MICAL1 activation by PAK1 mediates actin filament disassembly

The MICAL1 monooxygenase is an important regulator of filamentous actin (F-actin) structures. Although MICAL1 has been shown to be regulated via protein-protein interactions at the autoinhibitory carboxyl terminus, a link between actin-regulatory RHO GTPase signaling pathways and MICAL1 has not been established. We show that the CDC42 GTPase effector PAK1 associates with and phosphorylates MICAL1 on two serine residues, leading to accelerated F-actin disassembly. PAK1 binds to the amino-terminal catalytic monooxygenase and calponin homology domains, distinct from the autoinhibitory carboxyl terminus. Extracellular ligand stimulation leads to PAK-dependent phosphorylation, linking external signals to MICAL1 phosphorylation. Mass spectrometry indicates that MICAL1 co-expression with CDC42 and PAK1 increases MICAL1 association with hundreds of proteins, including the previously described MICAL1-interacting proteins RAB10 and RAB7A. These results provide insights into a redox-mediated pathway linking extracellular signals to cytoskeleton regulation via a RHO GTPase and indicate a means of communication between RHO and RAB GTPases.