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Updated: Mar 11, 2026

Specificity Analysis of Protein Lysine Methyltransferases Using SPOT Peptide Arrays
Published on: November 29, 2014
Protein kinase Msk1 physically and functionally interacts with the KMT2A/MLL1 methyltransferase complex and
Maaike Wiersma1, Marianne Bussiere2, John A Halsall1
1Chromatin and Gene Expression Group, Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT UK.
Background:
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.
Results:
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 genes HoxA4, HoxA5. Knockdown experiments also showed that KMT2A/MLL1 is required for the genomic targeting of Msk1, but not vice versa.
Conclusion:
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.
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