Essential role of Src-family protein tyrosine kinases in NF-κB activation during B cell development

Saijo, Kaoru; Schmedt, Christian; Su, I-hsin; Karasuyama, Hajime; Lowell, Clifford A.; Reth, Michael; Adachi, Takahiro; Patke, Alina; Santana, Angêla Patrícia; Tarakhovsky, Alexander

doi:10.1038/ni893

Cited by 275 publications

(232 citation statements)

References 49 publications

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“…Indeed, Lyn/Fyn/ Blk triple-deficient mice displayed profound block in B cell development that was not observed in Lyn 2/2 mice. However, the triple-deficient mice did not exhibit any defect in anti-Igb Abinduced BCR-like proximal signaling at the pro-B stage (33). These data suggest that SFKs are not essential for the initiation of BCR signaling and support the hypothesis of SFK-independent phosphorylation of Iga and Igb.…”

supporting

confidence: 52%

Nonredundant Roles of Src-Family Kinases and Syk in the Initiation of B-Cell Antigen Receptor Signaling

Štěpánek

Dráber

Drobek

et al. 2013

The Journal of Immunology

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When a BCR on a mature B cell is engaged by its ligand, the cell becomes activated, and the Ab-mediated immune response can be triggered. The initiation of BCR signaling is orchestrated by kinases of the Src and Syk families. However, the proximal BCR-induced phosphorylation remains incompletely understood. According to a model of sequential activation of kinases, Syk acts downstream of Src family kinases (SFKs). In addition, signaling independent of SFKs and initiated by Syk has been proposed. Both hypotheses lack sufficient evidence from relevant B cell models, mainly because of the redundancy of Src family members and the importance of BCR signaling for B cell development. We addressed this issue by analyzing controlled BCR triggering ex vivo on primary murine B cells and on murine and chicken B cell lines. Chemical and Csk-based genetic inhibitor treatments revealed that SFKs are required for signal initiation and Syk activation. In addition, ligand and anti-BCR Ab–induced signaling differ in their sensitivity to the inhibition of SFKs.

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supporting

confidence: 52%

Nonredundant Roles of Src-Family Kinases and Syk in the Initiation of B-Cell Antigen Receptor Signaling

Štěpánek

Dráber

Drobek

et al. 2013

The Journal of Immunology

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“…Consistent with this hypothesis, the atypical DAG/Ca 2ϩ -insensitive PKC in pre-B cells mediates NF-B activity through Src family protein tyrosine kinases including Fyn, Lyn, and Blk independently of Btk, PLC-␥2, Vav, or CD19 (73). Moreover, T1 B cell death may occur by an active process that involves production of ceramide, which triggers a proapoptotic program as observed in the immature B cell line WEHI 231 (74).…”

Section: Discussionmentioning

confidence: 72%

Transitional B Cell Fate Is Associated with Developmental Stage-Specific Regulation of Diacylglycerol and Calcium Signaling upon B Cell Receptor Engagement

Hoek¹,

Antony²,

Lowe³

et al. 2006

The Journal of Immunology

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Functional peripheral mature follicular B (FoB) lymphocytes are thought to develop from immature transitional cells in a BCR-dependent manner. We have previously shown that BCR cross-linking in vitro results in death of early transitional (T1) B cells, whereas late transitional (T2) B cells survive and display phenotypic characteristics of mature FoB cells. We now demonstrate that diacylglycerol (DAG), a lipid second messenger implicated in cell survival and differentiation, is produced preferentially in T2 compared with T1 B cells upon BCR cross-linking. Consistently, inositol 1,4,5-triphosphate is also produced preferentially in T2 compared with T1 B cells. Unexpectedly, the initial calcium peak appears similar in both T1 and T2 B cells, whereas sustained calcium levels are higher in T1 B cells. Pretreatment with 2-aminoethoxydiphenylborate, an inhibitor of inositol 1,4,5-triphosphate receptor-mediated calcium release, and verapamil, an inhibitor of L-type calcium channels, preferentially affects T1 B cells, suggesting that distinct mechanisms regulate calcium mobilization in each of the two transitional B cell subsets. Finally, BCR-mediated DAG production is dependent upon Bruton’s tyrosine kinase and phospholipase C-γ2, enzymes required for the development of FoB from T2 B cells. These results suggest that calcium signaling in the absence of DAG-mediated signals may lead to T1 B cell tolerance, whereas the combined action of DAG and calcium signaling is necessary for survival and differentiation of T2 into mature FoB lymphocytes.

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“…Syk is recruited via its SH2 domains to the BCR-associated immunoreceptor tyrosine-based activation motifs (ITAM) of CD79a and CD79b (Ig § and Ig g ) [9]. Recent results suggest that Syk can be activated following receptor cross-linking in a manner that is largely independent of Src-family kinases [10]. Syk is then thought to phosphorylate a number of substrates, such as the adapter protein SLP-65/BLNK and phospholipase C + 2 (PLC + 2) [11,12].…”

Section: Introductionmentioning

confidence: 99%

The tyrosine kinase Syk is required for light chain isotype exclusion but dispensable for the negative selection of B cells

2004

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In this study we set out to test whether Syk was required for negative selection of immature B cells. B cells expressing a B cell antigen receptor (BCR) transgene (3-83, anti-H-2K k ) underwent negative selection independently of Syk in both fetal liver organ culture and radiation chimera models. Furthermore, Syk-independent negative selection was not reversed by transgenic overexpression of Bcl-2. Receptor editing was not apparent in Syk-deficient B cells, presumably as a consequence of the failure of mature edited B cells to develop in the absence of Syk. Interestingly, light chain isotype exclusion by the BCR transgene failed in the absence of Syk. We observed a dramatic reduction in the overall BCR-mediated tyrosine phosphorylation of cellular proteins in Syk-deficient immature B cells. However, the tyrosine phosphorylation of a number of substrates including phospholipase C + 2, although reduced, was not completely abrogated. BCR ligation triggered an increase in calcium flux in the absence of Syk. Thus signaling events that mediate negative selection can still occur in the absence of Syk. This may be due to redundancy with zeta-associated protein 70 (ZAP-70), which we demonstrate to be expressed in immature B cells.

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Essential role of Src-family protein tyrosine kinases in NF-κB activation during B cell development

Cited by 275 publications

References 49 publications

Nonredundant Roles of Src-Family Kinases and Syk in the Initiation of B-Cell Antigen Receptor Signaling

Nonredundant Roles of Src-Family Kinases and Syk in the Initiation of B-Cell Antigen Receptor Signaling

Transitional B Cell Fate Is Associated with Developmental Stage-Specific Regulation of Diacylglycerol and Calcium Signaling upon B Cell Receptor Engagement

The tyrosine kinase Syk is required for light chain isotype exclusion but dispensable for the negative selection of B cells

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