The Transcription Factor<i>Bright</i>Associates with Bruton’s Tyrosine Kinase, the Defective Protein in Immunodeficiency Disease

Webb, Carol F.; Yamashita, Yoshio; Ayers, Neil; Evetts, Seth; Paulin, Yolene; Conley, Mary Ellen; Smith, Elizabeth A.

doi:10.4049/jimmunol.165.12.6956

Cited by 57 publications

(85 citation statements)

References 80 publications

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“…Btk has been suggested to regulate phosphoinositide 3-kinase signaling via PIP5K [5] and may interact with other proteins as an adaptor. Previous studies also indicate that Btk binds to and/or phosphorylates several molecules not necessarily related to PLCc signaling pathways [41][42][43][44][45][46][47][48][49][50][51]. In addition, activation of splenic B cells by CD38 requires Btk but is not affected by the pan-PLCc inhibitor U73122 [52].…”

Section: Discussionmentioning

confidence: 99%

Btk and phospholipase Cγ2 can function independently during B cell development

et al. 2007

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The pre-BCR and the BCR regulate B cell development via a signalosome nucleated by the adaptor protein B cell linker protein (BLNK). Formation of this complex facilitates activation of phospholipase C (PLC) c2 by Bruton's tyrosine kinase (Btk). To determine whether Btk and PLCc2 also have separate functions, we generated Btk -/-PLCc2 -/-mice. They demonstrated a block in development at the pre-B stage and increased pre-BCR surface expression. This phenotype was more severe than that of Btk -/-or PLCc2 -/-mice. Although both Btk and PLCc2 were required for proliferation of splenic B cells in response to BCR cross-linking, they contributed differently to anti-IgM-induced phosphorylation of ERK. Btk -/-and PLCc2 -/-mice each had a reduced frequency of Igk-expressing B cells and impaired migration of pre-B cells towards stromal cellderived factor 1. However, the increase in pre-B cell malignancy that occurs in BLNK -/-mice in the absence of Btk was not observed in the absence of PLCc2. Thus, Btk and PLCc2 act both in concert and independently throughout B cell development. IntroductionSignals from the B cell antigen receptor (BCR) regulate multiple stages of B lymphopoiesis [1]. In pre-B cells, the pre-BCR signals for proliferation, allelic exclusion of the IgH locus, down-regulation of VpreB and k5 expression, and light chain rearrangement. The pre-BCR is predominantly intracellular and is believed to signal in a ligand-independent manner. The BCR is first expressed on the surface of immature B cells. Antigen encounter at this stage results in negative selection via deletion, anergy, or receptor editing. A tonic BCR signal is required for differentiation beyond the T2 stage in the periphery and survival of mature B cells. Mature B cells proliferate and differentiate upon stimulation with foreign antigen in the appropriate context. BCR and pre-BCR signaling is mediated by a signalosome composed of Syk, Bruton's tyrosine kinase (Btk), B cell linker protein (BLNK; also known as SLP65 and BASH), and phospholipase C (PLC) c2 [2-4]. Receptor cross-linking activates Syk, which phosphorylates the adaptor protein BLNK. Btk and PLCc2 bind to phosphorylated BLNK via their SH2 domains. Btk then phosphorylates and activates PLCc2, resulting in changes in intracellular Ca 2+ and the activation of protein kinase Cb. Btk can also mediate BCR-stimulated Ca 2+ flux [5] and B cell development [6] independently of its catalytic activity. Btk acts as an adaptor to recruit and activate phosphatidylinositol 4-phosphate 5-kinase (PIP5K) [5], which produces the substrate for PLCc2. Thus, Btk signals through PLCc2 directly, by phosphorylation, and indirectly, by increasing substrate availability.Loss of Btk function causes the human immunodeficiency X-linked agammaglobulinemia (XLA) [7,8], which is characterized by a block in B cell development at the pre-B stage. A similar disease results from

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Section: Discussionmentioning

confidence: 99%

Btk and phospholipase Cγ2 can function independently during B cell development

et al. 2007

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“…The column was calibrated before and after use with Bio-Rad gel filtration standards to ensure maintenance of column integrity. 100-l fractions were collected and subjected to Western blotting for Bright as previously described (5).…”

Section: Methodsmentioning

confidence: 99%

“…The protein samples were subjected to SDS-polyacrylamide gel electrophoresis under standard denaturing conditions through a 7.5% acrylamide gel and transferred to nitrocellulose membranes as previously described (5). Bright was detected with rabbit anti-Bright, and Btk was detected with goat anti-Btk (C-20) (Santa Cruz Biotechnology, Santa Cruz, CA) followed by alkaline-phosphataseconjugated goat anti-rabbit IgG or rabbit anti-goat IgG (Southern Biotechnology, Birmingham, AL), respectively.…”

Section: Methodsmentioning

confidence: 99%

“…xid mice exhibit deficiencies in B cell development and abnormalities in immunoglobulin production (6,7). Initial evidence indicated that the Bright DNA-binding complex was supershifted by antibodies that reacted with several different domains of Btk (5). Furthermore, Bright co-precipitated with Btk from wild type, activated splenic B cells, but Btk and Bright did not co-precipitate from xid B cells despite both proteins being present.…”

