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Phosphorylation of p27Kip1 by JAK2 directly links cytokine receptor signaling to cell cycle control

Oncogene volume 30, pages 3502–3512 (2011)Cite this article

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Abstract

Janus kinase 2 (JAK2) couples ligand activation of cell surface cytokine receptors to the regulation of cellular functions including cell cycle progression, differentiation and apoptosis. It thereby coordinates biological programs such as development and hematopoiesis. Unscheduled activation of JAK2 by point mutations or chromosomal translocations can induce hyperproliferation and hematological malignancies. Typical signal transduction by the JAK2 tyrosine kinase comprises phosphorylation of STAT transcription factors. In this study, we describe the identification of the cyclin-dependent kinase (CDK) inhibitor p27Kip1 as a novel JAK2 substrate. JAK2 can directly bind and phosphorylate p27Kip1. Both, the JAK2 FERM domain and its kinase domain bind to p27Kip1. JAK2 phosphorylates tyrosine residue 88 (Y88) of p27Kip1. We previously reported that Y88 phosphorylation of p27Kip1 by oncogenic tyrosine kinases impairs p27Kip1-mediated CDK inhibition, and initiates its ubiquitin-dependent proteasomal degradation. Consistently, we now find that active oncogenic JAK2V617F reduces p27Kip1 stability and protein levels in patient-derived cell lines harboring the mutant JAK2V617F allele. Moreover, tyrosine phosphorylation of p27Kip1 is impaired and p27Kip1 expression is restored upon JAK2V617F inactivation by small hairpin RNA-mediated knockdown or by the pyridone-containing tetracycle JAK inhibitor-I, indicating that direct phosphorylation of p27Kip1 can contribute to hyperproliferation of JAK2V617F-transformed cells. Activation of endogenous JAK2 by interleukin-3 (IL-3) induces Y88 phosphorylation of p27Kip1, thus unveiling a novel link between cytokine signaling and cell cycle control in non-transformed cells. Oncogenic tyrosine kinases could use this novel pathway to promote hyperproliferation in tumor cells.

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Acknowledgements

We thank Jakob Troppmair and Justus Duyster for providing cell lines, Wolfgang Doppler for providing plasmids and antibodies and Stephan Geley for providing plasmids. We thank Wolfgang Doppler, Michael Kullmann, Jonathan Vosper and all members of the Hengst lab for support, stimulating discussions and critical reading of the manuscript. The work was funded by the FWF Grants SFB F21-B12 and P18873-B1.

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  1. Division of Medical Biochemistry, Biocenter, Innsbruck Medical University, Innsbruck, Austria

    H Jäkel, C Weinl & L Hengst

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  1. H Jäkel
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  2. C Weinl
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  3. L Hengst
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Correspondence to L Hengst.

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Jäkel, H., Weinl, C. & Hengst, L. Phosphorylation of p27Kip1 by JAK2 directly links cytokine receptor signaling to cell cycle control. Oncogene 30, 3502–3512 (2011). https://doi.org/10.1038/onc.2011.68

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