Hallmarks of the inflammatory process in Type I diabetes are macrophage activation, local release of β-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 β-cell Src-homology kinase and IYK for intestinal tyrosine kinase) in β-cells exhibit increased susceptibility to β-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 β-cell death, and inhibition of this kinase could provide means to suppress β-cell destruction in Type I diabetes.
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Research Article|
August 10 2004
The tyrosine kinase FRK/RAK participates in cytokine-induced islet cell cytotoxicity
Michael WELSH;
Michael WELSH
1
*Department of Medical Cell Biology, Uppsala University, 75123, Uppsala, Sweden
1To whom correspondence should be addressed (email michael.welsh@medcellbiol.uu.se).
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Charlotte WELSH;
Charlotte WELSH
*Department of Medical Cell Biology, Uppsala University, 75123, Uppsala, Sweden
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Maria EKMAN;
Maria EKMAN
*Department of Medical Cell Biology, Uppsala University, 75123, Uppsala, Sweden
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Johan DIXELIUS;
Johan DIXELIUS
†Department of Genetics and Pathology, Uppsala University, 75185, Uppsala, Sweden
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Robert HÄGERKVIST;
Robert HÄGERKVIST
*Department of Medical Cell Biology, Uppsala University, 75123, Uppsala, Sweden
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Cecilia ANNERÉN;
Cecilia ANNERÉN
*Department of Medical Cell Biology, Uppsala University, 75123, Uppsala, Sweden
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Björn ÅKERBLOM;
Björn ÅKERBLOM
*Department of Medical Cell Biology, Uppsala University, 75123, Uppsala, Sweden
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Siavosh MAHBOOBI;
Siavosh MAHBOOBI
‡University of Regensburg, D-93040, Germany
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Subhashini CHANDRASEKHARAN;
Subhashini CHANDRASEKHARAN
§University of North Carolina, Chapel Hill, NC, U.S.A.
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Edison T. LIU
Edison T. LIU
∥Genome Institute of Singapore, Singapore, Singapore
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Publisher: Portland Press Ltd
Received:
February 20 2004
Revision Received:
May 24 2004
Accepted:
June 08 2004
Accepted Manuscript online:
June 08 2004
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2004
Biochem J (2004) 382 (1): 261–268.
Article history
Received:
February 20 2004
Revision Received:
May 24 2004
Accepted:
June 08 2004
Accepted Manuscript online:
June 08 2004
Citation
Michael WELSH, Charlotte WELSH, Maria EKMAN, Johan DIXELIUS, Robert HÄGERKVIST, Cecilia ANNERÉN, Björn ÅKERBLOM, Siavosh MAHBOOBI, Subhashini CHANDRASEKHARAN, Edison T. LIU; The tyrosine kinase FRK/RAK participates in cytokine-induced islet cell cytotoxicity. Biochem J 15 August 2004; 382 (1): 261–268. doi: https://doi.org/10.1042/BJ20040285
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