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The tyrosine kinase FRK/RAK participates in cytokine-induced islet cell cytotoxicity. | LitMetric

AI Article Synopsis

  • The inflammatory process in Type I diabetes involves activated macrophages, harmful cytokines, and cytotoxic T lymphocytes attacking beta-cells.
  • Mice with overexpressed FRK/RAK in beta-cells show increased vulnerability to damage, prompting research into the specific role of this kinase in such processes.
  • Inhibiting FRK/RAK can reduce cytokine-induced beta-cell death, suggesting that targeting this kinase may offer therapeutic potential to protect beta-cells in Type I diabetes.

Article Abstract

Hallmarks of the inflammatory process in Type I diabetes are macrophage activation, local release of beta-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 beta-cell Src-homology kinase and IYK for intestinal tyrosine kinase) in beta-cells exhibit increased susceptibility to beta-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 beta-cell death, and inhibition of this kinase could provide means to suppress beta-cell destruction in Type I diabetes.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1133939PMC
http://dx.doi.org/10.1042/BJ20040285DOI Listing

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