Regulation of Btk Function by a Major Autophosphorylation Site Within the SH3 Domain

Park, Hyun Sun; Wahl, Matthew I.; Afar, Daniel; Turck, Christoph W.; Rawlings, David J.; Tam, Christina; Scharenberg, Andrew M.; Kinét, Jean-Pierre; Witte, Owen N.

doi:10.1016/s1074-7613(00)80417-3

Cited by 292 publications

(265 citation statements)

References 56 publications

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“…The E41K Btk mutant displays increased, PI3K-independent membrane localization [26] and therefore we expected that even low-level expression of E41K-Btk would affect B-cell development. First, expression of constitutive activated Btk resulted in a copy-number dependent deletion of peripheral B cells beyond the transitional B-cell stage, although absolute numbers of B-1 cells in the spleen were increased.…”

Section: Discussionmentioning

confidence: 99%

“…Whereas in humans Btk mutations cause a severe arrest of B-cell development at the pre-B-cell stage leading to X-linked agammaglobulinemia, in the mouse there is only a mild pre-B-cell defect, differentiation of transitional into mature peripheral B cells is impaired and B-1 cells are lacking [23][24][25]. The pleckstrin homology domain mutant E41K-Btk displayed robust transformation potential in a soft-agar assay, increased membrane localization and phosphorylation in quiescent cells, independent of PI3K activity [26]. This capacity was augmented by mutation of the main autophosphorylation site in the SH3 domain, Y223F, although the role of Y223 phosphorylation for Btk function in vivo remains unclear [22,27].…”

Section: Introductionmentioning

confidence: 99%

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Constitutive activation of Bruton's tyrosine kinase induces the formation of autoreactive IgM plasma cells

et al. 2010

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B-cell receptor (BCR)-mediated signals provide the basis for B-cell differentiation in the BM and subsequently into follicular, marginal zone, or B-1 B-cell subsets. We have previously shown that B-cell-specific expression of the constitutive active E41K mutant of the BCR-associated molecule Bruton's tyrosine kinase (Btk) leads to an almost complete deletion of immature B cells in the BM. Here, we report that low-level expression of the E41K or E41K-Y223F Btk mutants was associated with reduced follicular B-cell numbers and significantly increased proportions of B-1 cells in the spleen. Crosses with 3-83md and VH81X BCR Tg mice showed that constitutive active Btk expression did not change follicular, marginal zone, or B-1 B-cell fate choice, but resulted in selective expansion or survival of B-1 cells. Residual B cells were hyperresponsive and manifested sustained Ca 21 mobilization. They were spontaneously driven into germinal center-independent plasma cell differentiation, as evidenced by increased numbers of IgM 1 plasma cells in spleen and BM and significantly elevated serum IgM. Because anti-nucleosome autoantibodies and glomerular IgM deposition were present, we conclude that constitutive Btk activation causes defective B-cell tolerance, emphasizing that Btk signals are essential for appropriate regulation of B-cell activation. IntroductionSignals transmitted by the B-cell receptor (BCR) control the antigen response of B cells and are also essential regulators of survival, tolerance and differentiation (reviewed in [1,2]). Inducible and stage-specific targeting experiments demonstrated that mature B cells undergo apoptosis upon in vivo BCR ablation or mutation of one of its signaling units, Ig-a, and consequently disappear from the circulation [3,4]. A critical survival signal is provided by PI3K [5], but how this signaling is initiated in resting mature B cells is not fully understood. BCR signal strength is also a key factor in deciding between the three functionally distinct mature B-cell compartments of follicular, marginal zone (MZ) and B-1 B cells. Increases in BCR signaling strength, induced by low-dose selfantigen, direct maturation of naive immature B cells from the follicular into the B-1 or MZ B-cell fate [6,7]. Eur. J. Immunol. 2010. 40: 2643-2654 DOI 10.1002 Leukocyte signaling 2643In mature B cells, BCR engagement induces phosphorylation of Ig-a and Ig-b and the formation of a lipid raft-associated calcium-signaling module. In this complex Syk phosphorylates the adapter molecule Slp65, thereby providing docking sites for Bruton's tyrosine kinase (Btk) and phospholipase Cg2 (Plcg2). Activation of Plcg2 by Btk results in the generation of the Ca 21 -releasing factors inositol-1,4,5-trisphosphate and diacylglycerol (reviewed in [8,9]). During these events various co-receptors modulate BCR signaling either positively or negatively [10].Deficiencies of BCR signaling molecules, such as Btk, Slp65 or Plcg2 or the excitatory co-receptor CD19 result in a hyporesponsive phenotype, mainly characterize...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Constitutive activation of Bruton's tyrosine kinase induces the formation of autoreactive IgM plasma cells

et al. 2010

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“…The major autophosphorylation site of Btk (Y233) is located in its SH3 domain . It is interesting that phosphorylation of Y233 alters the binding speci®city for its protein partners (Morrogh et al, 1999;Park et al, 1996). The Btk SH3 domain binds to c-Cbl constitutively regardless of the phosphorylation status of Y233.…”

