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Gene Review

Btk  -  Bruton agammaglobulinemia tyrosine kinase

Rattus norvegicus

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Disease relevance of Btk

  • Bruton's tyrosine kinase (Btk) is encoded by the gene that when mutated causes the primary immunodeficiency disease X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (Xid) in mice [1].

High impact information on Btk

  • Two amino acids in the PLC-delta 1 PH domain that contact Ins(1,4,5)P3 have counterparts in the Bruton's tyrosine kinase (Btk) PH domain, where mutational changes cause inherited agammaglobulinemia, suggesting a mechanism for loss of function in Btk mutants [2].
  • ATP activates the Btk tyrosine kinase, Tec, and induces its association with PLCgamma [3].
  • The activity of Btk is partially regulated by transphosphorylation within its kinase domain by Src family kinases at residue Tyr-551 and subsequent autophosphorylation at Tyr-223 [4].
  • The Btk PH domain can bind in vitro to several lipid end products of the phosphatidylinositol 3-kinase (PI 3-kinase) family including phosphatidylinositol 3,4,5-trisphosphate [4].
  • Bruton's tyrosine kinase (Btk) is essential for normal B lymphocyte development and function [4].

Chemical compound and disease context of Btk


Biological context of Btk

  • This activation correlates with new sites of phosphorylation on Btk identified by two-dimensional phosphopeptide mapping [4].
  • In addition to the GAP catalytic domain, Gap1m has two domains with sequence closely related to those of the phospholipid-binding domain of synaptotagmin and a region with similarity to the unique domain of Btk tyrosine kinase [6].
  • The stable expression of Lyn-PLCgamma2 was not accompanied by an increase in substrate hydrolysis in resting cells, which followed stimulation and specifically required the presence and/or activation of Syk, Btk, phosphoinositide 3-kinase but not BLNK, as established using deficient cell lines or specific inhibitors [7].

Anatomical context of Btk

  • Mutations affecting Btk block B-lymphocyte development [1].
  • Activation correlates with Btk association with cellular membranes [4].
  • Etk (also called Bmx) is a member of the Btk tyrosine kinase family and is expressed in a variety of hematopoietic, epithelial, and endothelial cells [8].
  • A fraction of Bruton's tyrosine kinase (Btk) co-localizes with actin fibers upon stimulation of mast cells via the high affinity IgE receptor (FcepsilonRI) [9].
  • The negative regulatory effect of Pin1 was observed both in cell lines and in Pin(-/-) mice and was found to be dependent on a functionally intact Btk [10].

Associations of Btk with chemical compounds

  • Activation of Btk as monitored by elevation of phosphotyrosine content and a cellular transformation response was dramatically enhanced by coexpressing a weakly activated allele of Src (E378G) and the two subunits of PI 3-kinase-gamma [4].
  • Using a phosphomitotic antibody, it was found that Btk harbors a bona fide MPM2 epitope corresponding to a phosphorylated serine or threonine residue followed by a proline [10].

Other interactions of Btk

  • Activation of Btk was dependent on the catalytic activity of all three enzymes and an intact Btk PH domain and Src transphosphorylation site [4].


  1. Bruton's tyrosine kinase: cell biology, sequence conservation, mutation spectrum, siRNA modifications, and expression profiling. Lindvall, J.M., Blomberg, K.E., Väliaho, J., Vargas, L., Heinonen, J.E., Berglöf, A., Mohamed, A.J., Nore, B.F., Vihinen, M., Smith, C.I. Immunol. Rev. (2005) [Pubmed]
  2. Structure of the high affinity complex of inositol trisphosphate with a phospholipase C pleckstrin homology domain. Ferguson, K.M., Lemmon, M.A., Schlessinger, J., Sigler, P.B. Cell (1995) [Pubmed]
  3. A specific role of phosphatidylinositol 3-kinase gamma. A regulation of autonomic Ca(2)+ oscillations in cardiac cells. Bony, C., Roche, S., Shuichi, U., Sasaki, T., Crackower, M.A., Penninger, J., Mano, H., Pucéat, M. J. Cell Biol. (2001) [Pubmed]
  4. Phosphatidylinositol 3-kinase-gamma activates Bruton's tyrosine kinase in concert with Src family kinases. Li, Z., Wahl, M.I., Eguinoa, A., Stephens, L.R., Hawkins, P.T., Witte, O.N. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  5. Purification of a major tyrosine kinase from RBL-2H3 cells phosphorylating Fc epsilon RI gamma-cytoplasmic domain and identification as the Btk tyrosine kinase. Price, D.J., Kawakami, Y., Kawakami, T., Rivnay, B. Biochim. Biophys. Acta (1995) [Pubmed]
  6. A novel mammalian Ras GTPase-activating protein which has phospholipid-binding and Btk homology regions. Maekawa, M., Li, S., Iwamatsu, A., Morishita, T., Yokota, K., Imai, Y., Kohsaka, S., Nakamura, S., Hattori, S. Mol. Cell. Biol. (1994) [Pubmed]
  7. Requirements for distinct steps of phospholipase Cgamma2 regulation, membrane-raft-dependent targeting and subsequent enzyme activation in B-cell signalling. Rodriguez, R., Matsuda, M., Storey, A., Katan, M. Biochem. J. (2003) [Pubmed]
  8. Etk, a Btk family tyrosine kinase, mediates cellular transformation by linking Src to STAT3 activation. Tsai, Y.T., Su, Y.H., Fang, S.S., Huang, T.N., Qiu, Y., Jou, Y.S., Shih, H.M., Kung, H.J., Chen, R.H. Mol. Cell. Biol. (2000) [Pubmed]
  9. Pleckstrin homology domains interact with filamentous actin. Yao, L., Janmey, P., Frigeri, L.G., Han, W., Fujita, J., Kawakami, Y., Apgar, J.R., Kawakami, T. J. Biol. Chem. (1999) [Pubmed]
  10. Regulation of Bruton tyrosine kinase by the peptidylprolyl isomerase Pin1. Yu, L., Mohamed, A.J., Vargas, L., Berglöf, A., Finn, G., Lu, K.P., Smith, C.I. J. Biol. Chem. (2006) [Pubmed]
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