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JAK2 phosphorylates histone H3Y41 and excludes HP1alpha from chromatin.

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 oncogene lmo2 and the phosphorylation of H3Y41 at its promoter, while simultaneously increasing the binding of HP1alpha at the same site. Tauhese results identify a previously unrecognized nuclear role for JAK2 in the phosphorylation of H3Y41 and reveal a direct mechanistic link between two genes, jak2 and lmo2, involved in normal haematopoiesis and leukaemia.

Pubmed ID: 19783980

Authors

  • Dawson MA
  • Bannister AJ
  • Gƶttgens B
  • Foster SD
  • Bartke T
  • Green AR
  • Kouzarides T

Journal

Nature

Publication Data

October 8, 2009

Associated Grants

  • Agency: Wellcome Trust, Id: 089957
  • Agency: Cancer Research UK, Id: 12765
  • Agency: Medical Research Council, Id: G0800784
  • Agency: Medical Research Council, Id: MC_UP_1102/2
  • Agency: Cancer Research UK, Id:
  • Agency: Medical Research Council, Id:
  • Agency: Wellcome Trust, Id:

Mesh Terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Binding Sites
  • Cell Line
  • Cell Nucleus
  • Chromatin
  • Chromosomal Proteins, Non-Histone
  • DNA-Binding Proteins
  • Gene Expression Regulation, Neoplastic
  • Hematopoiesis
  • Hematopoietic Stem Cells
  • Histones
  • Humans
  • Janus Kinase 2
  • LIM Domain Proteins
  • Leukemia
  • Metalloproteins
  • Mice
  • Oncogenes
  • Phosphorylation
  • Promoter Regions, Genetic
  • Protein Binding
  • Proto-Oncogene Proteins
  • Signal Transduction
  • Tyrosine