Lysine methylation signaling regulated by SETD6

Abstract

Greater than fifty methyltransferases (PKMTs) are predicted to be present in the human proteome; however, the catalytic activity and substrate specificity for the majority of these enzymes is unknown. Using the protoarray system, we have identified the serine/threonine kinase, PAK4, which is over-expressed in numerous cancer tumors and is associated with oncogenic cell proliferation, migration and invasion, as a new substrate for methylation by SETD6. 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 overall reduction in adhesion-related features, such as filopodia structures and actin stress fibers. The altered adhesion of the PAK4 wild-type cells is accompanied with a decrease in the migrative and invasive characteristics of the cells. Taken together, our results suggest that methylation of PAK4 at K473 plays a vital role in the regulation of cell adhesion and migration and represent another example for the importance of lysine methylation in cellular signaling.