The Tyrosine Kinase Fer Is a Downstream Target of the PLD-PA Pathway that Regulates Cell Migration
The Tyrosine Kinase Fer Is a Downstream Target of the PLD-PA Pathway that Regulates Cell Migration
复制标题
DOI：
10.1126/scisignal.2000393
复制
发表时间：
2009-09-08
影响因子：
7.3
通讯作者：
Takenawa, Tadaomi
中科院分区：
文献类型：
--
作者：
Itoh, Toshiki;Hasegawa, Junya;Takenawa, Tadaomi
磷脂酸 (PA) 由磷脂酶 D (PLD) 产生，参与多种信号转导事件，例如细胞增殖、存活和迁移。然而，将 PA 与细胞迁移联系起来的分子机制在很大程度上尚不清楚。在这里，我们证明 PA 与酪氨酸激酶 Fer 结合并增强其磷酸化皮质蛋白（一种促进肌动蛋白聚合的蛋白质）的能力。我们发现 Fer 中与 F-BAR [Fes-Cdc42 相互作用蛋白 4 (CIP4) 同源性 (FCH) 和 bin-amphiphyn-Rvs] 域相邻的先前未知的脂质结合模块介导 PA 结合。我们将此脂质结合域称为 FX（F-BAR 扩展）域。 Fer 的过度表达以依赖于 PLD 活性和 PA-FX 相互作用的方式增强片状伪足的形成和细胞迁移。因此，PLD-PA 途径通过 Fer 诱导的肌动蛋白聚合增强来促进细胞迁移。
Phosphatidic acid (PA), which can be produced by phospholipase D (PLD), is involved in various signaling events, such as cell proliferation, survival, and migration. However, the molecular mechanisms that link PA to cell migration are largely unknown. Here, we show that PA binds to the tyrosine kinase Fer and enhances its ability to phosphorylate cortactin, a protein that promotes actin polymerization. We found that a previously unknown lipid-binding module in Fer adjacent to the F-BAR [Fes-Cdc42-interacting protein 4 (CIP4) homology (FCH) and bin-amphiphysin-Rvs] domain mediated PA binding. We refer to this lipid-binding domain as the FX (F-BAR extension) domain. Overexpression of Fer enhanced lamellipodia formation and cell migration in a manner dependent on PLD activity and the PA-FX interaction. Thus, the PLD-PA pathway promotes cell migration through Fer-induced enhancement of actin polymerization.