Disease relevance of Btk

• Emb turned out to be identical to Btk, a gene product defective in human X-linked agammaglobulinemia and in X-linked immunodeficient (xid) mice [1].
• We have isolated phage and cosmid clones that allowed us to deduce the genomic structure of mouse and human Btk loci [2].
• However, mast cells derived from these mice exhibited significant abnormalities in FcepsilonRI-dependent function. xid mice primed with anti-dinitrophenyl monoclonal IgE antibody exhibited mildly diminished early-phase and severely blunted late-phase anaphylactic reactions in response to antigen challenge in vivo [3].
• Autoimmunity, hypersensitivity to B cell receptor (BCR) cross-linking, and splenomegaly caused by myeloerythroid hyperplasia were alleviated by Btk deficiency in lyn-/- mice [4].
• The requirement for Btk and TxA2 receptor function in GPIb-dependent arterial thrombosis was confirmed in vivo by characterizing blood flow in ferric chloride-treated mouse carotid arteries [5].
• In striking contrast to the anti-B. hermsii IgM response in mice deficient only in Btk, mice deficient in both Btk and MyD88 were entirely incapable of generating B. hermsii-specific Ab or resolving bacteremia [6].

Psychiatry related information on Btk

• By Southern blot and nucleotide sequence analysis, the Vk genes used by two TGB5 Id+ 2 degrees HP from xid mice are highly homologous, if not identical to the Vk1A gene(s) used by 1 degree and 2 degrees Id+ HP from wild-type mice [7].

High impact information on Btk

• Data from knockout experiments in cell lines and mice have revealed distinct functions for the intracellular protein tyrosine kinases (Lyn, Syk, Btk) in BCR signaling and B cell development [8].
• Expression of an X-linked gene family (XLR) in late-stage B cells and its alteration by the xid mutation [9].
• This finding, together with data on the expression of the XLR locus in B cells, indicates that this gene family either includes the locus defined by the xid mutation or is adjacent to it in a gene complex which may be important in lymphocyte differentiation [10].
• In the accompanying paper we describe the isolation of a cDNA clone recognizing a family of genes on the X chromosome, at least some of whose members are closely linked to the xid trait [9].
• Isolation of a cDNA clone corresponding to an X-linked gene family (XLR) closely linked to the murine immunodeficiency disorder xid [10].

Chemical compound and disease context of Btk

• Mutations in the nonreceptor tyrosine kinase Btk result in the B cell immunodeficiencies X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (xid) in mice [11].
• Lyn-deficient xid mice exhibited greatly reduced numbers of peripheral mature B cells, disappearance of CD5+ B-1 cells, markedly reduced serum levels of IgM and IgG3, low proliferative response to anti-IgM or lipopolysaccharide stimulation and no evidence for autoimmune disease [12].
• RESULTS: Treatment of BPK mice with EKB-569 alone resulted in a marked reduction of kidney weight/body weight ratios, dramatically reduced collecting tubule cystic index, as well as BDE, and improved renal function [13].
• X-linked immunodeficient (xid) (CBA/N female x DBA/2 male) F1 male mice, when treated with cyclophosphamide, were much more susceptible to challenge with aerosolized Pseudomonas aeruginosa serotype 11 than were control F1 female littermates [14].

Biological context of Btk

• This phenotype is similar to defects observed in mice lacking the tyrosine kinase Btk [15].
• Taken together, these results demonstrate an important role for Btk in the full expression of FcepsilonRI signal transduction in mast cells [3].
• Polyclonal, phosphopeptide-specific antibodies were developed to evaluate the phosphorylation of Btk sites 1 and 2 [16].
• We have evaluated the mechanism underlying Btk enzyme activation and have explored the potential regulatory relationship between Btk and Src protein kinases [17].
• TH-SH3 binding in vitro is abolished by specific, single amino acid substitutions within the Btk TH domain or the Fyn SH3 domain [18].

Anatomical context of Btk

• The B cell antigen receptor controls integrin activity through Btk and PLCgamma2 [19].
• A small fraction of Btk translocated from the cytosol to the membrane compartment following receptor cross-linking [1].
• Consistent with this finding, cultured mast cells derived from the bone marrow cells of xid or btk null mice exhibited mild impairments in degranulation, and more profound defects in the production of several cytokines, upon FcepsilonRI cross-linking [3].
• To assess the importance of Btk function in murine lymphopoiesis, we generated multiple embryonic stem cell clones bearing a targeted disruption of the btk gene and examined their potential to produce lymphocytes in both C57BL/6 and RAG2-/- host chimeric animals [20].
• To elucidate unequivocally potential Btk functions in mice, we generated mutations in embryonic stem cells, which eliminated the ability to encode Btk pleckstrin homology or kinase domains, and assayed their effects by RAG2-deficient blastocyst complementation or introduction into the germline [21].

