Impaired Ca2+ mobilization by X-linked agammaglobulinaemia (XLA) B cells in response to ligation of the B cell receptor (BCR)

Genevier, Helen C.; Callard, Robin E.

doi:10.1046/j.1365-2249.1997.4581478.x

Cited by 20 publications

(14 citation statements)

References 41 publications

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“…41,42 Activated PLCγ2 produces diacylglycerol and inositol-1,4,5-trisphosphate (IP 3 ) in which diacylglycerol activates RAS/MAPK signaling, PKC/ NFκB signaling and RAP1 signaling, a hallmark for integrin activation, whereas IP 3 -mediated calcium release from the ER induces NFAT signaling and cytoskeleton rearrangements (see Figure 2a). [43][44][45][46][47][48][49] Furthermore, upon BCR engagement BTK recruits PIP5K, which is involved in production of PIP 2 , the substrate for BTK's upstream regulator PI3K as well as its downstream effector PLCγ2. 50 Another important BCR-controlled pathway is the PI3K/PKB-pathway, which controls mTOR-and FOXO signaling, however, this pathway is collateral and independent of BTK.…”

Section: The Physiological Role Of Btk Btk In B Cell Development Difmentioning

confidence: 99%

BTK inhibitors in chronic lymphocytic leukemia: a glimpse to the future

et al. 2014

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The treatment of chronic lymphocytic leukemia (CLL) with inhibitors targeting B cell receptor signaling and other survival mechanisms holds great promise. Especially the early clinical success of Ibrutinib, an irreversible inhibitor of Bruton's tyrosine kinase (BTK), has received widespread attention. In this review we will focus on the fundamental and clinical aspects of BTK inhibitors in CLL, with emphasis on Ibrutinib as the best studied of this class of drugs. Furthermore, we summarize recent laboratory as well as clinical findings relating to the first cases of Ibrutinib resistance. Finally, we address combination strategies with Ibrutinib, and attempt to extrapolate its current status to the near future in the clinic.

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Section: The Physiological Role Of Btk Btk In B Cell Development Difmentioning

confidence: 99%

BTK inhibitors in chronic lymphocytic leukemia: a glimpse to the future

et al. 2014

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“…Mutated forms of Btk result in immunodeficiency disease in both mice and humans (14,42,50). To assess how inactive forms of Btk affect Bright activity, we investigated whether the K430R (kinase-inactive) (26), xid (R28C), and pleckstrin and tec homology domain deletion (⌬PHTH) mutants of Btk affected V1 transcription levels (Fig.…”

Section: Btk Is Critically Required For Bright Activation Of An Ig Rementioning

confidence: 99%

Bruton's Tyrosine Kinase Regulates Immunoglobulin Promoter Activation in Association with the Transcription Factor Bright

Rajaiya

Hatfield

Nixon

et al. 2005

Molecular and Cellular Biology

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Bright (B-cell regulator of immunoglobulin heavy chain transcription) binding to immunoglobulin heavy chain loci after B-cell activation is associated with increased heavy chain transcription. Our earlier reports demonstrated that Bright coimmunoprecipitates with Bruton's tyrosine kinase (Btk) and that these proteins associate in a DNA-binding complex in primary B cells. B cells from immunodeficient mice with a mutation in Btk failed to produce stable Bright DNA-binding complexes. In order to determine if Btk is important for Bright function, a transcription activation assay was established and analyzed using real-time PCR technology. Cells lacking both Bright and Btk were transfected with Bright and/or Btk along with an immunoglobulin heavy chain reporter construct. Immunoglobulin gene transcription was enhanced when Bright and Btk were coexpressed. In contrast, neither Bright nor Btk alone led to activation of heavy chain transcription. Furthermore, Bright function required both Btk kinase activity and sequences within the pleckstrin homology domain of Btk. Bright was not appreciably phosphorylated by Btk; however, a third tyrosine-phosphorylated protein coprecipitated with Bright. Thus, the ability of Bright to enhance immunoglobulin transcription critically requires functional Btk.Bright (B-cell regulator of immunoglobulin [Ig] heavy chain transcription) is a B-cell-restricted transcription factor that binds specific A-T-rich sequences. The protein consists of an acidic amino-terminal domain, a DNA-binding A-T-rich interaction domain, a putative transactivation domain, and a protein interaction domain (18). The carboxyl-terminal domain of Bright currently has no assigned function. Bright was originally identified in an antigen-specific B-cell line, BCg3R-1d, as a mobility-shifted complex induced after stimulation with interleukin-5 (IL-5) and antigen (54). Binding sites for Bright were originally identified 5Ј of the basal promoter of the V1 S107 gene but also exist within the matrix association regions on either side of the intronic enhancer (53, 55). Bright binding to the 5Ј-flanking sequences of the V1 S107 variable heavy chain (V H ) promoter correlated with two-to sixfold increases in heavy chain mRNA levels in response to 55). Deletion of Bright binding sites flanking the V1 promoter resulted in lack of antigen-and IL-5-stimulated heavy chain transcription (55). Bright expression is tightly regulated in normal murine lymphocytes, occurring in pre-B cells and late stages of B-cell differentiation (58). However, Bright is not present in detectable amounts in immature B cells, suggesting that it may not play a role in maintenance of Ig expression (58). On the other hand, Bright activity is induced in B cells activated in response to lipopolysaccharide (LPS), CD40 ligand stimulation, and anti-CD38 (55, 59). These data suggest that Bright enhances Ig heavy chain transcription above basal levels following B-cell activation.Our earlier results revealed that Bruton's tyrosine kinase (Btk) associates with Brig...

