title: PAK4 Methylation by SETD6 Promotes the Activation of the Wnt/β-Catenin Pathway.
abstract: 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 non-histone 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 bothin vitroand 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 of β-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.
authors: From the Shraga Segal Department of Microbiology, Immunology, and Genetics and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Be'er-Sheva 84105, Israel.
authors: Zlata
authors: Z
authors: Vershinin
authors: From the Shraga Segal Department of Microbiology, Immunology, and Genetics and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Be'er-Sheva 84105, Israel.
authors: Michal
authors: M
authors: Feldman
authors: From the Shraga Segal Department of Microbiology, Immunology, and Genetics and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Be'er-Sheva 84105, Israel.
authors: Ayelet
authors: A
authors: Chen
authors: From the Shraga Segal Department of Microbiology, Immunology, and Genetics and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Be'er-Sheva 84105, Israel ledan@post.bgu.ac.il.
authors: Dan
authors: D
authors: Levy
mesh_terms: D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism*; D003001:Cloning, Molecular; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D055786:Gene Knockout Techniques; D057809:HEK293 Cells; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D008745:Methylation; D011485:Protein Binding; D011496:Protein Methyltransferases / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D011994:Recombinant Proteins; D014158:Transcription, Genetic; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: C495270:CTNNB1 protein, human; D002843:Chromatin; D011994:Recombinant Proteins; D051176:beta Catenin; D011496:Protein Methyltransferases; C562071:SETD6 protein, human; C116367:PAK4 protein, human; D054462:p21-Activated Kinases; D008239:Lysine
keywords: PAK4; S-adenosylmethionine (SAM); SETD6; Wnt pathway; Wnt signaling; chromatin; gene transcription; methylation; post-translational modification (PTM); β-catenin (β-catenin)