Reference : An unusual insertion in Jak2 is crucial for kinase activity and differentially affect...
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
http://hdl.handle.net/10993/10440
An unusual insertion in Jak2 is crucial for kinase activity and differentially affects cytokine responses
English
Haan, Claude mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit >]
Kroy, Daniela C. [> >]
Wüller, Stefan [> >]
Sommer, Ulrike [> >]
Nöcker, Tanja [> >]
Rolvering, Catherine mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit >]
Behrmann, Iris mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit >]
Heinrich, Peter C. [> >]
Haan, Serge mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit >]
2009
Journal of Immunology
American Association of Immunologists
182
5
2969-2977
Yes (verified by ORBilu)
International
0022-1767
1550-6606
Baltimore
MD
[en] The Janus kinases, Jaks, constitutively associate with the cytoplasmic region of cytokine receptors and play an important role in a multitude of biological processes. Jak2 dysfunction has been implicated in myeloproliferative diseases and leukemia. Although Jaks were studied extensively for many years, the molecular mechanism of Jak activation upon cytokine stimulation of cells is still incompletely understood. In this study, we investigated the importance of an unusual insertion located within the kinase domain in Jak2. We found that the deletion of this insertion, which we named the Jak-specific insertion (JSI), totally abrogates Jak2 autophosphorylation. We further point mutated four residues within the JSI that are conserved in all Jak family members. Three of these mutants showed abrogated or reduced autophosphorylation, whereas the fourth displayed increased autophosphorylation. We found that the phosphorylation state of these mutants is not influenced by other domains of the kinase. Our data further suggest that the JSI is not required for the negative regulation of kinase activity by the suppressor of cytokine signaling proteins, SOCS. Most importantly, we show that mutations in this region differentially affect IFN-gamma and erythropoietin signal transduction. Taken together, the dramatic effects on the phosphorylation status of Jak2 as well as the differential effects on the signaling via different cytokines highlight the importance of this unusual region for the catalytic activity of Jaks.
http://hdl.handle.net/10993/10440
10.4049/jimmunol.0800572
FREE FULL TEXT available at: http://www.jimmunol.org/content/182/5/2969.long

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