Lookup NU author(s): Dr Karen Wallace,
Dr Emma Fairhall,
Professor Matthew Wright
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Elevated glucocorticoid levels result in the transdifferentiation of pancreaticacinar cells into hepatocytes through a process that requires a transientrepression of WNT signalling upstream of the induction of C/EBP-β. However, themechanism by which glucocorticoid interacts with WNT signalling is unknown. Ascreen of microarray data showed that the serine/threonine protein kinase SGK1(serum- and glucocorticoid-regulated kinase 1) was markedly induced in the model B-13 pancreatic rat acinar cell line after glucocorticoid treatment (whichconverts them into hepatocyte-like 'B-13/H' cells) and this was confirmed at the level of mRNA (notably an alternatively transcribed SGK1C form) and protein.Knockdown of SGK1 using an siRNA designed to target all variant transcriptsinhibited glucocorticoid-dependent transdifferentiation, whereas overexpressionof the human C isoform (and also the human SGK1F isoform, for which no orthologuein the rat has been identified) alone - but not the wild-type A form - inhibited distal WNT signalling Tcf/Lef transcription factor activity, and converted B-13cells into B-13/H cells. These effects were lost when the kinase functions ofSGK1C and SGK1F were mutated. Inhibition of SGK1 kinase activity also inhibitedglucocorticoid-dependent transdifferentiation. Expression of SGK1C and SGK1Fresulted in the appearance of phosphorylated β-catenin, and recombinant SGK1 was shown to directly phosphorylate purified β-catenin in vitro in an ATP-dependentreaction. These data therefore demonstrate a crucial role for SGK1 induction inB-13 cell transdifferentiation to B-13/H hepatocytes and suggest that directphosphorylation of β-catenin by SGK1C represents the mechanism of crosstalkbetween glucocorticoid and WNT signalling pathways.
Author(s): Wallace K, Long Q, Fairhall EA, Charlton KA, Wright MC
Publication type: Article
Journal: Journal of Cell Science
Print publication date: 11/01/2011
ISSN (print): 0021-9533
ISSN (electronic): 1477-9137
Publisher: The Company of Biologists Ltd.
PubMed id: 21224398
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