PAK4 methylation at K473 by SETD6 attenuates cell adhesion and migration

P21-activated kinase 4 (PAK4), a member of serine/threonine kinases family is overexpressed in numerous cancer tumors and is associated with oncogenic cell proliferation, migration and invasion. Our recent work demonstrated that the SET-domain containing protein 6 (SETD6) interacts and methylates PAK4 at chromatin in mammalian cells, which leads to activation of Wnt/β-catenin signaling pathway. In our current work, we identified lysine 473 (K473) on PAK4 as the primary methylation site by SETD6. Methylation of PAK4 at K473 activates β-catenin transcriptional activity and inhibits cell adhesion. Specific methylation of PAK4 at K473 also attenuates paxillin localization to focal adhesions leading to reduced cell protrusions and reduction in the overall formation of filopodia structures. The altered adhesion of the PAK4 wild-type cells is accompanied with a decrease in the migration and invasive characteristics of the cells. Taken together, our results suggest that methylation of PAK4 at K473 plays a vital role in the activation of the Wnt/β-catenin pathway and in the regulation of cell adhesion and migration.