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Gene Review

BTK  -  Bruton agammaglobulinemia tyrosine kinase

Homo sapiens

Synonyms: AGMX1, AT, ATK, Agammaglobulinemia tyrosine kinase, B-cell progenitor kinase, ...
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Disease relevance of BTK

  • Fas-resistant DT-40 lymphoma B-cells rendered BTK-deficient through targeted disruption of the btk gene by homologous recombination knockout underwent apoptosis after Fas ligation, but wild-type DT-40 cells or BTK-deficient DT-40 cells reconstituted with wild-type human btk gene did not [1].
  • Similarly, LFM-A13 inhibited recombinant BTK expressed in a baculovirus expression vector system with an IC50 value of 2.5 microM [2].
  • BTK-deficient RAMOS-1 human Burkitt's leukemia cells underwent apoptosis after Fas ligation, whereas BTK-positive NALM-6-UM1 human B-cell precursor leukemia cells expressing similar levels of Fas did not [1].
  • EMT is related to the B-cell progenitor kinase (BPK), which has recently been implicated in X-linked hypogammaglobulinemia, to the TECI mammalian kinase, which has been implicated in liver neoplasia, to the more widely expressed TECII mammalian kinase, and to the Drosophila melanogaster Dsrc28 kinase [3].
  • In addition, a dominant negative form of Btk inhibited TLR4-mediated activation of a nuclear factor kappaB (NFkappaB)-dependent reporter gene in HEK293 cells as well as LPS-induced activation of NFkappaB in the astrocytoma cell line U373 and the monocytic cell line RAW264 [4].

High impact information on BTK


Chemical compound and disease context of BTK


Biological context of BTK

  • Inhibition of BTK activity specifically induces apoptosis in BCR-ABL1+ leukemia cells to a similar extent as inhibition of BCR-ABL1 kinase activity itself [14].
  • As opposed to full-length BTK, truncated BTK lacks kinase activity yet can bind to BCR-ABL1 through its SRC-homology domain 3 [14].
  • Activated BTK is essential for survival signals that otherwise would arise from the pre-B cell receptor, including activation of PLCgamma1, autonomous Ca2+ signaling, STAT5-phosphorylation, and up-regulation of BCLX(L) [14].
  • BTK-mediated tyrosine phosphorylation of ectopically expressed wild type (but not Tyr(694) mutant) STAT5A enhanced its DNA binding activity [15].
  • The dimensions of this rectangle are approximately 18 x 8 x 9 x 17 A, and the thickness of the pocket is approximately 7 A. Advanced docking procedures were employed for the rational design of leflunomide metabolite (LFM) analogs with a high likelihood to bind favorably to the catalytic site within the kinase domain of BTK [2].

Anatomical context of BTK

  • To determine whether a highly conserved 3.5-kb segment flanking the first exon of BTK contains transcriptional regulatory signals, we tested various portions of the segment for promoter and expression activity in several appropriate cell lines [16].
  • These findings provide unprecedented experimental evidence that BTK plays a nonredundant and pivotal role in B cell antigen receptor-mediated STAT5A activation in B cells [15].
  • Here, we provide unique biochemical and genetic evidence that BTK is an inhibitor of the Fas/APO-1 death-inducing signaling complex in B-lineage lymphoid cells [1].
  • IkappaB alpha degradation activated by LPS was intact in macrophages from X-linked immunodeficiency (Xid) mice, which contain inactive Btk [17].
  • Deficient oxidative burst and myeloid differentiation have been reported in the X-linked immunodeficiency mouse, but the precise mechanism and relevance of Btk activity in human monocytes is poorly understood [18].

Associations of BTK with chemical compounds

  • To our knowledge, LFM-A13 is the first BTK-specific tyrosine kinase inhibitor and the first anti-leukemic agent targeting BTK [2].
  • Treatment of the anti-Fas-resistant NALM-6-UM1 cells with the leflunomide metabolite analog alpha-cyano-beta-methyl-beta-hydroxy-N-(2, 5-dibromophenyl)propenamide, a potent inhibitor of BTK, abrogated the BTK-Fas association without affecting the expression levels of BTK or Fas and rendered them sensitive to Fas-mediated apoptosis [1].
  • In accordance with the anti-apoptotic function of BTK, treatment of BTK+ B-lineage leukemic cells with LFM-A13 enhanced their sensitivity to ceramide- or vincristine-induced apoptosis [2].
  • Accordingly, TaqMan quantitative PCR analysis of actinomycin D time courses presented in this work shows that overexpression of Btk is able to stabilize TNF, but not IL-6 mRNA [19].
  • Multiple downstream signaling pathways were involved, including phosphatidylinositol 3-kinase (PI3K), Bruton's tyrosine kinase (Btk), and phospholipase C (PLC)-mediated release of Ca(2+) from inositol 1,4,5-trisphosphate (IP(3))-sensitive stores [20].

