The B Cell Antigen Receptor Regulates the Transcriptional Activator β-Catenin Via Protein Kinase C-Mediated Inhibition of Glycogen Synthase Kinase-3

Christian, Sherri L.; Sims, Peter V.; Gold, Michael R.

doi:10.4049/jimmunol.169.2.758

Cited by 58 publications

(46 citation statements)

References 77 publications

(50 reference statements)

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“…Interestingly, mutations of b-catenin exon 3 were not detected in any of the analyzed samples, indicating that while deregulation of b-catenin expression is frequent, mutations in its gene are rare in cutaneous lymphomas. 23,24 When b-catenin is absent, the transcription factor TCF-1/LEF-1 acts in the nucleus as a transcriptional repressor interacting with the corepressors (TLE/Groucho and/or CtBP) of the target gene promoters. 25 Actually, it has been previously reported that b-catenin nuclear retention is mediated by the LEF-1/TCF-1 transcription factors.…”

Section: Discussionmentioning

confidence: 99%

Frequent β-catenin overexpression without exon 3 mutation in cutaneous lymphomas

et al. 2004

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b-Catenin is a ubiquitously cytoplasmic protein that has a critical role in embryonic development and mature tissue homeostasis through its effects on E-cadherin-mediated cell adhesion and Wnt-dependent signal transduction. Mutations that alter specific b-catenin residues important for GSK-3b phosphorylation, or increase the half-life of the protein, were identified in human cancer. However, the role of the Wnt pathway in B-and T-cell oncogenesis has not been extensively investigated. To assess the role of b-catenin defects in primary cutaneous lymphomas, we examined the expression pattern and the genetic alteration of b-catenin on 79 samples from 74 patients with primary cutaneous lymphomas from B-and T-cell origin. Immunohistochemical analysis revealed b-catenin deregulation in five primary cutaneous B-cell lymphomas (21%) and in 21 primary cutaneous T-cell lymphomas (42%) without nuclear accumulation suggesting that activation and accumulation of b-catenin may play an important role in the development of skin lymphomas. Mutation analysis of b-catenin exon 3, which included the responsible element for Wnt signaling, was therefore done in 19 samples. However, genetic alterations of b-catenin exon 3 were not detected in any of these cases suggesting that other regulatory mechanisms may be relevant in activating b-catenin signaling in cutaneous lymphomas.

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Section: Discussionmentioning

confidence: 99%

Frequent β-catenin overexpression without exon 3 mutation in cutaneous lymphomas

et al. 2004

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“…However, upon BCR stimulation GSK-3 is phosphorylated and GSK-3 mediated phosphorylation of ␤-catenin is inhibited. The subsequent accumulation of ␤-catenin leads to its nuclear translocation and transcriptional activity (47). Interestingly, mutations of ␤-catenin are frequently associated with NK and T cell lymphoproliferative disorders (49,50) suggesting that ␤-catenin defects may also contribute to a loss of lymphocyte homeostasis.…”

Section: Discussionmentioning

confidence: 99%

“…Both GSK-3␣ and GSK-3␤ are expressed ubiquitously in mammalian tissues and have been shown to regulate a wide selection of cell functions including cell growth (44), cell polarity (45), and cell fate (46). In resting B lymphocytes unstimulated through their BCR, GSK-3 phosphorylates the transcriptional regulator ␤-catenin thus targeting it for degradation (47,48). However, upon BCR stimulation GSK-3 is phosphorylated and GSK-3 mediated phosphorylation of ␤-catenin is inhibited.…”

Section: Discussionmentioning

confidence: 99%

Role for Glycogen Synthase Kinase-3 in NK Cell Cytotoxicity and X-Linked Lymphoproliferative Disease