Section: Interaction With Syk/zap-70mentioning

confidence: 99%

Signaling network of the Btk family kinases

Qiu¹,

2000

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The Btk family kinases represent new members of nonreceptor tyrosine kinases, which include Btk/Atk, Itk/ Emt/Tsk, Bmx/Etk, and Tec. They are characterized by having four structural modules: PH (pleckstrin homology) domain, SH3 (Src homology 3) domain, SH2 (Src homology 2) domain and kinase (Src homology 1) domain. Increasing evidence suggests that, like Srcfamily kinases, Btk family kinases play central but diverse modulatory roles in various cellular processes. They participate in signal transduction in response to virtually all types of extracellular stimuli which are transmitted by growth factor receptors, cytokine receptors, G-protein coupled receptors, antigen-receptors and integrins. They are regulated by many non-receptor tyrosine kinases such as Src, Jak, Syk and FAK family kinases. In turn, they regulate many of major signaling pathways including those of PI3K, PLCg and PKC. Both genetic and biochemical approaches have been used to dissect the signaling pathways and elucidate their roles in growth, di erentiation and apoptosis. An emerging new role of this family of kinases is cytoskeletal reorganization and cell motility. The physiological importance of these kinases was amply demonstrated by their link to the development of immunode®ciency diseases, due to germ-line mutations. The present article attempts to review the structure and functions of Btk family kinases by summarizing our current knowledge on the interacting partners associated with the di erent modules of the kinases and the diverse signaling pathways in which they are involved. Oncogene (2000) 19, 5651 ± 5661.

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“…1B) (22,23). Btk then autophosphorylates at Y223 in the SH3 domain (23,67) and becomes fully active. CD19 feeds into this pathway by amplifying BCR-induced activation of Src family kinases (68).…”

Section: Resultsmentioning

confidence: 99%

A sensitized genetic system for the analysis of murine B lymphocyte signal transduction pathways dependent on Bruton's tyrosine kinase

Satterthwaite

Willis

Kanchanastit

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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Modifier screens have been powerful genetic tools to define signaling pathways in lower organisms. The identification of modifier loci in mice has begun to allow a similar dissection of mammalian signaling pathways. Transgenic mice (Btk lo ) expressing 25% of endogenous levels of Bruton's tyrosine kinase (Btk) have B cell functional responses between those of wild-type and Btk ؊/؊ mice. We asked whether reduced dosage or complete deficiency of genes previously implicated as Btk regulators would modify the Btk lo phenotype. We used two independent assays of Btk-dependent B cell function. Proliferative response to B cell antigen receptor cross-linking in vitro was chosen as an example of a relatively simple, well-defined signaling system. In vivo response to type II T-independent antigens (TI-II) measures complex interactions among multiple cell types over time and may identify additional Btk pathways. All modifiers identified differentially affected these two assays, indicating that Btk mediates these processes via distinct mechanisms. Loss of Lyn, PTEN (phosphatase and tensin homolog), or SH2-containing inositol phosphatase suppressed the Btk lo phenotype in vitro but not in vivo, whereas CD19 and the p85␣ form of phosphoinositide 3-kinase behaved as Btk lo enhancers in vivo but not in vitro. Effects of Lyn, PTEN, or p85␣ haploinsufficiency were observed. Haploinsufficiency or complete deficiency of protein kinase C ␤, Fyn, CD22, G␣q, or G␣11 had no detectable effect on the function of Btk lo B cells. A transgenic system creating a reduction in dosage of Btk can therefore be used to identify modifier loci that affect B cell responses and quantitatively rank their contribution to Btk-mediated processes.In vivo genetic analysis is a powerful approach to define the relative contribution of signaling interactions to physiological processes. Small genomes, ease of mutagenesis, and rapid generation time have made Drosophila melanogaster, Caenorhabditis elegans, and Saccharomyces cerevisiae the major models for genetic dissection of eukaryotic signaling pathways. Although there are some examples of large-scale genetic screens in mice (1-3), time, space, and financial resources generally limit mammalian genetic studies to targeted mutations in known genes or the characterization of naturally occurring mutations.In a commonly used type of genetic screen, organisms carrying a defined mutation affecting the process of interest are further mutagenized and screened for second site mutations, or modifiers, that enhance (increase) or suppress (reduce) the severity of the parental phenotype (4, 5). The initial mutation often renders the system responsive to subtle changes in modifiers that would not be penetrant on an otherwise wild-type background. This sensitivity often permits a dominant screen, decreasing the time and resources required to identify new mutations.Complete deficiency of many signaling molecules results in loss of the cell type of interest or pleiotropic or lethal phenotypes, making the effects of additional m...

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Regulation of Btk Function by a Major Autophosphorylation Site Within the SH3 Domain

Cited by 292 publications

References 56 publications

Constitutive activation of Bruton's tyrosine kinase induces the formation of autoreactive IgM plasma cells

Constitutive activation of Bruton's tyrosine kinase induces the formation of autoreactive IgM plasma cells

Signaling network of the Btk family kinases

A sensitized genetic system for the analysis of murine B lymphocyte signal transduction pathways dependent on Bruton's tyrosine kinase

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