Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China.
School of Life Sciences, Tsinghua University, Beijing 100084, China.
Proc Natl Acad Sci U S A. 2020 Jun 23;117(25):14270-14279. doi: 10.1073/pnas.2003019117. Epub 2020 Jun 8.
Directional cell migration involves signaling cascades that stimulate actin assembly at the leading edge, and additional pathways must inhibit actin polymerization at the rear. During neuroblast migration in , the transmembrane protein MIG-13/Lrp12 acts through the Arp2/3 nucleation-promoting factors WAVE and WASP to guide the anterior migration. Here we show that a tyrosine kinase, SRC-1, directly phosphorylates MIG-13 and promotes its activity on actin assembly at the leading edge. In GFP knockin animals, SRC-1 and MIG-13 distribute along the entire plasma membrane of migrating cells. We reveal that a receptor-like tyrosine phosphatase, PTP-3, maintains the F-actin polarity during neuroblast migration. Recombinant PTP-3 dephosphorylates SRC-1-dependent MIG-13 phosphorylation in vitro. Importantly, the endogenous PTP-3 accumulates at the rear of the migrating neuroblast, and its extracellular domain is essential for directional cell migration. We provide evidence that the asymmetrically localized tyrosine phosphatase PTP-3 spatially restricts MIG-13/Lrp12 receptor activity in migrating cells.
定向细胞迁移涉及信号级联反应，这些反应刺激前缘的肌动蛋白组装，而其他途径必须抑制后缘的肌动蛋白聚合。在 中神经母细胞迁移过程中，跨膜蛋白 MIG-13/Lrp12 通过 Arp2/3 成核促进因子 WAVE 和 WASP 发挥作用，指导前缘迁移。在这里，我们表明一种酪氨酸激酶 SRC-1 直接磷酸化 MIG-13 并促进其在前缘肌动蛋白组装中的活性。在 GFP 定点敲入动物中，SRC-1 和 MIG-13 沿迁移细胞的整个质膜分布。我们揭示了一种受体样酪氨酸磷酸酶 PTP-3 在神经母细胞迁移过程中维持 F-肌动蛋白的极性。重组 PTP-3 在体外使 SRC-1 依赖性 MIG-13 磷酸化去磷酸化。重要的是，内源性 PTP-3 在迁移神经母细胞的后部积累，其细胞外结构域对于定向细胞迁移是必不可少的。我们提供的证据表明，不对称定位的酪氨酸磷酸酶 PTP-3 在迁移细胞中空间限制了 MIG-13/Lrp12 受体的活性。
