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Molecular and Cellular Biology, May 2000, p. 3387-3395, Vol. 20, No. 10
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Regulation of the Jak2 Tyrosine Kinase by Its Pseudokinase Domain

Pipsa Saharinen,1 Kati Takaluoma,2 and Olli Silvennoinen1,2,3,*

Department of Virology, Haartman Institute, FIN-00014 University of Helsinki,1 and Institute of Medical Technology, University of Tampere,2 and Department of Clinical Microbiology, Tampere University Hospital,3 FIN-33101 Tampere, Finland

Received 11 October 1999/Returned for modification 7 December 1999/Accepted 14 February 2000

Activation of Jak tyrosine kinases through hematopoietic cytokine receptors occurs as a consequence of ligand-induced aggregation of receptor-associated Jaks and their subsequent autophosphorylation. Jak kinases consist of a C-terminal tyrosine kinase domain, a pseudokinase domain of unknown function, and Jak homology (JH) domains 3 to 7, implicated in receptor-Jak interaction. We analyzed the functional roles of the different protein domains in activation of Jak2. Deletion analysis of Jak2 showed that the pseudokinase domain but not JH domains 3 to 7 negatively regulated the catalytic activity of Jak2 as well as Jak2-mediated activation of Stat5. Phosphorylation of Stat5 by wild-type Jak2 was dependent on the SH2 domain of Stat5; however, this requirement was lost upon deletion of the pseudokinase domain of Jak2. Investigation of the mechanisms of the pseudokinase domain-mediated inhibition of Jak2 suggested that this regulation did not involve protein tyrosine phosphatases. Instead, analysis of interactions between the tyrosine kinase domain and Jak2 suggested that the pseudokinase domain interacted with the kinase domain. Furthermore, coexpression of the pseudokinase domain inhibited the activity of the single tyrosine kinase domain. Finally, deletion of the pseudokinase domain of Jak2 deregulated signal transduction through the gamma interferon receptor by significantly increasing ligand-independent activation of Stat transcription factors. These results indicate that the pseudokinase domain negatively regulates the activity of Jak2, probably through an interaction with the kinase domain, and this regulation is required to keep Jak2 inactive in the absence of ligand stimulation. Furthermore, the pseudokinase domain may have a role in regulation of Jak2-substrate interactions.

* Corresponding author. Mailing address: Department of Virology, Haartman Institute, Haartmaninkatu 3, P.O. Box 21, FIN-00014 University of Helsinki, Finland. Phone: 358-9-191 26484. Fax: 358-9-191 26491. E-mail: ltolsi{at}uta.fi.

Molecular and Cellular Biology, May 2000, p. 3387-3395, Vol. 20, No. 10
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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