Physical interactions of BTK

  • Purified recombinant BTK was capable of directly binding purified recombinant STAT5A with high affinity (K(d) = 44 nm), as determined by surface plasmon resonance using a BIAcore biosensor system [15].
  • Our findings implicate Btk as a Toll/interleukin-1 receptor domain-binding protein that is important for NFkappaB activation by TLR4 [4].
  • Transient overexpression of PKCmu deletion mutants as well as expression of selected PKCmu domains in 293T cells revealed that both the kinase domain and the regulatory C1 region are independently capable of binding to the Btk PH-TH domain [21].
  • Tyrosine-phosphorylated SLP-65 assembles intracellular signaling complexes such as the Ca(2 +) initiation complex encompassing phospholipase C-gamma2 and Bruton's tyrosine kinase [22].
  • Here, we demonstrate that G protein Gqalpha binds directly to the nonreceptor Bruton's tyrosine kinase (Btk) to a region composed of a Tec-homology (TH) domain and a sarcoma virus tyrosine kinase (Src)-homology 3 (SH3) domain both in vitro and in vivo [23].

Enzymatic interactions of BTK


Regulatory relationships of BTK


Other interactions of BTK

  • Taken together, it seems that EMT is a member of a new family of intracellular kinases that includes BPK, TECI, and TECII [3].
  • Our previous data suggested that Btk lies within a p38-dependent pathway that stabilizes TNF mRNA [19].
  • Because B cells in these models are predominantly immature, experiments were also performed using mature B cells expressing low levels of Btk and BLNK [31].
  • Bruton's tyrosine kinase as an inhibitor of the Fas/CD95 death-inducing signaling complex [1].
  • Detailed analysis of the interaction between Btk and TLR8 demonstrates that the presence of both Box 2 and 3 motifs in the Toll/interleukin-1 receptor domain was required for the interaction [4].

Analytical, diagnostic and therapeutic context of BTK

  • Introduction of wild-type BTK protein by electroporation rendered BTK-deficient DT-40 cells resistant to the apoptotic effects of Fas ligation [1].
  • Large-scale comparative sequence analysis of the human and murine Bruton's tyrosine kinase loci reveals conserved regulatory domains [16].
  • Btk protein expression was detectable by Western blotting in six cases, in one case Btk expression was drastically reduced, and in three cases no Btk expression could be observed [32].
  • This work may provide clues about critical sites in the molecule and give support for gene therapy as a potential successful approach to XLA [33].
  • A similar expression pattern was obtained when BTK protein was analyzed by immunoprecipitation and Western blotting [10].