Associations of Btk with chemical compounds

• Furthermore, Btk is also involved in the control of integrin-mediated adhesion of preB cells [19].
• CD38 ligation on mouse B cells by CS/2, an anti-mouse CD38 mAb, induced proliferation, interleukin 5 (IL-5) receptor alpha chain expression, and tyrosine phosphorylation of Bruton tyrosine kinase (Btk) from wild-type, but not from X chromosome-linked, immunodeficient mice [22].
• Here we report that Fc epsilon RI cross-linking induced rapid phosphorylation on tyrosine, serine, and threonine residues and activation of Btk in mouse bone marrow-derived mast cells [1].
• Tyrosine phosphorylation of Btk was not induced by either a Ca2+ ionophore (A23187), phorbol 12-myristate 13-acetate, or a combination of the two reagents [1].
• Second, in cell lysates Btk is found in association with an as yet unidentified 72-kDa phosphotyrosine-containing protein; this interaction requires a functional SH3-binding site in the TH domain [18].
• Decreased IL-10 production may be responsible for increased IL-6 because blocking IL-10 in WT cultures increased IL-6 production, and supplementation of IL-10 to Btk-deficient cultures decreased IL-6 production [23].

Physical interactions of Btk

• 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 [24].
• Phospholipase C-gamma 2 couples Bruton's tyrosine kinase to the NF-kappaB signaling pathway in B lymphocytes [25].

Enzymatic interactions of Btk

• With total spleen B cells, Btk was maximally phosphorylated at a lower concentration of anti-kappa than Syk [26].
• BTK is phosphorylated after cross-linking of CD79b on RAG2-deficient pro-B cells [27].

Regulatory relationships of Btk

• Collectively, these data demonstrate that Btk regulates the transcription of the IL-2 gene through the JNK-regulatable transcription factors in FcepsilonRI-stimulated mast cells [28].
• Collectively, our data demonstrate that a dramatically reduced frequency of responsive cells underlies the low proliferation of anti-IgM plus IL-4-stimulated Btk-deficient B cells and point towards an early block in the G1 phase due to inadequate activation of a pathway that regulates PKC activation [29].
• The present study provides genetic, biochemical, and pharmacological evidence that, on FcepsilonRI stimulation, Syk regulates Btk, and Btk selectively regulates the membrane translocation and enzymatic activity of PKCbetaI among the conventional PKC isoforms (alpha, betaI, and betaII) expressed in mast cells [30].
• Src family protein tyrosine kinases induce autoactivation of Bruton's tyrosine kinase [17].
• Together, these results suggest that BCR employs distinct BTK-dependent molecular mechanisms to regulate the activation of NF-kappaB versus NFAT [31].
• Btk appears to regulate directly the classical pathway in response to BAFF such that Btk-deficient B cells exhibit reduced kinase activity of IkappaB kinase gamma-containing complexes and defective IkappaBalpha degradation [32].
• The addition of exogenous recombinant IL-10 could suppress IL-12 production by TLR9-activated Btk(-/-) B cells, suggesting that in B cells, Btk negatively regulates IL-12 through the induction of autocrine IL-10 production [33].

Other interactions of Btk

• Severe B cell deficiency in mice lacking the tec kinase family members Tec and Btk [34].
• Calcium depletion did not influence BCR-induced Akt phosphorylation/activation, showing that neither Syk nor Btk mediates its effects via changes in calcium levels [35].
• The sequence of rlk showed that it is most closely related to the subfamily of cytoplasmic tyrosine kinases that includes the Btk, Itk, and Tec proteins [36].
• Reconstitution of Btk signaling by the atypical tec family tyrosine kinases Bmx and Txk [37].
• These data demonstrate, for the first time, that Btk is a key regulator of a Kit-mediated amplification pathway that augments Fc epsilonRI-mediated mast cell activation [38].

Analytical, diagnostic and therapeutic context of Btk

• Co-immunoprecipitation between Btk and receptor subunit beta or gamma was not detected [1].
• We have used purified CFSE-labeled B cells and an adoptive transfer model system to show that immature and mature B cells divide in a variety of B cell-deficient (scid, xid, IL-7(-/-), and sublethally irradiated) hosts [39].
• We used DNA microarrays to determine what fraction of genes this pathway influences and to investigate whether PI3K and Btk mediate distinct gene regulation events [40].
• In order to determine if Btk is important for Bright function, a transcription activation assay was established and analyzed using real-time PCR technology [24].
• The domain structure of Btk was analysed using X-ray synchrotron radiation scattering in solution [41].

References