title: Protein kinase Msk1 physically and functionally interacts with the KMT2A/MLL1 methyltransferase complex and contributes to the regulation of multiple target genes.
abstract: The KMT2A/MLL1 lysine methyltransferase complex is an epigenetic regulator of selected developmental genes, in part through the SET domain-catalysed methylation of H3K4. It is essential for normal embryonic development and haematopoiesis and frequently mutated in cancer. The catalytic properties and targeting of KMT2A/MLL1 depend on the proteins with which it complexes and the post-translational protein modifications which some of these proteins put in place, though detailed mechanisms remain unclear.
  
  
  
  KMT2A/MLL1 (both native and FLAG-tagged) and Msk1 (RPS6KA5) co-immunoprecipitated in various cell types. KMT2A/MLL1 and Msk1 knockdown demonstrated that the great majority of genes whose activity changed on KTM2A/MLL1 knockdown, responded comparably to Msk1 knockdown, as did levels of H3K4 methylation and H3S10 phosphorylation at KTM2A target genesHoxA4,HoxA5. Knockdown experiments also showed that KMT2A/MLL1 is required for the genomic targeting of Msk1, but not vice versa.
  
  
  
  The KMT2A/MLL1 complex is associated with, and functionally dependent upon, the kinase Msk1, part of the MAP kinase signalling pathway. We propose that Msk1-catalysed phosphorylation at H3 serines 10 and 28, supports H3K4 methylation by the KMT2A/MLL1 complex both by making H3 a more attractive substrate for its SET domain, and improving target gene accessibility by prevention of HP1- and Polycomb-mediated chromatin condensation.
authors.affiliation: Chromatin and Gene Expression Group, Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT UK.
authors.forename: Maaike
authors.initials: M
authors.lastname: Wiersma
authors.affiliation: Chromatin and Gene Expression Group, Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT UK ; Molecular Imaging and Photonics, KU Leuven, Celestijnenlaan 22f, Box 2404, 3001 Louvain, Belgium.
authors.forename: Marianne
authors.initials: M
authors.lastname: Bussiere
authors.affiliation: Chromatin and Gene Expression Group, Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT UK.
authors.forename: John A
authors.initials: JA
authors.lastname: Halsall
authors.affiliation: Chromatin and Gene Expression Group, Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT UK.
authors.forename: Nil
authors.initials: N
authors.lastname: Turan
authors.affiliation: Department of Biology, Friedrich-Alexander-University of Erlangen-Nürnberg, 91058 Erlangen, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Slany
authors.affiliation: Chromatin and Gene Expression Group, Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT UK.
authors.forename: Bryan M
authors.initials: BM
authors.lastname: Turner
authors.affiliation: Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT UK.
authors.forename: Karl P
authors.initials: KP
authors.lastname: Nightingale
mesh_terms: D000818:Animals; D002460:Cell Line; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D008745:Methylation; D008780:Methyltransferases / Q000378:metabolism; D051379:Mice; D051788:Myeloid-Lymphoid Leukemia Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors
chemical_list: C489213:HOXA5 protein, human; D006657:Histones; D018398:Homeodomain Proteins; C497422:KMT2A protein, human; D034741:RNA, Small Interfering; D014157:Transcription Factors; C073547:HOXA4 protein, human; D051788:Myeloid-Lymphoid Leukemia Protein; D008780:Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1
keywords: Chromatin; Gene regulation; Histone modification; MLL1 complex; Signal transduction