The B cell antigen receptor regulates the transcriptional activator beta-catenin via protein kinase C-mediated inhibition of glycogen synthase kinase-3.
Beta-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 beta-catenin, targeting beta-catenin for rapid degradation. Receptor-induced inhibition of GSK-3 allows beta-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 beta-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 beta-catenin via a PI3K/Akt/GSK-3 pathway. We now show that BCR ligation causes an increase in the level of beta-catenin in the nuclear fraction of B cells as well as an increase in beta-catenin-dependent transcription. Direct inhibition of GSK-3 by LiCl also increased beta-catenin levels in B cells. This suggests that GSK-3 keeps beta-catenin levels low in unstimulated B cells and that BCR-induced inhibition of GSK-3 allows the accumulation of beta-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 beta-catenin, was not mediated by Akt but by the phospholipase C-dependent activation of protein kinase C. Thus, the BCR regulates beta-catenin levels via a phospholipase C/protein kinase C/GSK-3 pathway.
Christian
Sherri L
SL
Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada.
Sims
Peter V
PV
Gold
Michael R
MR
D000818:Animals; D001402:B-Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000502:physiology; D003546:Cysteine Endopeptidases / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D006801:Humans; D007527:Isoenzymes / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009097:Multienzyme Complexes / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000502:physiology; D051966:Phospholipase C gamma; D046988:Proteasome Endopeptidase Complex; D011493:Protein Kinase C / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D011947:Receptors, Antigen, B-Cell / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology; D015534:Trans-Activators / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D014158:Transcription, Genetic / Q000276:immunology; D014407:Tumor Cells, Cultured; D010738:Type C Phospholipases / Q000502:physiology; D051176:beta Catenin
D017871:Calcium-Calmodulin-Dependent Protein Kinases; D003546:Cysteine Endopeptidases; D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D007527:Isoenzymes; D009097:Multienzyme Complexes; D019869:Phosphatidylinositol 3-Kinases; D051966:Phospholipase C gamma; D046988:Proteasome Endopeptidase Complex; D011493:Protein Kinase C; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011947:Receptors, Antigen, B-Cell; D015534:Trans-Activators; D010738:Type C Phospholipases; D051176:beta Catenin; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; C494918:AKT1 protein, human