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confidence: 99%

“…Recent studies suggest that Bruton's tyrosine kinase (〉tk), 1 the defective enzyme in xid (X-linked immunodeficiency disease) mice, is a component of the Bright DNA-binding complex (5). xid mice exhibit deficiencies in B cell development and abnormalities in immunoglobulin production (6,7).…”

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Mutations in the DNA-binding Domain of the Transcription Factor Bright Act as Dominant Negative Proteins and Interfere with Immunoglobulin Transactivation

Nixon

Rajaiya

Webb

2004

Journal of Biological Chemistry

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The transcription factor Bright (or B cell regulator of IgH transcription) is a B cell-specific protein that was first discovered in a mature mouse B cell line, BCg3R1-d, as a mobilityshifted protein complex that caused 3-6-fold increases in heavy chain mRNA levels in response to stimulation with a T-dependent antigen and interleukin-5 (1, 2). Bright binds to AϩT-rich regions of the intronic heavy chain enhancer that have been identified as matrix association regions and regions 5Ј of some V H promoters, including the V1 S107 family gene (3, 4). The cDNA for Bright was isolated in 1995, and the protein was shown to interact with DNA as a multimeric complex that includes multiple copies of Bright (4).Recent studies suggest that Bruton's tyrosine kinase (〉tk), 1 the defective enzyme in xid (X-linked immunodeficiency disease) mice, is a component of the Bright DNA-binding complex (5). xid mice exhibit deficiencies in B cell development and abnormalities in immunoglobulin production (6, 7). Initial evidence indicated that the Bright DNA-binding complex was supershifted by antibodies that reacted with several different domains of Btk (5). Furthermore, Bright co-precipitated with Btk from wild type, activated splenic B cells, but Btk and Bright did not co-precipitate from xid B cells despite both proteins being present. These data suggested that Bright and Btk are functionally linked. However, the role of Bright in normal B cell development is unknown. Expression of Bright in both mouse and human tissues is tightly regulated at the level of transcription (8, 9). In the mouse, Bright mRNA was detected in all embryonic tissues, but became B-lymphocyte restricted in the adult. Bright mRNA is apparent at the pre-B and activated germinal center stages of B cell differentiation (8). The human Bright homologue (10) shows a similar expression pattern in the adult where mRNA expression is primarily limited to B lymphocytes of the pro-B cell, germinal center centroblasts, and mature recirculating subpopulations (9). Thus, in both the adult mouse and human, Bright expression is predominantly B cell-specific.Bright belongs to a growing family of proteins that bind DNA through an AϩT-rich interacting domain (ARID) (11). ARIDcontaining proteins are highly conserved throughout evolution where many of them play important roles as developmental regulators (11). ARID-containing proteins occur in all eukaryotic organisms and include 13 sequences in the human data base (11,12). Bright is the only member of the ARID family for which gene target sequences have been identified. One of the best characterized members of this family is the Dri (Drosophila homologue Dead Ringer) gene, first identified in 1996 (13). The ARID region of Dri is essential for anterior-posterior patterning and for muscle development in the fly embryo (14 -16). The crystal structure of the ARID region of Dri has been solved and revealed a unit of eight ␣-helices with a short two-stranded anti-parallel ␤-sheet (17). NMR analysis predicted that helices 5 and 6 together ...

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The Tec family of cytoplasmic tyrosine kinases: mammalian Btk, Bmx, Itk, Tec, Txk and homologs in other species

et al. 2001

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Cytoplasmic protein-tyrosine kinases (PTKs) are enzymes involved in transducing a vast number of signals in metazoans. The importance of the Tec family of kinases was immediately recognized when, in 1993, mutations in the gene encoding Bruton's tyrosine kinase (Btk) were reported to cause the human disease X-linked agammaglobulinemia (XLA). Since then, additional kinases belonging to this family have been isolated, and the availability of full genome sequences allows identification of all members in selected species enabling phylogenetic considerations. Tec kinases are endowed with Pleckstrin homology (PH) and Tec homology (TH) domains and are involved in diverse biological processes related to the control of survival and differentiation fate. Membrane translocation resulting in the activation of Tec kinases with subsequent Ca2+ release seems to be a general feature. However, nuclear translocation may also be of importance. The purpose of this essay is to characterize members of the Tec family and discuss their involvement in signaling. The three-dimensional structure, expression pattern and evolutionary aspects will also be considered.

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The Transcription FactorBrightAssociates with Bruton’s Tyrosine Kinase, the Defective Protein in Immunodeficiency Disease

Cited by 57 publications

References 80 publications

Btk and phospholipase Cγ2 can function independently during B cell development

Btk and phospholipase Cγ2 can function independently during B cell development

Mutations in the DNA-binding Domain of the Transcription Factor Bright Act as Dominant Negative Proteins and Interfere with Immunoglobulin Transactivation

The Tec family of cytoplasmic tyrosine kinases: mammalian Btk, Bmx, Itk, Tec, Txk and homologs in other species

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