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Protein kinase Cepsilon modulates insulin receptor localization and trafficking in mouse embryonic fibroblasts

Abstract

We have previously shown that deletion of protein kinase C epsilon (PKCepsilon) in mice results in protection against glucose intolerance caused by a high fat diet. This was in part due to reduced insulin uptake by hepatocytes and insulin clearance, which enhanced insulin availability. Here we employed mouse embryonic fibroblasts (MEFs) derived from wildtype (WT) and PKCepsilon-deficient (PKCepsilon(-/-)) mice to examine this mechanistically. PKCepsilon(-/-) MEFs exhibited reduced insulin uptake which was associated with decreased insulin receptor phosphorylation, while downstream signalling through IRS-1 and Akt was unaffected. Cellular fractionation demonstrated that PKCepsilon deletion changed the localization of the insulin receptor, a greater proportion of which co-fractionated with flotillin-1, a marker of membrane microdomains. Insulin stimulation resulted in redistribution of the receptor in WT cells, while this was markedly reduced in PKCepsilon(-/-) cells. These alterations in insulin receptor trafficking were associated with reduced expression of CEACAM1, a receptor substrate previously shown to modulate insulin clearance. Virally-mediated reconstitution of PKCepsilon in MEFs increased CEACAM1 expression and partly restored the sensitivity of the receptor to insulin-stimulated redistribution. These data indicate that PKCepsilon can affect insulin uptake in MEFs through promotion of receptor-mediated endocytosis, and that this may be mediated by regulation of CEACAM1 expression.

Type Journal
ISBN 1932-6203 (Electronic) 1932-6203 (Linking)
Authors Pedersen, D. J.; Diakanastasis, B. ; Stockli, J. ; Schmitz-Peiffer, C.;
Garvan Authors A/Prof Carsten Schmitz-Peiffer
Publisher Name PLoS ONE
Published Date 2013-04-01 00:00:00
Published Volume 8
Published Issue 3
Published Pages e58046
URL http://www.ncbi.nlm.nih.gov/pubmed/23469261
Status Published In-print
OpenAccess Link https://publications.gimr.garvan.org.au/download.php?12003_12593/13_Pedersen_Plosone_.pdf