To migrate, cells assume a polarized morphology, extending forward with a leading edge with their trailing edge retracting back toward the cell body. Both cell extension and retraction critically depend on the organization and dynamics of the actin cytoskeleton, and the small, monomeric GTPases Rac and Rho are important regulators of actin. Activation of Rac induces actin polymerization and cell extension whereas activation of Rho enhances acto-myosin II contractility and cell retraction. To coordinate migration, these processes must be carefully regulated. The myosin Myo9b, a Rho GTPase activating protein (GAP), negatively regulates Rho activity and deletion of Myo9b in leukocytes impairs cell migration through increased Rho activity. However, it is not known whether cell motility is regulated by global or local inhibition of Rho activity by Myo9b. Here, we addressed this question by using Myo9b-deficient macrophage-like cells that expressed different recombinant Myo9b constructs. We found that Myo9b accumulates in lamellipodial extensions generated by Rac-induced actin polymerization as a function of its motor activity. Deletion of Myo9b in HL-60 derived macrophages altered cell morphology and impaired cell migration. Reintroduction of Myo9b or Myo9b motor and GAP mutants revealed that local GAP activity rescues cell morphology and migration. In summary, Rac activation leads to actin polymerization and recruitment of Myo9b, which locally inhibits Rho activity to enhance directional cell migration. In summary, Rac activation leads to actin polymerization and recruitment of Myo9b, which locally inhibits Rho activity to enhance directional cell migration.

中文翻译：

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局部 Myo9b RhoGAP 活性调节细胞运动

为了迁移，细胞呈现极化形态，前缘向前延伸，后缘向后缩回细胞体。细胞的伸展和收缩都严重依赖于肌动蛋白细胞骨架的组织和动力学，而小的单体 GTPases Rac 和 Rho 是肌动蛋白的重要调节因子。Rac 的激活诱导肌动蛋白聚合和细胞延伸，而 Rho 的激活则增强肌动球蛋白 II 的收缩性和细胞收缩。为了协调移民，必须仔细监管这些过程。肌球蛋白 Myo9b 是一种 Rho GTP 酶激活蛋白 (GAP)，可负向调节 Rho 活性，白细胞中 Myo9b 的缺失会通过增加 Rho 活性来损害细胞迁移。然而，目前尚不清楚细胞运动是否受到 Myo9b 对 Rho 活性的整体或局部抑制的调节。在这里，我们通过使用表达不同重组 Myo9b 构建体的 Myo9b 缺陷型巨噬细胞样细胞解决了这个问题。我们发现 Myo9b 在 Rac 诱导的肌动蛋白聚合产生的片状足延伸中积累，作为其运动活动的函数。HL-60 衍生巨噬细胞中 Myo9b 的缺失改变了细胞形态并损害了细胞迁移。重新引入 Myo9b 或 Myo9b 运动和 GAP 突变体表明，局部 GAP 活性可挽救细胞形态和迁移。总之，Rac 激活导致肌动蛋白聚合和 Myo9b 的募集，从而局部抑制 Rho 活性以增强定向细胞迁移。总之，Rac 激活导致肌动蛋白聚合和 Myo9b 的募集，