Welsh, Michael and Welsh, Charlotte and Ekman, Maria and Dixelius, Johan and Hagerkvist, Robert and Anneren, Cecilia and Akerblom, Björn and Mahboobi, Siavosh and Chandrasekharan, Subhashini and Liu, Edison T. (2004) The tyrosine kinase FRK/RAK participates in cytokine-induced islet cell cytotoxicity. BIOCHEMICAL JOURNAL, 382. pp. 261-268. ISSN 0264-6021, 1470-8728
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | GROWTH-FACTOR RECEPTOR; INSULIN-PRODUCING CELLS; PANCREATIC BETA-CELLS; NITRIC-OXIDE SYNTHASE; ADAPTER PROTEIN; DISTINCT ROLES; FACTOR-I; SRC; INHIBITION; ACTIVATION; beta-cell; cytokine; cytotoxicity; fyn-related kinase (FRK)/RAK; kinase inhibitor; knockout |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry I (Prof. Elz) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 05 Jul 2021 08:19 |
| Last Modified: | 05 Jul 2021 08:19 |
| URI: | https://pred.uni-regensburg.de/id/eprint/37333 |
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