The tyrosine kinase FRK/RAK participates in cytokine-induced islet cell cytotoxicity
2004 (English)In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 382, 261-268 p.Article in journal (Refereed) Published
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.
b-cell, cytokine, cytotoxicity, fyn-related kinase (FRK)/RAK, kinase inhibitor, knockout.
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-72036DOI: 10.1042/BJ20040285OAI: oai:DiVA.org:uu-72036DiVA: diva2:99947