  1. Bruton's tyrosine kinase as an inhibitor of the Fas/CD95 death-inducing signaling complex. Vassilev, A., Ozer, Z., Navara, C., Mahajan, S., Uckun, F.M. J. Biol. Chem. (1999) [Pubmed]
  2. Rational design and synthesis of a novel anti-leukemic agent targeting Bruton's tyrosine kinase (BTK), LFM-A13 [alpha-cyano-beta-hydroxy-beta-methyl-N-(2, 5-dibromophenyl)propenamide]. Mahajan, S., Ghosh, S., Sudbeck, E.A., Zheng, Y., Downs, S., Hupke, M., Uckun, F.M. J. Biol. Chem. (1999) [Pubmed]
  3. Identification, cloning, and characterization of a novel human T-cell-specific tyrosine kinase located at the hematopoietin complex on chromosome 5q. Gibson, S., Leung, B., Squire, J.A., Hill, M., Arima, N., Goss, P., Hogg, D., Mills, G.B. Blood (1993) [Pubmed]
  4. Bruton's tyrosine kinase is a Toll/interleukin-1 receptor domain-binding protein that participates in nuclear factor kappaB activation by Toll-like receptor 4. Jefferies, C.A., Doyle, S., Brunner, C., Dunne, A., Brint, E., Wietek, C., Walch, E., Wirth, T., O'Neill, L.A. J. Biol. Chem. (2003) [Pubmed]
  5. Molecular approaches to analysis of X-linked immunodeficiencies. Conley, M.E. Annu. Rev. Immunol. (1992) [Pubmed]
  6. Mutations in the mu heavy-chain gene in patients with agammaglobulinemia. Yel, L., Minegishi, Y., Coustan-Smith, E., Buckley, R.H., Trübel, H., Pachman, L.M., Kitchingman, G.R., Campana, D., Rohrer, J., Conley, M.E. N. Engl. J. Med. (1996) [Pubmed]
  7. Brief report: a point mutation in the SH2 domain of Bruton's tyrosine kinase in atypical X-linked agammaglobulinemia. Saffran, D.C., Parolini, O., Fitch-Hilgenberg, M.E., Rawlings, D.J., Afar, D.E., Witte, O.N., Conley, M.E. N. Engl. J. Med. (1994) [Pubmed]
  8. Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. Tsukada, S., Saffran, D.C., Rawlings, D.J., Parolini, O., Allen, R.C., Klisak, I., Sparkes, R.S., Kubagawa, H., Mohandas, T., Quan, S. Cell (1993) [Pubmed]
  9. Structure-based design of novel anticancer agents. Uckun, F.M., Sudbeck, E.A., Mao, C., Ghosh, S., Liu, X.P., Vassilev, A.O., Navara, C.S., Narla, R.K. Current cancer drug targets. (2001) [Pubmed]
  10. Expression of Bruton's agammaglobulinemia tyrosine kinase gene, BTK, is selectively down-regulated in T lymphocytes and plasma cells. Smith, C.I., Baskin, B., Humire-Greiff, P., Zhou, J.N., Olsson, P.G., Maniar, H.S., Kjellén, P., Lambris, J.D., Christensson, B., Hammarström, L. J. Immunol. (1994) [Pubmed]
  11. The anti-leukemic Bruton's tyrosine kinase inhibitor alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-dibromophenyl) propenamide (LFM-A13) prevents fatal thromboembolism. Uckun, F.M., Vassilev, A., Bartell, S., Zheng, Y., Mahajan, S., Tibbles, H.E. Leuk. Lymphoma (2003) [Pubmed]
  12. Stimulation of Bruton's tyrosine kinase (BTK) and inositol 1,4,5-trisphosphate production in leukemia and lymphoma cells exposed to low energy electromagnetic fields. Dibirdik, I., Bofenkamp, M., Skeben, P., Uckun, F. Leuk. Lymphoma (2000) [Pubmed]
  13. Recombinant adeno-associated virus-mediated expression of O6-alkylguanine-DNA-alkyltransferase protects human epithelial and hematopoietic cells against chloroethylating agent toxicity. Longhurst, S.J., Rafferty, J.A., Arrand, J.R., Cortez, N., Giraud, C., Berns, K.I., Fairbairn, L.J. Hum. Gene Ther. (1999) [Pubmed]
  14. Mimicry of a constitutively active pre-B cell receptor in acute lymphoblastic leukemia cells. Feldhahn, N., Klein, F., Mooster, J.L., Hadweh, P., Sprangers, M., Wartenberg, M., Bekhite, M.M., Hofmann, W.K., Herzog, S., Jumaa, H., Rowley, J.D., Müschen, M. J. Exp. Med. (2005) [Pubmed]
  15. Transcription factor STAT5A is a substrate of Bruton's tyrosine kinase in B cells. Mahajan, S., Vassilev, A., Sun, N., Ozer, Z., Mao, C., Uckun, F.M. J. Biol. Chem. (2001) [Pubmed]
  16. Large-scale comparative sequence analysis of the human and murine Bruton's tyrosine kinase loci reveals conserved regulatory domains. Oeltjen, J.C., Malley, T.M., Muzny, D.M., Miller, W., Gibbs, R.A., Belmont, J.W. Genome Res. (1997) [Pubmed]
