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-Catenin Via Protein Kinase C-Mediated Inhibition of Glycogen Synthase Kinase-31
Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada
-Catenin is a transcriptional activator that is regulated by
glycogen synthase kinase-3 (GSK-3). GSK-3 is constitutively active in
unstimulated cells where it phosphorylates -catenin, targeting
-catenin for rapid degradation. Receptor-induced inhibition of GSK-3
allows -catenin to accumulate in the cytoplasm and then translocate
to the nucleus where it promotes the transcription of genes such as
c-myc and cyclin D1. Wnt hormones, the
best known regulators of -catenin, inhibit GSK-3 via the Disheveled
protein. However, GSK-3 is also inhibited when it is phosphorylated by
Akt, a downstream target of phosphatidylinositol 3-kinase (PI3K). We
have previously shown that B cell Ag receptor (BCR) signaling leads to
activation of PI3K and Akt as well as inhibition of GSK-3. Therefore,
we hypothesized that BCR engagement would induce the accumulation of
-catenin via a PI3K/Akt/GSK-3 pathway. We now show that BCR ligation
causes an increase in the level of -catenin in the nuclear fraction
of B cells as well as an increase in -catenin-dependent
transcription. Direct inhibition of GSK-3 by LiCl also increased
-catenin levels in B cells. This suggests that GSK-3 keeps
-catenin levels low in unstimulated B cells and that BCR-induced
inhibition of GSK-3 allows the accumulation of -catenin.
Surprisingly, we found that the BCR-induced phosphorylation of GSK-3 on
its negative regulatory sites, as well as the subsequent up-regulation
of -catenin, was not mediated by Akt but by the phospholipase
C-dependent activation of protein kinase C. Thus, the BCR regulates
-catenin levels via a phospholipase C/protein kinase C/GSK-3
pathway.
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