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J. Biol. Chem., Vol. 276, Issue 48, 45088-45097, November 30, 2001
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From the Dipartimento di Biologia e Patologia Cellulare e
Molecolare and Centro di Endocrinologia ed Oncologia Sperimentale del
CNR, Federico II University of Naples, 80131 Naples, Italy
In L6 skeletal muscle cells and immortalized
hepatocytes, insulin induced a 2-fold increase in the activity of the
pyruvate dehydrogenase (PDH) complex. This effect was almost completely blocked by the protein kinase C (PKC)
Activation and Mitochondrial Translocation of Protein
Kinase C
Are Necessary for Insulin Stimulation of Pyruvate
Dehydrogenase Complex Activity in Muscle and Liver Cells*
,§,
inhibitor Rottlerin and by
PKC antisense oligonucleotides. At variance, overexpression of
wild-type PKC or of an active PKC mutant induced PDH complex activity in both L6 and liver cells. Insulin stimulation of the activity of the PDH complex was accompanied by a 2.5-fold increase in
PDH phosphatases 1 and 2 (PDP1/2) activity with no change in the
activity of PDH kinase. PKC antisense blocked insulin activation of
PDP1/2, the same as with PDH. In insulin-exposed cells, PDP1/2 activation was paralleled by activation and mitochondrial translocation of PKC, as revealed by cell subfractionation and confocal microscopy studies. The mitochondrial translocation of PKC, like its
activation, was prevented by Rottlerin. In extracts from
insulin-stimulated cells, PKC co-precipitated with PDP1/2. PKC
also bound to PDP1/2 in overlay blots, suggesting that direct
PKC-PDP interaction may occur in vivo as well. In intact
cells, insulin exposure determined PDP1/2 phosphorylation, which was
specifically prevented by PKC antisense. PKC also phosphorylated
PDP in vitro, followed by PDP1/2 activation. Thus, in
muscle and liver cells, insulin causes activation and mitochondrial
translocation of PKC, accompanied by PDP phosphorylation and
activation. These events are necessary for insulin activation of the
PDH complex in these cells.
*
This work was supported in part by European Community Grant
QLRT-1999-00674 (to F. B.), grants from the Associazione Italiana per
la Ricerca sul Cancro (to F. B. and P. F.), the Ministero dell'
Università e della Ricerca Scientifica, and the CNR, Target Project on Biotechnology grant (to F. B.), and Telethon-Italy Grant
0896 (to F. B.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Both authors contributed equally to this work.
§
Recipient of fellowship from the Federazione Italiana per la
Ricerca sul Cancro.
¶
Current address: Dept. di Ginecologia, Ostetricia e
Fisiopatologia della Riproduzione Umana, Federico II University of
Naples Medical School.
To whom correspondence should be addressed: Dept. di Biologia
e Patologia Cellulare e Molecolare, Università di Napoli Federico II, Via S. Pansini, 5, 80131 Naples, Italy. Tel.: 39 081 7463248; Fax:
39 081 7463235; E-mail: beguino@unina.it.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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