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“…Tec family kinases are characterized by a C-terminal proline-rich region, Src homology 1, 2, and 3 domains, and an N-terminal pleckstrin homology (PH) and Tec homology domains. Btk is expressed in cells of hematopoietic origin including platelets and has been shown to mediate calcium influx in these cells (2)(3)(4)(5). Btk has been shown to play an important role in platelet activation by collagen because collagen stimulation induces tyrosine phosphorylation and activation of Btk (6), and in platelets lacking functional Btk, collagen-induced platelet aggregation and calcium influx are impaired significantly (7).…”

Section: From the Department Of Pharmacology School Of Medical Scienmentioning

confidence: 99%

Interaction of Bruton's Tyrosine Kinase and Protein Kinase Cθ in Platelets

Crosby

Poole

2002

Journal of Biological Chemistry

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The nonreceptor Bruton's tyrosine kinase (Btk) has been previously shown to associate physically and functionally with members of the protein kinase C (PKC) family of serine/threonine kinases in a variety of cell types. Here we show evidence for a novel interaction between Btk and PKC in platelets activated through the adhesion receptors GP Ib-V-IX and GP VI. Alboaggregin A, a snake venom component capable of activating both receptors in combination, leads to tyrosine phosphorylation of Btk downstream of Src family kinases. Inhibition of Btk by the selective antagonist LFM-A13 causes a reduction in calcium entry, although secretion of 5-hydroxytryptamine is potentiated. Btk is also phosphorylated on threonine residues in a PKC-dependent manner and associates with PKC upon platelet activation by either alboaggregin A or activation of GP Ib-V-IX alone by von Willebrand factor/ristocetin. PKC in turn becomes tyrosine-phosphorylated in a manner dependent upon Src family and Btk kinase activity. Inhibition of Btk activity by LFM-A13 leads to enhancement of PKC activity, whereas nonselective inhibition of PKC activity by bisindolylmaleimide I leads to reduction in Btk activity. We propose a reciprocal feedback interaction between Btk and PKC in platelets, in which PKC positively modulates activity of Btk, which in turn feeds back negatively upon PKC.Bruton's tyrosine kinase (Btk) 1 is a member of the Tec family of nonreceptor tyrosine kinases, which includes Itk, Tec, Txk, and Bmx and is of pathological significance when deficient or functionally mutated in the severe immunodeficiency syndrome X-linked agammaglobulinemia (1). Tec family kinases are characterized by a C-terminal proline-rich region, Src homology 1, 2, and 3 domains, and an N-terminal pleckstrin homology (PH) and Tec homology domains. Btk is expressed in cells of hematopoietic origin including platelets and has been shown to mediate calcium influx in these cells (2-5). Btk has been shown to play an important role in platelet activation by collagen because collagen stimulation induces tyrosine phosphorylation and activation of Btk (6), and in platelets lacking functional Btk, collagen-induced platelet aggregation and calcium influx are impaired significantly (7). The activity of Btk is controlled by several factors including phosphorylation. Btk has been shown to be phosphorylated at tyrosine 551 within the catalytic domain by associated Src family kinases, leading to autophosphorylation at tyrosine 223 within the Src homology 3 domain, which is necessary for full activation (8 -11). It has also been shown that for full activation, the PH domain of Btk must interact with the lipid product of phosphatidylinositol 3-kinase, phosphatidylinositol 3,4,5-trisphosphate (12). It has been hypothesized that the function of this interaction is to recruit Btk from the cytosol to the plasma membrane, where it can be subsequently activated by Src family kinases.Btk has been shown to associate with members of the protein kinase C (PKC) family of serine/threonine kina...

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Impaired Ca2+ mobilization by X-linked agammaglobulinaemia (XLA) B cells in response to ligation of the B cell receptor (BCR)

Cited by 20 publications

References 41 publications

BTK inhibitors in chronic lymphocytic leukemia: a glimpse to the future

BTK inhibitors in chronic lymphocytic leukemia: a glimpse to the future

Bruton's Tyrosine Kinase Regulates Immunoglobulin Promoter Activation in Association with the Transcription Factor Bright

Interaction of Bruton's Tyrosine Kinase and Protein Kinase Cθ in Platelets

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