Syk tyrosine kinase required for mouse viability and B-cell development

Cheng, Alec M.; Rowley, Bruce; Pao, William; Hayday, Adrian; Bolen, Joseph B.; Pawson, Tony

doi:10.1038/378303a0

Cited by 580 publications

(440 citation statements)

References 29 publications

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“…Further evidence for excluding Syk as the cause for 129/J nonresponsiveness is the general health of 129/J mice. Syk Ϫ/Ϫ mice exhibit severe hemorrhaging and die perinatally (48,49).…”

Section: Discussionmentioning

confidence: 99%

Aberrant DAP12 Signaling in the 129 Strain of Mice: Implications for the Analysis of Gene-Targeted Mice

McVicar

Winkler‐Pickett

Taylor

et al. 2002

The Journal of Immunology

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NK cells are implicated in antiviral responses, bone marrow transplantation and tumor immunosurveillance. Their function is controlled, in part, through the Ly49 family of class I binding receptors. Inhibitory Ly49s suppress signaling, while activating Ly49s (i.e., Ly49D) activate NK cells via the DAP12 signaling chain. Activating Ly49 signaling has been studied primarily in C57BL/6 mice, however, 129 substrains are commonly used in gene-targeting experiments. In this study, we show that in contrast to C57BL/6 NK cells, cross-linking of DAP12-coupled receptors in 129/J mice induces phosphorylation of DAP12 but not calcium mobilization or cytokine production. Consistent with poor-activating Ly49 function, 129/J mice reject bone marrow less efficiently than C57BL/6 mice. Sequence analysis of receptors and DAP12 suggests no structural basis for inactivity, and both the 129/J and C57BL/6 receptors demonstrate normal function in a reconstituted receptor system. Most importantly, reconstitution of Ly49D in 129/J NK cells demonstrated that the signaling deficit is within the NK cells themselves. These unexpected findings bring into question any NK analysis of 129/J, 129Sv, or gene-targeted mice derived from these strains before complete backcrossing, and provide a possible explanation for the differences observed in the immune response of 129 mice in a variety of models.

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“…Further evidence for excluding Syk as the cause for 129/J nonresponsiveness is the general health of 129/J mice. Syk Ϫ/Ϫ mice exhibit severe hemorrhaging and die perinatally (48,49).…”

Section: Discussionmentioning

confidence: 99%

Aberrant DAP12 Signaling in the 129 Strain of Mice: Implications for the Analysis of Gene-Targeted Mice

McVicar

Winkler‐Pickett

Taylor

et al. 2002

The Journal of Immunology

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“…This latter transition, sometimes termed B cell positive selection, is associated with migration of the cells from the bone marrow to the spleen, lymph nodes and other organs of the peripheral immune system. In the absence of Syk, murine B cell development is partially arrested at the pro-B to pre-B cell transition and completely arrested at the immature B cell stage, such that no mature B cells are produced [12][13][14]. This suggests that Syk transduces critical developmental signals from both the pre-BCR and the BCR, presumably by binding to phospho-ITAM on the associated Iga and Igb subunits.…”

Section: Introductionmentioning

confidence: 99%

Redundant role for Zap70 in B cell development and activation

Fallah-Arani

Schweighoffer²,

Vanes³

et al. 2008

Eur J Immunol

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Expression of the Syk family tyrosine kinase Zap70 is strongly correlated with poor clinical outcome in chronic lymphocytic leukemia, the most common human leukemia characterized by B cell accumulation. The expression of Zap70 may reflect the specific cell of origin of the tumor or may contribute to pathology. Thus, the normal role of Zap70 in B cell physiology is of great interest. While initial studies reported that Zap70 expression in the mouse was limited to T and NK cells, more recent work has shown expression in early B cell progenitors and in splenic B cells, suggesting that the kinase may play a role in the development or activation of B cells. In this study, we show that Zap70 is expressed in all developing subsets of B cells as well as in recirculating B cells, marginal zone B cells and peritoneal B1 cells. Analysis of Zap70-deficient mice shows no unique role for Zap70 in either the development of B cells or in their in vitro and in vivo activation. However, we show that Zap70 can rescue the defective positive selection of immature B cells into the recirculating pool in Syk-deficient mice, demonstrating functional redundancy between these two kinases.

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“…Syk has been shown to play important roles in both the pre-BCR and BCR checkpoints [8,13,14]. Similarly ZAP-70 has been found to have an important role in T cell development in the thymus.…”

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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Syk tyrosine kinase required for mouse viability and B-cell development

Cited by 580 publications

References 29 publications

Aberrant DAP12 Signaling in the 129 Strain of Mice: Implications for the Analysis of Gene-Targeted Mice

Aberrant DAP12 Signaling in the 129 Strain of Mice: Implications for the Analysis of Gene-Targeted Mice

Redundant role for Zap70 in B cell development and activation

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

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