Serine/threonine protein kinase SGK1 in glucocorticoid-dependent transdifferentiation of pancreatic acinar cells to hepatocytes

  1. Lookup NU author(s)
  2. Dr Karen Wallace
  3. QUAN LONG
  4. Emma Fairhall
  5. Professor Matthew Wright
Author(s)Wallace K, Long Q, Fairhall EA, Charlton KA, Wright MC
Publication type Article
JournalJournal of Cell Science
Year2011
Volume124
Issue3
Pages405-413
ISSN (print)0021-9533
ISSN (electronic)1477-9137
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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.
PublisherThe Company of Biologists Ltd.
URLhttp://dx.doi.org/10.1242/jcs.077503
DOI10.1242/jcs.077503
PubMed id21224398
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