TY - JOUR PB - NATURE PUBLISHING GROUP N1 - This version is the author accepted manuscript. For information on re-use, please refer to the publisher?s terms and conditions. TI - RPEL-family rhoGAPs link Rac/Cdc42 GTP loading to G-actin availability SP - 845 EP - 855 N2 - 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. VL - 21 AV - public Y1 - 2019/07// ID - discovery10093058 JF - Nature Cell Biology SN - 1476-4679 UR - https://doi.org/10.1038/s41556-019-0337-y A1 - Diring, J A1 - Mouilleron, S A1 - McDonald, NQ A1 - Treisman, R ER -