RPEL family rhoGAPs link Rac/Cdc42 GTP loading to G-actin availability

Diring, J. and Mouilleron, S. and McDonald, Neil Q. and Treisman, R. (2019) RPEL family rhoGAPs link Rac/Cdc42 GTP loading to G-actin availability. Nature Cell Biology 21 , pp. 845-855. ISSN 1465-7392.

Abstract

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 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 melanoma cells, ArhGAP12 suppresses basal Rac and Cdc42 activity, F-actin assembly, invadopodia formation, and experimental metastasis. In B16 melanoma cells, ArhGAP12 mutants defective for G-actin binding exhibit more effective downregulation of Rac.GTP loading following HGF stimulation, and enhanced Rac-dependent processes, including invadopodia formation. Potentiation or disruption of G-actin/ArhGAP12 interaction, by treatment with the actin-binding drugs latrunculin B or cytochalasin D, has corresponding effects on Rac.GTP loading. G-actin interaction with RPEL family rhoGAPs thus provides a negative feedback loop that couples Rac activity to actin dynamics

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