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Molecular and Cellular Biology, May 2002, p. 3316-3326, Vol. 22, No. 10
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.10.3316-3326.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Regulation of Jak2 through the Ubiquitin-Proteasome Pathway Involves Phosphorylation of Jak2 on Y1007 and Interaction with SOCS-1

Daniela Ungureanu,1 Pipsa Saharinen,2 Ilkka Junttila,1 Douglas J. Hilton,3 and Olli Silvennoinen1,2,4*

Institute of Medical Technology, University of Tampere, FIN-33014 Tampere,1 Program of Developmental and Reproduction Biology, Biomedicum Helsinki, and Department of Virology, Haartman Institute, University of Helsinki, FIN-00014 Helsinki,2 Department of Clinical Microbiology, Tampere University Hospital, FIN-33521 Tampere, Finland,4 The Walter and Eliza Hall Institute of Medical Research and the Cooperative Research Center for Cellular Growth Factors, Parkville, Victoria 3050, Australia3

Received 6 June 2001/ Returned for modification 26 July 2001/ Accepted 19 February 2002

The family of cytoplasmic Janus (Jak) tyrosine kinases plays an essential role in cytokine signal transduction, regulating cell survival and gene expression. Ligand-induced receptor dimerization results in phosphorylation of Jak2 on activation loop tyrosine Y1007 and stimulation of its catalytic activity, which, in turn, results in activation of several downstream signaling cascades. Recently, the catalytic activity of Jak2 has been found to be subject to negative regulation through various mechanisms including association with SOCS proteins. Here we show that the ubiquitin-dependent proteolysis pathway is involved in the regulation of the turnover of activated Jak2. In unstimulated cells Jak2 was monoubiquitinated, and interleukin-3 or gamma interferon stimulation induced polyubiquitination of Jak2. The polyubiquitinated Jak2 was rapidly degraded through proteasomes. By using different Jak2 mutants we show that tyrosine-phosphorylated Jak2 is preferentially polyubiquitinated and degraded. Furthermore, phosphorylation of Y1007 on Jak2 was required for proteasomal degradation and for SOCS-1-mediated downregulation of Jak2. The proteasome inhibitor treatment stabilized the Jak2-SOCS-1 protein complex and inhibited the proteolysis of Jak2. In summary, these results indicate that the ubiquitin-proteasome pathway negatively regulates tyrosine-phosphorylated Jak2 in cytokine receptor signaling, which provides an additional mechanism to control activation of Jak2 and maintain cellular homeostasis.

* Corresponding author. Mailing address: Institute of Medical Technology, University of Tampere, Lenkkeilijankatu 8, FIN-33014 Tampere, Finland. Phone: 358-3-215 7845. Fax: 358-3-215 7332. E-mail: olli.silvennoinen{at}uta.fi.

Molecular and Cellular Biology, May 2002, p. 3316-3326, Vol. 22, No. 10
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.10.3316-3326.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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