Protein Kinase C (cid:1) -Mediated Phosphorylation of Phospholipase D Controls Integrin-Mediated Cell Spreading (cid:1)
Protein Kinase C (cid:1) -Mediated Phosphorylation of Phospholipase D Controls Integrin-Mediated Cell Spreading (cid:1)
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整合素信号在细胞的黏附、扩散和迁移中起着关键作用，人们普遍认为，为了准确地调节这些整合素的功能，需要局部的肌动蛋白重塑。然而，控制肌动蛋白调节分子靶向适当位置的分子机制尚不清楚。我们先前已经证明，整合素介导的细胞在fi连接蛋白上的扩散和迁移依赖于磷脂酶D(Pld)的局部激活。然而，整合素激活PLD的机制在很大程度上还不清楚。在这里，我们证明了蛋白激酶C(Cid：1)(PKC(Cid：1))是整合素介导的PLD信号转导所必需的。整合素刺激后，PKC(CID：1)被激活并移位到片状脂膜的边缘，在那里它与PLD2共定位。PKC(Cid：1)活性的降低抑制了整合素诱导的PLD激活和细胞铺展。最后，我们发现PLD2的Thr566被PKC(Cid：1)直接磷酸化，该区域的PLD2突变阻止了PLD2的激活，阻止了PLD2易位到片状脂膜边缘，阻止了RAC易位，并阻止了整合素激活后的细胞扩散。综上所述，这些结果表明，PKC(Cid：1)是通过PLD的直接磷酸化来激活整合素介导的PLD的主要调节因子，而PLD直接磷酸化是引导整合素诱导的细胞扩散的关键。SignifiCance由学生确定
Integrin signaling plays critical roles in cell adhesion, spreading, and migration, and it is generally accepted that to regulate these integrin functions accurately, localized actin remodeling is required. However, the molecular mechanisms that control the targeting of actin regulation molecules to the proper sites are unknown. We previously demonstrated that integrin-mediated cell spreading and migration on fibronectin are dependent on the localized activation of phospholipase D (PLD). However, the mechanism underlying PLD activation by integrin is largely unknown. Here we demonstrate that protein kinase C (cid:1) (PKC (cid:1) ) is required for integrin-mediated PLD signaling. After integrin stimulation, PKC (cid:1) is activated and translocated to the edges of lamellipodia, where it colocalizes with PLD2. The abrogation of PKC (cid:1) activity inhibited integrin-induced PLD activation and cell spreading. Finally, we show that Thr566 of PLD2 is directly phosphorylated by PKC (cid:1) and that PLD2 mutation in this region prevents PLD2 activation, PLD2 translocation to the edge of lamellipodia, Rac translocation, and cell spreading after integrin activation. Together, these results suggest that PKC (cid:1) is a primary regulator of integrin-mediated PLD activation via the direct phosphorylation of PLD, which is essential for directing integrin-induced cell spreading. significance determined using Student