Lysine methylation of non-histone proteins has emerged as a key regulator of many cellular functions. Although less studied than other post- Translational modifications such as phosphorylation and acetylation, the number of known methylated nonhistone proteins is rapidly expanding. We have identified the p21- Activated kinase 4 (PAK4) as a new substrate for methylation by the protein lysine methyltransferase SETD6. Our data demonstrate that SETD6 methylates PAK4 both in vitro and at chromatin in cells. Interestingly, depletion of SETD6 in various cellular systems significantly hinders the activation of the Wnt/ β-catenin target genes. PAK4 was recently shown to regulate β-catenin signaling, and we show that SETD6 is a key mediator of this pathway. In the presence of SETD6, the physical interaction between PAK4 and β-catenin is dramatically increased, leading to a significant increase in the transcription ofβ-catenin target genes. Taken together, our results uncover a new regulatory layer of the Wnt/β-catenin signaling cascade and provide new insight into SETD6 biology.