Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA.
Faculty of Physics, Astronomy, and Applied Computer Science, Institute of Physics, Jagiellonian University, Krakow, Poland.
FASEB J. 2019 Jan;33(1):631-642. doi: 10.1096/fj.201800296R. Epub 2018 Jul 24.
Phosphatidylinositol 4-phosphate 5-kinase type I γ (PIPKIγ90) regulates cell migration, invasion, and metastasis. However, it is unknown how cellular signals regulate those processes. Here, we show that cyclin-dependent kinase 5 (Cdk5), a protein kinase that regulates cell migration and invasion, phosphorylates PIPKIγ90 at S453, and that Cdk5-mediated PIPKIγ90 phosphorylation is essential for cell invasion. Moreover, Cdk5-mediated phosphorylation down-regulates the activity of PIPKIγ90 and the secretion of fibronectin, an extracellular matrix protein that regulates cell migration and invasion. Furthermore, inhibition of PIPKIγ activity with the chemical inhibitor UNC3230 suppresses fibronectin secretion in a dose-dependent manner, whereas depletion of Cdk5 enhances fibronectin secretion. With total internal reflection fluorescence microscopy, we found that secreted fibronectin appears as round dots, which colocalize with Tks5 and CD9 but not with Zyxin. These data suggest that Cdk5-mediated PIPKIγ90 phosphorylation regulates cell invasion by controlling PIPKIγ90 activity and fibronectin secretion.-Li, L., Kołodziej, T., Jafari, N., Chen, J., Zhu, H., Rajfur, Z., Huang, C. Cdk5-mediated phosphorylation regulates phosphatidylinositol 4-phosphate 5-kinase type I γ 90 activity and cell invasion.
磷脂酰肌醇 4,5-二磷酸激酶 I 型 γ（PIPKIγ90）调节细胞迁移、侵袭和转移。然而，细胞信号如何调节这些过程尚不清楚。在这里，我们表明细胞周期蛋白依赖性激酶 5（Cdk5），一种调节细胞迁移和侵袭的蛋白激酶，磷酸化 PIPKIγ90 的 S453 残基，并且 Cdk5 介导的 PIPKIγ90 磷酸化对于细胞侵袭是必不可少的。此外，Cdk5 介导的磷酸化下调 PIPKIγ90 的活性和细胞外基质蛋白纤维连接蛋白的分泌，纤维连接蛋白调节细胞迁移和侵袭。此外，用化学抑制剂 UNC3230 抑制 PIPKIγ 活性以剂量依赖性方式抑制纤维连接蛋白分泌，而 Cdk5 的耗竭增强纤维连接蛋白分泌。通过全内反射荧光显微镜，我们发现分泌的纤维连接蛋白呈圆形斑点，与 Tks5 和 CD9 共定位，但与 Zyxin 不共定位。这些数据表明 Cdk5 介导的 PIPKIγ90 磷酸化通过控制 PIPKIγ90 活性和纤维连接蛋白分泌来调节细胞侵袭。
