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Bruton Tyrosine Kinase / BTK Kinase  Protéine

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Bruton Tyrosine Kinase / BTK Kinase Voies apparentées

Bruton Tyrosine Kinase / BTK Kinase Récapitulatif et informations sur les protéines

Bruton Tyrosine Kinase / BTK Kinase Fond

Résumé du gène: Bruton tyrosine kinase protein encoded by BTK gene plays a crucial role in B-cell development. Mutations in BTK gene cause X-linked agammaglobulinemia type 1, which is an immunodeficiency characterized by the failure to produce mature B lymphocytes, and associated with a failure of Ig heavy chain rearrangement.
General information above from NCBI
Activité catalytique: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
Cofacteur: Binds 1 zinc ion per subunit.
Régulation enzymatique: Activated by phosphorylation. In primary B lymphocytes, is almost always non-phosphorylated and is thus catalytically inactive. Stimulation of TLR8 and TLR9 causes BTK activation. As a negative feedback mechanism to fine-tune BCR signaling, activated PRKCB down-modulates BTK function via direct phosphorylation of BTK at Ser-180, resulting in translocation of BTK back to the cytoplasmic fraction. PIN1, SH3BP5, and IBTK were also identified as BTK activity inhibitors. Interaction with CAV1 leads to dramatic down-regulation of the kinase activity of BTK. LFM-13A is a specific inhibitor of BTK. Dasatinib, a cancer drug acting as a tyrosine kinase inhibitor, also blocks BTK activity.
Structure de sous-unités: Binds GTF2I through the PH domain. Interacts with SH3BP5 via the SH3 domain. Interacts with IBTK via its PH domain. Interacts with ARID3A, CAV1, FASLG, PIN1, TLR8 and TLR9.
Domaine: The PH domain mediates the binding to inositol polyphosphate and phosphoinositides, leading to its targeting to the plasma membrane. It is extended in the BTK kinase family by a region designated the TH (Tec homology) domain, which consists of about 80 residues preceding the SH3 domain.
Localisation subcellulaire: Cytoplasm. Cell membrane; Peripheral membrane protein. Nucleus. Note=In steady state, BTK is predominantly cytosolic. Following B-cell receptor (BCR) engagement by antigen, translocates to the plasma membrane through its PH domain. Plasma membrane localization is a critical step in the activation of BTK. A fraction of BTK also shuttles between the nucleus and the cytoplasm, and nuclear export is mediated by the nuclear export receptor CRM1.
Spécificité tissulaire: Predominantly expressed in B-lymphocytes.
Post-traductionnel: Following B-cell receptor (BCR) engagement, translocates to the plasma membrane where it gets phosphorylated at Tyr-551 by LYN and SYK. Phosphorylation at Tyr-551 is followed by autophosphorylation of Tyr-223 which may create a docking site for a SH2 containing protein. Phosphorylation at Ser-180 by PRKCB, leads in translocation of BTK back to the cytoplasmic fraction. Phosphorylation at Ser-21 and Ser-115 creates a binding site for PIN1 at these Ser-Pro motifs, and promotes it's recruitment.
Implication dans la maladie: X-linked agammaglobulinemia (XLA) [MIM:300755]: Humoral immunodeficiency disease which results in developmental defects in the maturation pathway of B-cells. Affected boys have normal levels of pre-B-cells in their bone marrow but virtually no circulating mature B-lymphocytes. This results in a lack of immunoglobulins of all classes and leads to recurrent bacterial infections like otitis, conjunctivitis, dermatitis, sinusitis in the first few years of life, or even some patients present overwhelming sepsis or meningitis, resulting in death in a few hours. Treatment in most cases is by infusion of intravenous immunoglobulin. Note=The disease is caused by mutations affecting the gene represented in this entry.
X-linked hypogammaglobulinemia and isolated growth hormone deficiency (XLA-IGHD) [MIM:307200]: In rare cases XLA is inherited together with isolated growth hormone deficiency (IGHD). Note=The disease may be caused by mutations affecting the gene represented in this entry.
Similarité de séquence: Belongs to the protein kinase superfamily. Tyr protein kinase family. TEC subfamily.
Contains 1 Btk-type zinc finger.
Contains 1 PH domain.
Contains 1 protein kinase domain.
Contains 1 SH2 domain.
Contains 1 SH3 domain.
General information above from UniProt

Bruton's tyrosine kinase (or BTK) is a type of kinase protein expressed in B lymphocytes and T cells. BTK contains a PH domain which binds phosphatidylinositol(3,4,5)-trisphosphate (PIP3). After binding to PIP3, BTK is induced to phosphorylate phospholipase C, which in turn hydrolyzes PIP2 into two second messagers, IP3 and DAG, which then modulate the activity of downstream proteins during B-cell signaling. Btk is also found implicated in the primary immunodeficiency disease X-linked agammaglobulinemia(Bruton's agammaglobulinemia). BTK played a key role in B-cell maturation as well as mast cell activation through the high-affinity IgE receptor. Patients with X-linked agammaglobulinemia have normal pre-B cell populations in their bone marrow but these B-cells can not mature and enter the circulation.

Bruton Tyrosine Kinase / BTK Kinase Autre dénomination

AT,ATK,BPK,XLA,IMD1,AGMX1,PSCTK1, [homo-sapiens]
BPK,MGC126261,MGC126262,PSCTK1,RP1-164F3.2,AGMX1,AT,ATK,BTK,IMD1,XLA, [human]
RP23-91G19.5,AI528679,Btk,xid, [mouse]
xid,AI528679, [mus-musculus]

Bruton Tyrosine Kinase / BTK Kinase Études apparentées

  • Hashimoto S, et al. (1996) Identification of Bruton's tyrosine kinase (Btk) gene mutations and characterization of the derived proteins in 35 X-linked agammaglobulinemia families: a nationwide study of Btk deficiency in Japan. Blood. 88(2): 561-73.
  • Ohta Y, et al. (1994) Genomic organization and structure of Bruton agammaglobulinemia tyrosine kinase: localization of mutations associated with varied clinical presentations and course in X chromosome-linked agammaglobulinemia. PNAS. 91(19): 9062-6.
  • Smith C, et al. (1994) Expression of Bruton's agammaglobulinemia tyrosine kinase gene, BTK, is selectively down-regulated in T lymphocytes and plasma cells. The Journal of Immunology. 152(2): 557-65.
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