Aoukaty

Tan

2005

The Journal of Immunology

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NK cells from individuals with X-linked lymphoproliferative (XLP) disease exhibit functional defects when stimulated through the NK receptor, 2B4 (CD244). These defects are likely a consequence of aberrant intracellular signaling initiated by mutations of the adaptor molecule SLAM-associated protein. In this report, we show that NK cells from individuals with XLP but not healthy individuals fail to phosphorylate and thereby inactivate glycogen synthase kinase-3 (GSK-3) following 2B4 stimulation. Lack of GSK-3 phosphorylation prevented the accumulation of the transcriptional coactivator β-catenin in the cytoplasm and its subsequent translocation to the nucleus. Potential signaling pathways leading from 2B4 stimulation to GSK-3 phosphorylation were also investigated. Ligation of 2B4 resulted in the phosphorylation of the guanine nucleotide exchange factor, Vav-1, and subsequent activation of the GTP-binding protein Rac-1 (but not Ras) and the serine-threonine kinase Raf-1 in healthy but not XLP-derived NK cells. In addition, the activity of MEK-2 (but not MEK-1) was up-regulated, and Erk1/2 was phosphorylated in normal NK cells but not those from an individual with XLP suggesting that these proteins relay SLAM-associated protein-dependent signals from 2B4. Finally, inactivation of GSK-3 using a specific inhibitor of GSK-3β increased the cytotoxicity and cytokine secretion of both healthy and XLP NK cells. These data indicate that the signaling of 2B4 in NK cells is mediated by GSK-3 and β-catenin, possibly through a signal transduction pathway that involves Vav-1, Rac-1, Raf-1, MEK-2, and Erk1/2 and that this pathway is aberrant in individuals with XLP.

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“…16 However, inhibition of GSK-3 does not inhibit the apoptotic effect of PI3K inhibitors. 7 As GSK-3 is inhibited by PKC, 37 perhaps the over-expression of active PKC-βII 38 blocks this pathway in CLL cells. We found that B cells from CLL samples were more sensitive to Akt inhibitors than T cells from CLL samples, and B or T cells from healthy donors.…”

Section: Discussionmentioning

confidence: 99%

Akt inhibitors induce apoptosis in chronic lymphocytic leukemia cells

Frías

Iglesias-Serret²,

Cosialls³

et al. 2009

Haematologica

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The online version of this article contains a supplementary appendix. BackgroundThe phosphatidylinositol-3-kinase/Akt pathway has been described to be critical in the survival of chronic lymphocytic leukemia cells. In this study we analyzed the effect of two selective chemical inhibitors of Akt (Akti-1/2 and A-443654) on the survival of chronic lymphocytic leukemia cells. Design and MethodsUsing cytometry we studied the cytotoxic effects of Akt inhibitors on peripheral B and T lymphocytes from patients with chronic lymphocytic leukemia and from healthy donors. We studied the changes induced by Akti-1/2 and A-443654 at the mRNA level by performing reverse transcriptase multiplex ligation-dependent probe amplification. We also studied the changes induced by both Akt inhibitors in some BCL-2 protein family members on chronic lymphocytic leukemia cells by western blotting. Moreover, we analyzed the cytotoxic effect of Akt inhibitors in patients' cells with deleted/mutated TP53. ResultsBoth inhibitors induced apoptosis in chronic lymphocytic leukemia cells in a dose-dependent manner. Moreover, B cells from patients with chronic lymphocytic leukemia were more sensitive to Akt inhibitors than T cells from leukemic patients, and B or T cells from healthy donors. Survival factors for chronic lymphocytic leukemia cells, such as interleukin-4 and stromal cell-derived factor-1α, were not able to block the apoptosis induced by either Akt inhibitor. Akti-1/2 did not induce any change in the mRNA expression profile of genes involved in apoptosis, while A-443654 induced some changes, including an increase in NOXA and PUMA mRNA levels, suggesting the existence of additional targets for A-443654. Both inhibitors induced an increase in PUMA and NOXA protein levels, and a decrease in MCL-1 protein level. Moreover, Akti-1/2 and A-443654 induced apoptosis irrespective of TP53 status. ConclusionsThese results demonstrate that Akt inhibitors induce apoptosis of chronic lymphocytic leukemia cells and might be a new therapeutic option for the treatment of chronic lymphocytic leukemia.

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The B Cell Antigen Receptor Regulates the Transcriptional Activator β-Catenin Via Protein Kinase C-Mediated Inhibition of Glycogen Synthase Kinase-3

Cited by 58 publications

References 77 publications

Frequent β-catenin overexpression without exon 3 mutation in cutaneous lymphomas

Frequent β-catenin overexpression without exon 3 mutation in cutaneous lymphomas

Role for Glycogen Synthase Kinase-3 in NK Cell Cytotoxicity and X-Linked Lymphoproliferative Disease

Akt inhibitors induce apoptosis in chronic lymphocytic leukemia cells

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