Local Myo9b RhoGAP activity regulates cell motility

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...

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Bibliographic Details
Published in:The Journal of biological chemistry 2021-01, Vol.296, p.100136-100136, Article 100136
Main Authors: Hemkemeyer, Sandra A., Vollmer, Veith, Schwarz, Vera, Lohmann, Birgit, Honnert, Ulrike, Taha, Muna, Schnittler, Hans-Joachim, Bähler, Martin
Format: Article
Language:English
Subjects:
actin
Actin Cytoskeleton - metabolism
cell migration
Cell Movement - physiology
Cells, Cultured
GTPase-Activating Proteins - genetics
GTPase-Activating Proteins - metabolism
HL-60 cells
Humans
lamellipodia
macrophages
Macrophages - cytology
Macrophages - metabolism
Myo9b
myosin
Myosins - genetics
Myosins - metabolism
Pseudopodia - metabolism
Rac1
RhoA
RhoGAP
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Summary: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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.RA120.013623