  17. Bruton's tyrosine kinase is involved in p65-mediated transactivation and phosphorylation of p65 on serine 536 during NFkappaB activation by lipopolysaccharide. Doyle, S.L., Jefferies, C.A., O'Neill, L.A. J. Biol. Chem. (2005) [Pubmed]
  18. Bruton's tyrosine kinase is not essential for LPS-induced activation of human monocytes. Pérez de Diego, R., López-Granados, E., Pozo, M., Rodríguez, C., Sabina, P., Ferreira, A., Fontan, G., García-Rodríguez, M.C., Alemany, S. J. Allergy Clin. Immunol. (2006) [Pubmed]
  19. Bruton's tyrosine kinase is required for TLR2 and TLR4-induced TNF, but not IL-6, production. Horwood, N.J., Page, T.H., McDaid, J.P., Palmer, C.D., Campbell, J., Mahon, T., Brennan, F.M., Webster, D., Foxwell, B.M. J. Immunol. (2006) [Pubmed]
  20. CCL5 evokes calcium signals in microglia through a kinase-, phosphoinositide-, and nucleotide-dependent mechanism. Shideman, C.R., Hu, S., Peterson, P.K., Thayer, S.A. J. Neurosci. Res. (2006) [Pubmed]
  21. Bruton's tyrosine kinase (Btk) associates with protein kinase C mu. Johannes, F.J., Hausser, A., Storz, P., Truckenmüller, L., Link, G., Kawakami, T., Pfizenmaier, K. FEBS Lett. (1999) [Pubmed]
  22. Association of SLP-65/BLNK with the B cell antigen receptor through a non-ITAM tyrosine of Ig-alpha. Engels, N., Wollscheid, B., Wienands, J. Eur. J. Immunol. (2001) [Pubmed]
  23. Identification of the binding site for Gqalpha on its effector Bruton's tyrosine kinase. Ma, Y.C., Huang, X.Y. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  24. Control of erythropoiesis by erythropoietin and stem cell factor: a novel role for Bruton's tyrosine kinase. von Lindern, M., Schmidt, U., Beug, H. Cell Cycle (2004) [Pubmed]
  25. The protein product of the c-cbl protooncogene is phosphorylated after B cell receptor stimulation and binds the SH3 domain of Bruton's tyrosine kinase. Cory, G.O., Lovering, R.C., Hinshelwood, S., MacCarthy-Morrogh, L., Levinsky, R.J., Kinnon, C. J. Exp. Med. (1995) [Pubmed]
  26. Bruton's tyrosine kinase is activated upon CD40 stimulation in human B lymphocytes. Brunner, C., Avots, A., Kreth, H.W., Serfling, E., Schuster, V. Immunobiology (2002) [Pubmed]
  27. Bruton's tyrosine kinase is required for lipopolysaccharide-induced tumor necrosis factor alpha production. Horwood, N.J., Mahon, T., McDaid, J.P., Campbell, J., Mano, H., Brennan, F.M., Webster, D., Foxwell, B.M. J. Exp. Med. (2003) [Pubmed]
  28. The transcription factor, Bright, is not expressed in all human B lymphocyte subpopulations. Nixon, J.C., Rajaiya, J.B., Ayers, N., Evetts, S., Webb, C.F. Cell. Immunol. (2004) [Pubmed]
  29. G Protein beta gamma subunits act on the catalytic domain to stimulate Bruton's agammaglobulinemia tyrosine kinase. Lowry, W.E., Huang, X.Y. J. Biol. Chem. (2002) [Pubmed]
  30. Early arrest in B cell development in transgenic mice that express the E41K Bruton's tyrosine kinase mutant under the control of the CD19 promoter region. Maas, A., Dingjan, G.M., Grosveld, F., Hendriks, R.W. J. Immunol. (1999) [Pubmed]
  31. B Cell Receptor Signaling Down-Regulates Forkhead Box Transcription Factor Class O 1 mRNA Expression via Phosphatidylinositol 3-Kinase and Bruton's Tyrosine Kinase. Hinman, R.M., Bushanam, J.N., Nichols, W.A., Satterthwaite, A.B. J. Immunol. (2007) [Pubmed]
  32. Unimpaired activation of c-Jun NH2-terminal kinase (JNK) 1 upon CD40 stimulation in B cells of patients with X-linked agammaglobulinemia. Brunner, C., Kreth, H.W., Ochs, H.D., Schuster, V. J. Clin. Immunol. (2002) [Pubmed]
  33. Insight into B cell development and differentiation. Moschese, V., Orlandi, P., Di Matteo, G., Chini, L., Carsetti, R., Di Cesare, S., Rossi, P. Acta paediatrica (Oslo, Norway : 1992). Supplement. (2004) [Pubmed]
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