Editors' ChoiceGene Regulation

JAK Goes Nuclear

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Science Signaling  13 Oct 2009:
Vol. 2, Issue 92, pp. ec331
DOI: 10.1126/scisignal.292ec331

Members of the Janus kinase (JAK) family of nonreceptor protein tyrosine kinases associate with cytokine receptors and phosphorylate the STAT (signal transducers and activators of transcription) transcription factors, which then move to the nucleus and regulate transcription. Results from Dawson et al. now show that JAK2 can influence transcription in another way as well—through action of the kinase itself in the nucleus, where it phosphorylates a histone protein. The authors found that a portion of the JAK2 protein in mammalian hematopoietic cells was present in the nucleus. The authors suspected histones as a potential target and showed that histone H3 appears to be a direct target of phosphorylation by JAK2 in vitro and in vivo. Further experiments indicated that phosphorylation of histone H3 prevented its association with a binding partner, heterochromatin protein 1α (HP1α). Pharmacological inhibition of JAK2 increased association of HP1α with chromatin. Gene expression arrays identified decreased abundance of mRNA from many genes in cells in which JAK2 was inhibited. Some obviously were targets of STATs, but others had no predicted STAT5 binding sites. For one such gene, lmo2 (a hematopoietic oncogene implicated in leukemia), chromatin immunoprecipitation studies showed decreased phosphorylation of associated histone H3 and increased binding of HP1α after inhibition of JAK2. The results show a previously unrecognized mechanism of gene regulation by JAK2 through modification of chromatin, one that may influence, through the lmo2 gene product, the disease phenotypes associated with deregulated function of JAK2.

M. A. Dawson, A. J. Bannister, B. Göttgens, S. D. Foster, T. Bartke, A. R. Green, T. Kouzarides, JAK2 phosphorylates histone H3Y41 and excludes HP1α from chromatin. Nature 461, 819–822 (2009). [PubMed]

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