JAK2 phosphorylates histone H3Y41 and excludes HP1 alpha from chromatin
Mark A Dawson, Andrew J Bannister, Berthold Goettgens, Samuel D Foster, Till Bartke, Anthony R Green, Tony Kouzarides
NATURE | NATURE PUBLISHING GROUP | Published : 2009
Activation of Janus kinase 2 (JAK2) by chromosomal translocations or point mutations is a frequent event in haematological malignancies. JAK2 is a non-receptor tyrosine kinase that regulates several cellular processes by inducing cytoplasmic signalling cascades. Here we show that human JAK2 is present in the nucleus of haematopoietic cells and directly phosphorylates Tyr 41 (Y41) on histone H3. Heterochromatin protein 1alpha (HP1alpha), but not HP1beta, specifically binds to this region of H3 through its chromo-shadow domain. Phosphorylation of H3Y41 by JAK2 prevents this binding. Inhibition of JAK2 activity in human leukaemic cells decreases both the expression of the haematopoietic oncogen..View full abstract
Awarded by Medical Research Council
We thank P. Flicek, S. Wilder, B. Huntly, S. J. Dawson and all the members of the A. R. G., B. G. and T. K. laboratories, in particular P. Hurd, B. Xhemalce, E. J. Baxter and P. Beer, for helpful discussions; A. Wood for sharing unpublished data; and J. LeQuesne for help with image analysis. This work was supported by PhD fellowship grants to M. A. D. from the General Sir John Monash Foundation, the Cambridge Commonwealth Trust and Raymond and Beverly Sackler. The Green ( A. R. G.) laboratory is funded by the UK Leukaemia Research Fund, the Wellcome Trust, the Leukemia & Lymphoma Society of America and the National Institute for Health Research Cambridge Biomedical Research Centre. The Gottgens ( B. G.) laboratory is funded by the Leukaemia Research Fund, Cancer Research UK, the Leukemia & Lymphoma Society of America and a Medical Research Council studentship to S. D. F. The Kouzarides ( T. K.) laboratory is funded by grants from Cancer Research UK and the 6th Research Framework Programme of the European Union ( Epitron, HEROIC and SMARTER).