ArhGAP9, a novel MAP kinase docking protein, inhibits Erk and p38 activation through WW domain binding.

We have identified human ArhGAP9 as a novel MAP kinase docking protein that interacts with Erk2 and p38alpha through complementarily charged residues in the WW domain of ArhGAP9 and the CD domains of Erk2 and p38alpha. This interaction sequesters the MAP kinases in their inactive states through displacement of MAP kinase kinases targeting the same sites. While over-expression of wild type ArhGAP9 caused MAP kinase activation by the epidermal growth factor receptor (EGFR) to be suppressed and preserved the actin stress fibres in quiescent Swiss 3T3 fibroblasts, over-expression of an ArhGAP9 mutant defective in MAP kinase binding restored EGFR-induced MAP kinase activation and resulted in significant disruption of the stress fibres, consistent with the role of Erk activation in disassembly of actin stress fibres. The interaction between ArhGAP9 and the MAP kinases represents a novel mechanism of cross-talk between Rho GTPase and MAP kinase signaling.