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Glucose-induced translocation of protein kinase C isoforms in rat-1 fibroblasts is paralleled by inhibition of the insulin receptor tyrosine kinase
Rat-1 fibroblasts stably overexpressing high levels of human insulin receptor were used as a model system to study the effects of hyperglycemia on insulin receptor tyrosine kinase (IRK) activity and protein kinase C (PKC) translocation in parallel in the intact cell. Glucose (10-25 mM) induced a sig...
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Published in: | The Journal of biological chemistry 1994-02, Vol.269 (5), p.3381-3386 |
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Main Authors: | , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | Rat-1 fibroblasts stably overexpressing high levels of human insulin receptor were used as a model system to study the effects
of hyperglycemia on insulin receptor tyrosine kinase (IRK) activity and protein kinase C (PKC) translocation in parallel in
the intact cell. Glucose (10-25 mM) induced a significant reduction of IRK activity (tyrosine phosphorylation of IR-beta-subunit
and IR-substrate-1) within 10 min. This effect was paralleled by a rapid translocation of several PKC isoforms (cPKC alpha,
nPKC delta, nPKC epsilon, nPKC zeta) to the plasma membrane within 1 min. Kinetics of IRK inhibition and PKC translocation
are consistent with the idea that the glucose effect on IRK is mediated by PKC activation. This hypothesis is supported by
further observations. Addition of the protein kinase C inhibitor H-7 can prevent the effect of glucose on IRK. Inhibition
of IRK is also observed after stimulation of the cells with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate, which
can substitute for a physiological activator of PKC. Glucose (25 mM) increases the 32P incorporation in serine residues of
the beta-subunit of IRK. We conclude that high levels of glucose induce inhibition of IRK in vivo. There is indirect evidence
that this effect is mediated by a glucose-induced PKC translocation/activation and serine phosphorylation of the insulin receptor. |
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ISSN: | 0021-9258 1083-351X |
DOI: | 10.1016/S0021-9258(17)41873-4 |