Redundant role for Zap70 in B cell development and activation

Fallah-Arani, Farnaz; Schweighoffer, Edina; Vanes, Lesley; Tybulewicz, Victor L. J.

doi:10.1002/eji.200738026

Cited by 23 publications

(17 citation statements)

References 43 publications

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“…Why would it be important for RAG DSBs to inhibit both proteins? In the absence of SYK, ZAP-70 can phosphorylate BLNK, activating downstream signaling cascades (Chen et al, 2005;Fallah-Arani et al, 2008). Thus, the isolated inhibition of SYK would not attenuate pre-BCR signaling.…”

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confidence: 99%

RAG-mediated DNA double-strand breaks activate a cell type–specific checkpoint to inhibit pre–B cell receptor signals

Bednarski¹,

Pandey²,

Schulte³

et al. 2016

J Cell Biol

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Section: Downloaded Frommentioning

confidence: 99%

RAG-mediated DNA double-strand breaks activate a cell type–specific checkpoint to inhibit pre–B cell receptor signals

Bednarski¹,

Pandey²,

Schulte³

et al. 2016

J Cell Biol

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“…However, this issue remained controversial because other investigators failed to detect ZAP70 expression in mature human B cells (11). In marked contrast to T cells, ZAP70 is considered to be dispensable for mature B cell function in the presence of the closely related tyrosine kinase Syk (12,13); thus far, only one study has described a specific role for ZAP70 in BCR-triggered pro-to pre-B cell development (14).…”

mentioning

confidence: 99%

TLR9-Activating DNA Up-Regulates ZAP70 via Sustained PKB Induction in IgM+ B Cells

Bekeredjian‐Ding

Doster

Schiller

et al. 2008

The Journal of Immunology

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In the past, ZAP70 was considered a T cell-specific kinase, and its aberrant expression in B-CLL cells was interpreted as a sign of malignant transformation and dedifferentiation. It was only recently that ZAP70 was detected in normal human B cells. In this study, we show that TLR9-activated B cells resemble B-cell chronic lymphocytic leukemia cells with regard to CD5, CD23, CD25, and heat shock protein 90 expression. Furthermore, stimulatory CpG and GpC DNA oligonucleotides target CD27+IgM+ and CD27−IgM+ B cells (but not IgM− B cells) and enhance ZAP70 expression predominantly in the IgM+CD27+ B cell subset. ZAP70 is induced via activation of TLR-7 or -9 in a MyD88-dependent manner, depends on protein kinase B (PKB)/mammalian target of rapamycin signaling and is rapamycin sensitive. Furthermore, ZAP70 expression levels correlate with induction of cyclin A2, prolonged B cell proliferation, and sustained induction of PKB. These events are not observed upon CD40 ligation. However, this deficit can be overcome by the expression of constitutively active PKB, given that CD40 ligation of PKB-transgenic B cells induces B cell proliferation and ZAP70 expression. These results highlight a major difference between CD40- and TLR-7/9-mediated B cell activation and suggest that ZAP70 expression levels in B cells give an estimate of the proliferative potential and the associated PKB availability.

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“…It is thus feasible that Zap70 employs either the TCR or BCR signaling components to promote the expansion and differentiation of pro/pre-B cells. Interestingly, the pre-B cell differentiation is also partially affected in Zap70 single KO mice, as these mice have a decrease in the absolute numbers of pre-B cells and immature B cells (54). In the DKO mice, the percentages and the total number of pre-B cells (fraction C) are higher than in Syk-deficient mice, indicating that Shp-1 acts as a gatekeeper downstream the pre-BCR (Fig.…”

Section: Discussionmentioning

confidence: 93%

The Role of the Syk/Shp-1 Kinase-Phosphatase Equilibrium in B Cell Development and Signaling

Alsadeq

Hobeika

Medgyesi

et al. 2014

The Journal of Immunology

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Signal transduction from the BCR is regulated by the equilibrium between kinases (e.g., spleen tyrosine kinase [Syk]) and phosphatases (e.g., Shp-1). Previous studies showed that Syk-deficient B cells have a developmental block at the pro/pre–B cell stage, whereas a B cell–specific Shp-1 deficiency promoted B-1a cell development and led to autoimmunity. We generated B cell–specific Shp-1 and Syk double-knockout (DKO) mice and compared them to the single-knockout mice deficient for either Syk or Shp-1. Unlike Syk-deficient mice, the DKO mice can generate mature B cells, albeit at >20-fold reduced B cell numbers. The DKO B-2 cells are all Syk-negative, whereas the peritoneal B1 cells of the DKO mice still express Syk, indicating that they require this kinase for their proper development. The DKO B-2 cells cannot be stimulated via the BCR, whereas they are efficiently activated via TLR or CD40. We also found that in DKO pre-B cells, the kinase Zap70 is associated with the pre-BCR, suggesting that Zap70 is important to promote B cell maturation in the absence of Syk and SHP-1. Together, our data show that a properly balanced kinase/phosphatase equilibrium is crucial for normal B cell development and function.

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Redundant role for Zap70 in B cell development and activation

Cited by 23 publications

References 43 publications

RAG-mediated DNA double-strand breaks activate a cell type–specific checkpoint to inhibit pre–B cell receptor signals

RAG-mediated DNA double-strand breaks activate a cell type–specific checkpoint to inhibit pre–B cell receptor signals

TLR9-Activating DNA Up-Regulates ZAP70 via Sustained PKB Induction in IgM+ B Cells

The Role of the Syk/Shp-1 Kinase-Phosphatase Equilibrium in B Cell Development and Signaling

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