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The tyrosine kinase...
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Welsh, MichaelUppsala universitet,Institutionen för medicinsk cellbiologi
(författare)
The tyrosine kinase FRK/RAK participates in cytokine-induced islet cell cytotoxicity
- Artikel/kapitelEngelska2004
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Nummerbeteckningar
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LIBRIS-ID:oai:DiVA.org:uu-72036
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https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-72036URI
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https://doi.org/10.1042/BJ20040285DOI
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Språk:engelska
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Sammanfattning på:engelska
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Ämneskategori:ref swepub-contenttype
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Ämneskategori:art swepub-publicationtype
Anmärkningar
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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.
Ämnesord och genrebeteckningar
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b-cell
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cytokine
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cytotoxicity
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fyn-related kinase (FRK)/RAK
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kinase inhibitor
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knockout.
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MEDICINE
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MEDICIN
Biuppslag (personer, institutioner, konferenser, titlar ...)
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Welsh, CharlotteUppsala universitet,Institutionen för medicinsk cellbiologi(Swepub:uu)lottwels
(författare)
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Ekman, MariaUppsala universitet,Institutionen för medicinsk cellbiologi(Swepub:uu)maekm172
(författare)
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Dixelius, JohanUppsala universitet,Institutionen för genetik och patologi(Swepub:uu)jdi21046
(författare)
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Hägerkvist, RobertUppsala universitet,Institutionen för medicinsk cellbiologi(Swepub:uu)rohag287
(författare)
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Annerén, CeciliaUppsala universitet,Institutionen för medicinsk cellbiologi(Swepub:uu)cecianne
(författare)
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Åkerblom, BjörnUppsala universitet,Institutionen för medicinsk cellbiologi(Swepub:uu)bjake676
(författare)
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Mahboob, Siavosh
(författare)
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Chandrasekharan, Subhashini
(författare)
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Liu, Edison T
(författare)
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Uppsala universitetInstitutionen för medicinsk cellbiologi
(creator_code:org_t)
Sammanhörande titlar
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Ingår i:Biochemical Journal382, s. 261-2680264-60211470-8728
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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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Åkerblom, Björn
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Mahboob, Siavosh
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Chandrasekharan, ...
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Liu, Edison T
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