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SOCS-mediated downregulation of mutant Jak2 (V617F, T875N and K539L) counteracts cytokine-independent signaling

Oncogene volume 28, pages 3069–3080 (2009)Cite this article

Abstract

Recently, mutations in the gene of Janus kinase 2 (Jak2) were discovered in patients suffering from chronic myeloproliferative disorders (MPD) and leukemia. As suppressors of cytokine signaling (SOCS) proteins are potent feedback inhibitors of Jak-mediated signaling, we investigated their role in signal transduction through constitutively active Jak2 mutants. We selected two mutants, Jak2-V617F and Jak2-K539L, found in patients with MPDs and Jak2-T875N identified in acute megakaryoblastic leukemia. We found SOCS family members to be induced through Jak2-V617F in human leukemia cell lines expressing the mutant allele and in stable HEK transfectants inducibly expressing constitutively active Jak2 mutants. SOCS proteins were recruited to the membrane and bound to the constitutively active Jaks. In contrast to wild-type Jak2, the mutant proteins were constitutively ubiquitinated and degraded through the proteasome. Taken together, we show a SOCS-mediated downregulation of the constitutively active, disease-associated mutant Jak2 proteins. Furthermore, a threshold level of mutant Jak expression has to be overcome to allow full cytokine-independent constitutive activation of signaling proteins, which may explain progression to homozygocity in MPDs as well as gene amplification in severe phenotypes and leukemia.

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Acknowledgements

This work was supported by the UL Grant nos. R1F105L01 and R1F107L01, the Marie Curie Research Training Network ReceptEUR, and by Serono GmbH (Unterschleißheim, Germany).

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  1. S Haan and S Wüller: These authors contributed equally to this work.

Authors and Affiliations

  1. Life Sciences Research Unit, University of Luxembourg, Luxembourg, Luxembourg

    S Haan, J Kaczor, C Rolvering, I Behrmann & C Haan

  2. Department of Biochemistry; Rheinisch-Westfälische Technische Hochschule Aachen, Pauwelsstrasse, Aachen, Germany,

    S Wüller & T Nöcker

  3. Rheinisch-Westfälische Technische Hochschule Aachen, Pauwelsstrasse, Aachen, Germany,

    S Wüller & T Nöcker

  4. Department of Pediatrics, Rheinisch-Westfälische Technische Hochschule Aachen, Pauwelsstrasse, Aachen, Germany,

    S Wüller

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Correspondence to S Haan or C Haan.

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Haan, S., Wüller, S., Kaczor, J. et al. SOCS-mediated downregulation of mutant Jak2 (V617F, T875N and K539L) counteracts cytokine-independent signaling. Oncogene 28, 3069–3080 (2009). https://doi.org/10.1038/onc.2009.155

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