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首页> 外文期刊>Molecular biology of the cell >Integrin-mediated Protein Kinase A Activation at the Leading Edge of Migrating Cells
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Integrin-mediated Protein Kinase A Activation at the Leading Edge of Migrating Cells

机译：整合素介导的蛋白激酶A在迁移细胞的前沿激活。

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cAMP-dependent protein kinase A (PKA) is important in processes requiring localized cell protrusion, such as cell migration and axonal path finding. Here, we used a membrane-targeted PKA biosensor to reveal activation of PKA at the leading edge of migrating cells. Previous studies show that PKA activity promotes protrusion and efficient cell migration. In live migrating cells, membrane-associated PKA activity was highest at the leading edge and required ligation of integrins such as α4β1 or α5β1 and an intact actin cytoskeleton. α4 integrins are type I PKA-specific A-kinase anchoring proteins, and we now find that type I PKA is important for localization of α4β1 integrin-mediated PKA activation at the leading edge. Accumulation of 3′ phosphorylated phosphoinositides [PtdIns(3,4,5)P3] products of phosphatidylinositol 3-kinase (PI3-kinase) is an early event in establishing the directionality of migration; however, polarized PKA activation did not require PI3-kinase activity. Conversely, inhibition of PKA blocked accumulation of a PtdIns(3,4,5)P3-binding protein, the AKT-pleckstrin homology (PH) domain, at the leading edge; hence, PKA is involved in maintaining cell polarity during migration. In sum, we have visualized compartment-specific PKA activation in migrating cells and used it to reveal that adhesion-mediated localized activation of PKA is an early step in directional cell migration.
机译：cAMP依赖性蛋白激酶A（PKA）在需要局部细胞突出的过程中很重要，例如细胞迁移和轴突路径查找。在这里，我们使用膜靶向的PKA生物传感器来揭示PKA在迁移细胞前沿的激活。先前的研究表明，PKA活性可促进突起和有效的细胞迁移。在活的迁移细胞中，与膜相关的PKA活性在前缘最高，需要连接整联蛋白（例如α4β1或α5β1）和完整的肌动蛋白细胞骨架。 α4整联蛋白是I型PKA特异的A激酶锚定蛋白，我们现在发现I型PKA对于将α4β1整联蛋白介导的PKA激活定位在前沿非常重要。磷脂酰肌醇3-激酶（PI3-激酶）的3'磷酸化磷酸肌醇[PtdIns（3,4,5）P 3 ]产物的积累是确定迁移方向的早期事件。然而，极化的PKA激活不需要PI3激酶活性。相反，抑制PKA会在前端阻止PtdIns（3,4,5）P 3 结合蛋白AKT-pleckstrin同源性（PH）域的积累。因此，PKA在迁移过程中参与维持细胞极性。总而言之，我们已经可视化了迁移细胞中的隔室特异性PKA激活，并用它来揭示粘附介导的PKA局部激活是定向细胞迁移的早期步骤。

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