β-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 β-catenin, targeting β-catenin for rapid degradation. Receptor-induced inhibition of GSK-3 allows β-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 β-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 β-catenin via a PI3K/Akt/GSK-3 pathway. We now show that BCR ligation causes an increase in the level of β-catenin in the nuclear fraction of B cells as well as an increase in β-catenin-dependent transcription. Direct inhibition of GSK-3 by LiCl also increased β-catenin levels in B cells. This suggests that GSK-3 keeps β-catenin levels low in unstimulated B cells and that BCR-induced inhibition of GSK-3 allows the accumulation of β-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 β-catenin, was not mediated by Akt but by the phospholipase C-dependent activation of protein kinase C. Thus, the BCR regulates β-catenin levels via a phospholipase C/protein kinase C/GSK-3 pathway.
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