Local Myo9b RhoGAP activity regulates cell motility.
Local Myo9b RhoGAP activity regulates cell motility.
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DOI：
10.1074/jbc.ra120.013623
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Bähler M
中科院分区：
文献类型：
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作者：
Hemkemeyer SA;Vollmer V;Schwarz V;Lohmann B;Honnert U;Taha M;Schnittler HJ;Bähler M
为了迁移，细胞呈现极化形态，其前缘向前延伸，后缘朝向细胞体缩回。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GTP酶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的激活增强肌动蛋白-肌球蛋白II收缩性和细胞收缩。为了协调移徙，必须对这些进程进行认真监管。肌球蛋白Myo 9 b是一种Rho GTP酶激活蛋白（GAP），负调节Rho活性，白细胞中Myo 9 b的缺失通过增加Rho活性损害细胞迁移。然而，目前尚不清楚细胞运动性是否受Myo 9 b对Rho活性的全局或局部抑制的调节。在这里，我们通过使用表达不同重组Myo 9 b构建体的Myo 9 b缺陷型巨噬细胞样细胞来解决这个问题。我们发现，Myo 9 b积累在由Rac诱导的肌动蛋白聚合所产生的片状伪足延伸作为其电机活动的函数。HL-60衍生的巨噬细胞中Myo 9 b的缺失改变了细胞形态并损害了细胞迁移。重新引入Myo 9 b或Myo 9 b马达和GAP突变体揭示了局部GAP活性拯救细胞形态和迁移。总之，Rac激活导致肌动蛋白聚合和Myo 9 b的募集，其局部抑制Rho活性以增强定向细胞迁移。
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.