Bruton’s tyrosine kinase

Btk (Bruton s tyrosine kinase) is a phosphatidylinositol 3 -kinase sensitive cytoplasmic tyrosine kinase. Germline loss of function mutations of Btk cause X-linked agammaglobulinaemia in human and X-linked immunodeficiency in mice. 

BTK Bruton s tyrosine kinase Cys-rich motif E(M) 0(0) 0(0) 1B55... 

A variety of domain or motif families occur only as extensions to other domains. The Bruton s tyrosine kinase motif (BTK), for example, is found only at the C terminus of PH domains. Similarly, a C-terminal extension (the S TK X domain) to some subfamilies of serine/threonine kinases (S TK) is not found in isolation. Cases where only the extension, and not the preceding domain, is found are strong evidence that the proteins are wrongly assembled from genomic sequence or else represent partial cDNA sequences (Fig. 9, see Color insert). Indeed, all five proteins annotated in SMART as containing a S TK X domain with no catalytic domain are noted to be fragments in their corresponding sequence database entries. 

Human Bruton s tyrosine kinase IBTK HiSa/i 10 CySa/i 0 CyS2a/i 9 Cysb/i... 

E. Baraldi, K.D. Carugo, M. Hyvonen, P.L. Surdo, A M. Riley, B.V. Potter, R. O Brien, J.E. Ladbury, and M. Saraste. 1999. Structure of the PH domain from Bruton s tyrosine kinase in complex with inositol 1,3,4,5-tetrakisphosphate... 

PBKs phosphorylate inositol lipids at the 3 position of the inositol ring to generate the 3-phosphoinositide PI(3,4,5)P3, (PIP3). PBKs of class IB are directly activated by GP t, but others PBK also belong to pathways of receptors with or coupled to tyrosine kinase activity. PIP3 may recruit to tlie membrane various protein kinases, phosphoinositide-dependent kinase-1 (PDK-1), protein kinase B (PKB, or Akt), protein kinase (PKCQ, PLC t and cytosolic tyrosine kinases such as the Bruton s tyrosine kinase (Btk). 

X-linked agamma-globulinaemia (XLA) lack of mature immunoglobulin-producing B cells Mutations in Bruton s tyrosine kinase (BTK) Arthritis, dermatomyositis, autoimmune haemolytic anaemia (AIHA), scleroderma... 

Baba, K. Takeshita, A. Majima, K. Ueda, R. Kondo, S. Jimi, N. Yamamoto, D. The Drosophila Bruton s tyrosine kinase (Btk) homolog is required for adult survival and male genital formation. Mol. Cell. Biol., 19, 4405-4413 (1999)... 

Morrogh, L. M., Hinshelwood, S., Costello, E, Cory, G. O., and Kinnon, C. (1999). The SH3 domain of Bruton s tyrosine kinase displays altered ligand binding properties when auto-phosphorylated in vitro. Eur. J. Immunol. 29, 2269-2279. 

D. Helgason, R. Keith Humphries, Clifford A. LoweU, Melvin Simon, Michael Leitges, Alexander Tarakhovsky, Thomas F. Tedder, Ralf Lesche, Hong Wu and Owen N. Witte, A sensitized genetic system for the analysis of murine B lympho-cyte signal transduction pathways dependent on Bruton s tyrosine kinase. Proceedings of the National Academy of Sciences USA, 97 (2000), 6687-6692. 

Gq family including Oq, an, a, ais and aie, which activate phosphohpase CP and Bruton s tyrosine kinase (Btk) ... 

Iyer AS, Morales JL, Huang W, Ojo E, Ning G, Wills E, Baines JD, August A. Absence of Tec family kinases interleukin-2 inducible T cell kinase (Itk) and Bruton s tyrosine kinase (Btk) severely impairs Fc epsilonRI-dependent mast cell responses. J Biol Chem. 2011 286 9503-13. 

Bruton s tyrosine kinase inhibitors Approaches to potent and selective inhibition, preclinical and clinical evaluation for inflammatory diseases and B cell mahgnancies 12JMC4539. 

The B-cell receptor (BCR), a transmembrane receptor protein on the outer surface of B-cells, initiates the BCR pathway regulating several essential cellular processes including proliferation, differentiation, and apoptosis, which are critical for the functions and survival of both normal and malignant B cells.The BCR pathway involves multiple protein tyrosine kinases (PTKs), such as Lyn, Syk, and Bruton s tyrosine kinase (Btk). These PTKs have been found to be constitutively active and/or overexpressed that lead to uncontrolled proliferation and survival of malignant B cells. Btk, a kinase in the Tec family, is a unique therapeutic target. Upon BCR activation, Btk becomes activated by other PTKs, such as Lyn and/or Syk, resulting in activation of downstream events necessary for B-cell proliferation and differentiation. Inhibition of Btk activity prevents... 

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