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The tyrosine kinase FRK/RAK participates in cytokine-induced islet cell cytotoxicity
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
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2004 (English)In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 382, 261-268 p.Article in journal (Refereed) Published
Abstract [en]

Hallmarks of the inflammatory process in Type I diabetes are macrophage activation, local release of b-cell-toxic cytokines and infiltration of cytotoxic T lymphocytes. We have observed recently that mice overexpressing active FRK (fyn-related kinase)/RAK (previously named GTK/Bsk/IYK, where GTK stands for gut tyrosine kinase, Bsk for b-cell Src-homology kinase and IYK for intestinal tyrosine kinase) in b-cells exhibit increased susceptibility to b-cell-toxic events, and therefore, we now attempt to find a more precise role for FRK/RAK in these processes. Phosphopeptide mapping of baculovirus-produced mouse FRK/RAK revealed an autophosphorylation pattern compatible with Tyr-394 being the main site. No evidence for in vitro phosphorylation of the C-terminal regulatory sites Tyr-497 and Tyr-504 was obtained, nor was there any indication of in vitro regulation of FRK/RAK kinase activity. Screening a panel of known tyrosine kinase inhibitors for their ability to inhibit FRK/RAK revealed several compounds that inhibited FRK/RAK, with a potency similar to that reported for their ability to inhibit other tyrosine kinases. Cytokine-induced islet toxicity was reduced in islets isolated from FRK/RAK knockout mice and this occurred without effects on the production of nitric oxide. Addition of the nitric oxide inhibitor nitroarginine to FRK/RAK knockout islets exposed to cytokines decreased cell death to a basal level. In normal islets, cytokine-induced cell death was inhibited by the addition of two FRK/RAK inhibitors, SU4984 and D-65495, or by transfection with short interfering RNA against FRK/RAK. It is concluded that FRK/RAK contributes to cytokine-induced b-cell death, and inhibition of this kinase could provide means to suppress b-cell destruction in Type I diabetes.

Place, publisher, year, edition, pages
2004. Vol. 382, 261-268 p.
Keyword [en]
b-cell, cytokine, cytotoxicity, fyn-related kinase (FRK)/RAK, kinase inhibitor, knockout.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-72036DOI: 10.1042/BJ20040285OAI: oai:DiVA.org:uu-72036DiVA: diva2:99947
Available from: 2005-05-17 Created: 2005-05-17 Last updated: 2017-11-21Bibliographically approved

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Welsh, MichaelWelsh, CharlotteEkman, MariaDixelius, JohanHägerkvist, RobertAnnerén, CeciliaÅkerblom, Björn

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Welsh, MichaelWelsh, CharlotteEkman, MariaDixelius, JohanHägerkvist, RobertAnnerén, CeciliaÅkerblom, Björn
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Department of Medical Cell BiologyDepartment of Genetics and Pathology
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