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The tyrosine kinase...
The tyrosine kinase FRK/RAK participates in cytokine-induced islet cell cytotoxicity
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- Welsh, Michael (author)
- Uppsala universitet,Institutionen för medicinsk cellbiologi
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- Welsh, Charlotte (author)
- Uppsala universitet,Institutionen för medicinsk cellbiologi
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- Ekman, Maria (author)
- Uppsala universitet,Institutionen för medicinsk cellbiologi
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- Dixelius, Johan (author)
- Uppsala universitet,Institutionen för genetik och patologi
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- Hägerkvist, Robert (author)
- Uppsala universitet,Institutionen för medicinsk cellbiologi
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- Annerén, Cecilia (author)
- Uppsala universitet,Institutionen för medicinsk cellbiologi
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- Åkerblom, Björn (author)
- Uppsala universitet,Institutionen för medicinsk cellbiologi
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Mahboob, Siavosh (author)
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Chandrasekharan, Subhashini (author)
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Liu, Edison T (author)
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(creator_code:org_t)
- 2004
- 2004
- English.
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In: Biochemical Journal. - 0264-6021 .- 1470-8728. ; 382, s. 261-268
- Related links:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Subject headings
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- 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.
Keyword
- b-cell
- cytokine
- cytotoxicity
- fyn-related kinase (FRK)/RAK
- kinase inhibitor
- knockout.
- MEDICINE
- MEDICIN
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Welsh, Michael
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Welsh, Charlotte
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Ekman, Maria
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Dixelius, Johan
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Hägerkvist, Robe ...
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Annerén, Cecilia
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show more...
-
Åkerblom, Björn
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Mahboob, Siavosh
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Chandrasekharan, ...
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Liu, Edison T
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show less...
- Articles in the publication
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Biochemical Jour ...
- By the university
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Uppsala University