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First published online 3 May 2005
doi: 10.1242/jcs.02373

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MAP kinase-mediated phosphorylation of distinct pools of histone H3 at S10 or S28 via mitogen- and stress-activated kinase 1/2

¹ Nuclear Signalling Laboratory, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK
² Aichi Cancer Centre Research Instititute, 1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi 46 8681, Japan
³ MRC Protein Phosphorylation Unit, School of Life Sciences, Dundee, DD1 5EH, UK
⁴ Chromatin and Gene Expression, Institute of Biomedical Research, University of Birmingham, Vincent Drive, Edgbaston, Birmingham, B15 2TT, UK
⁵ The Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, OX3 9DS, UK

^* Author for correspondence (e-mail: louiscm{at}bioch.ox.ac.uk)

Accepted 10 March 2005

ERK and p38 MAP kinases, acting through the downstream mitogen- and stress-activated kinase 1/2 (MSK1/2), elicit histone H3 phosphorylation on a subfraction of nucleosomes – including those at Fos and Jun – concomitant with gene induction. S10 and S28 on the H3 tail have both been shown to be phospho-acceptors in vivo. Both phospho-epitopes appear with similar time-courses and both occur on H3 tails that are highly sensitive to TSA-induced hyperacetylation, similarities which might suggest that MSK1/2 phosphorylates both sites on the same H3 tails. Indeed, on recombinant histone octamers in vitro, MSK1 efficiently phosphorylates both sites on the same H3 tail. However, sequential immunoprecipitation studies show that antibodies against phosphorylated S10-H3 recover virtually all this epitope without depletion of phosphorylated S28-H3, and vice versa, indicating that the two phospho-epitopes are not located on the same H3 tail in vivo. Confocal immunocytochemistry confirms the clear physical separation of the two phospho-epitopes in the intact mouse nucleus. Finally, we used transfection-based experiments to test models that might explain such differential targeting. Overexpression and delocalisation of MSK1 does not result in the breakdown of targeting in vivo despite the fact that the ectopic kinase is fully activated by external stimuli. These studies reveal a remarkable level of targeting of S10 and S28 phosphorylation to distinct H3 tails within chromatin in the interphase mouse nucleus. Possible models for such exquisite targeting are discussed.

Key words: MAP kinases, MSK, Histone H3 phosphorylation, Gene induction

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