing α4 have impaired cell spreading, which is rescued by WT Abi1 but not an Abi1 mutant lacking the α4-binding site. These data reveal a direct link between the α4 integrin and actin polymerization and uncover a role for Abi1 in the regulation of morphogenesis in vivo. The Abi1-α4 interaction establishes a mechanistic paradigm for signaling between adhesion events and enhanced actin polymerization at the earliest stages of protrusion.
机译：连接肌动蛋白细胞骨架和细胞粘附受体的动态信号对于发育和正常组织稳态过程中的形态发生至关重要。 Abi1是通过与多种蛋白质复合物相互作用而产生的肌动蛋白聚合反应的主要调节剂。但是，Abi1的体内作用仍有待确定。 α4整联蛋白粘附受体与增强的突出活性和定向细胞迁移的调节有关。在整联蛋白亚基中，α4表现出独特的特性，因为它主要聚集在迁移细胞的前缘。然而，在前缘将肌动蛋白调节机制与α4连接的途径仍然难以捉摸。我们生成了Abi1 KO小鼠，发现α4的Abi1表型KO缺失。缺乏Abi1或a4的小鼠表现出妊娠致命性，胎盘和心血管发育异常。值得注意的是，纯化的Abi1蛋白直接与α4细胞质尾巴结合，内源性Abi1与磷酸化的α4在铺展细胞的前沿共定位。此外，表达α4的Abi1缺陷细胞的细胞扩散受损，可通过WT Abi1挽救，但缺少缺乏α4结合位点的Abi1突变体则不能。这些数据揭示了α4整联蛋白与肌动蛋白聚合之间的直接联系，并揭示了Abi1在体内形态发生的调节中的作用。 Abi1-α4相互作用建立了一种机制范式，用于在伸出的最早阶段在粘附事件和增强的肌动蛋白聚合反应之间发出信号。

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