期刊
NATURE CELL BIOLOGY
卷 21, 期 7, 页码 845-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41556-019-0337-y
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资金
- Crick Science Technology Platforms
- Cancer Research UK
- Francis Crick Institute
- UK Medical Research Council [FC001-190, FC001-115]
- Wellcome Trust [FC001-190, FC001115]
- ERC Advanced Grant [268690]
- Cancer Research UK [FC001-190, FC001-115]
- European Research Council (ERC) [268690] Funding Source: European Research Council (ERC)
RPEL proteins, which contain the G-actin-binding RPEL motif, coordinate cytoskeletal processes with actin dynamics. We show that the ArhGAP12- and ArhGAP32-family GTPase-activating proteins (GAPs) are RPEL proteins. We determine the structure of the ArhGAP12/G-actin complex, and show that G-actin contacts the RPEL motif and GAP domain sequences. G-actin inhibits ArhGAP12 GAP activity, and this requires the G-actin contacts identified in the structure. In B16 melanoma cells, ArhGAP12 suppresses basal Rac and Cdc42 activity, F-actin assembly, invadopodia formation and experimental metastasis. In this setting, ArhGAP12 mutants defective for G-actin binding exhibit more effective downregulation of Rac GTP loading following HGF stimulation and enhanced inhibition of Rac-dependent processes, including invadopodia formation. Potentiation or disruption of the G-actin/ArhGAP12 interaction, by treatment with the actin-binding drugs latrunculin B or cytochalasin D, has corresponding effects on Rac GTP loading. The interaction of G-actin with RPEL-family rhoGAPs thus provides a negative feedback loop that couples Rac activity to actin dynamics.
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