Inhibition of Anti-IgM-induced Translocation of Protein Kinase C βI Inhibits ERK2 Activation and Increases Apoptosis

Cao, Ming; Shinjo, Fukiko; Heinrichs, Svinda; Soh, Jae-Won; Jongstra‐Bilen, Jenny; Jongstra, Jan

doi:10.1074/jbc.m103883200

Cited by 21 publications

(21 citation statements)

References 44 publications

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“…BCR engagement leads to the activation of PKC-␣, -␤, -␦, -⑀, and - (72)(73)(74)(75)(76). Because each PKC isoform is likely to have a unique set of substrates, we are currently attempting to identify which PKC isoform is responsible for the BCR-induced phosphorylation and inhibition of GSK-3.…”

Section: Discussionmentioning

confidence: 99%

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

Christian

Sims

Gold

2002

The Journal of Immunology

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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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Section: Discussionmentioning

confidence: 99%

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

Christian

Sims

Gold

2002

The Journal of Immunology

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“…LSP1 could be phosphorylated by mitogen-activated protein kinase activated protein kinase 2 of the p38 pathway (37) which has been implicated in fMLPinduced chemotaxis and adhesion of neutrophils (63). The regulatory function of LSP1 in adhesion may also involve its recently demonstrated role in modulating extracellular signal-regulated kinase activity (64), because fMLP-induced extracellular signal-regulated kinase activation contributes to Mac-1-mediated adhesion of neutrophils (65)(66)(67).…”

Section: Discussionmentioning

confidence: 99%

Modulation of Mac-1 (CD11b/CD18)-Mediated Adhesion by the Leukocyte-Specific Protein 1 Is Key to Its Role in Neutrophil Polarization and Chemotaxis

Wang

Hayashi

Harrison

et al. 2002

The Journal of Immunology

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Leukocyte-specific protein 1 (LSP1) is an intracellular filamentous-actin binding protein which modulates cell motility. The cellular process in which LSP1 functions to regulate motility is not yet identified. In this study, we show that LSP1 negatively regulates fMLP-induced polarization and chemotaxis of neutrophils through its function on adhesion via specific integrins. Using LSP1-deficient (Lsp1−/−) mice, we show increased neutrophil migration into mouse knee joints during zymosan-induced acute inflammation, an inflammatory model in which the number of resident synoviocytes are not affected by LSP1-deficiency. In vitro chemotaxis experiments performed by time-lapse videomicroscopy showed that purified Lsp1−/− bone-marrow neutrophils exhibit an increased migration rate toward a gradient of fMLP as compared with wild-type neutrophils. This difference was observed when cells migrated on fibrinogen, but not fibronectin, suggesting a role for LSP1 in modulating neutrophil adhesion by specific integrins. LSP1 is also a negative regulator of fMLP-induced adhesion to fibrinogen or ICAM-1, but not to ICAM-2, VCAM-1, or fibronectin. These results suggest that LSP1 regulates the function of Mac-1 (CD11b/CD18), which binds only to fibrinogen and ICAM-1 among the substrates we tested. fMLP-induced filamentous actin polarization is also increased in the absence of LSP1 when cells were layered on fibrinogen, but not on fibronectin. Our findings suggest that the increased neutrophil recruitment in Lsp1−/− mice during acute inflammation derives from the negative regulatory role of LSP1 on neutrophil adhesion, polarization, and migration via specific integrins, such as Mac-1, which mediate neutrophil responses to chemotactic stimuli.

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“…Previous studies have suggested that PKC is required for the BCRinduced activation of ERK, a MAP kinase (Sakata et al, 1999;Cao et al, 2001;Teixeira et al, 2003;Nishida et al, 2003;Aiba et al, 2004). We examined the roles played by TRPC3 channels in BCRinduced ERK activation via PKC in DT40 B cells (Fig.…”

Section: Sustained Pm Translocation Of Pkc Is Important For Bcrinducmentioning

confidence: 99%

Ca2+ influx and protein scaffolding via TRPC3 sustain PKCβ and ERK activation in B cells

Numaga

Nishida

Kiyonaka

et al. 2010

Journal of Cell Science

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Summary Ca2+ signaling mediated by phospholipase C that produces inositol 1,4,5-trisphosphate [Ins(1,4,5)P 3 ] and diacylglycerol (DAG) controls lymphocyte activation. In contrast to store-operated Ca 2+ entry activated by Ins(1,4,5)P 3 -induced Ca 2+ release from endoplasmic reticulum, the importance of DAG-activated Ca 2+ entry remains elusive. Here, we describe the physiological role of DAG-activated Ca 2+ entry channels in B-cell receptor (BCR) signaling. In avian DT40 B cells, deficiency of transient receptor potential TRPC3 at the plasma membrane (PM) impaired DAG-activated cation currents and, upon BCR stimulation, the sustained translocation to the PM of protein kinase C (PKC) that activated extracellular signal-regulated kinase (ERK). Notably, TRPC3 showed direct association with PKC that maintained localization of PKC at the PM. Thus, TRPC3 functions as both a Ca 2+ -permeable channel and a protein scaffold at the PM for downstream PKC activation in B cells.

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Inhibition of Anti-IgM-induced Translocation of Protein Kinase C βI Inhibits ERK2 Activation and Increases Apoptosis

Cited by 21 publications

References 44 publications

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

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

Modulation of Mac-1 (CD11b/CD18)-Mediated Adhesion by the Leukocyte-Specific Protein 1 Is Key to Its Role in Neutrophil Polarization and Chemotaxis

Ca2+ influx and protein scaffolding via TRPC3 sustain PKCβ and ERK activation in B cells

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