Bruton tyrosine kinase

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 Related Areas

Enzyme>>Protein Kinase>>Intracellular Kinase>>BTK

Signal Transduction>>Protein Kinase>>Intracellular Kinase>>BTK

Immunology>>Adaptive Immunity >>B Cell>>BTK

Bruton tyrosine kinase Alternative Names

BTK, RP1-164F3.2, AGMX1, AT, ATK, BPK, IMD1, MGC126261, MGC126262, PSCTK1, XLA [Homo sapiens]

Btk, RP23-91G19.5, AI528679, xid [Mus musculus]

Summaries for Bruton tyrosine kinase

Entrez Gene summary for BTK:

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.

OMIM - description for Bruton tyrosine kinase:

Bruton tyrosine kinase is a key regulator of B-cell development. Mutations in the BTK gene result in X-linked agammaglobulinemia (XLA; 300755), an immunodeficiency characterized by failure to produce mature B lymphocytes and associated with a failure of Ig heavy chain rearrangement (Rawlings and Witte, 1994).

Human Bruton tyrosine kinase Protein General Information

 

• Protein names: Tyrosine-protein kinase BTK, Short Name=BTK
• Sequence length: 659 AA.
• Domain: 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.
• Sequence similarities: Bruton tyrosine kinase 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.
• Post-translational modification: 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.
• Cofactor: Bruton tyrosine kinase binds 1 zinc ion per subunit.
• Subunit structure: Bruton tyrosine kinase 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.
• Subcellular location: 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 CRM
• Tissue specificity: Bruton tyrosine kinase is predominantly expressed in B lymphocytes.
• Involvement in disease: Defects in Bruton tyrosine kinase are the cause of X-linked agammaglobulinemia (XLA) [MIM:300755]; also known as X-linked agammaglobulinemia type 1 (AGMX1) or immunodeficiency type 1 (IMD1). XLA is a 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
• Catalytic activity: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
• Enzyme regulation: Bruton tyrosine kinase is activated by phosphorylation. In primary B lymphocytes, is almost always non-phosphorylated and is thus catalytically inactive. Stimulation of TLR8 and TLR9 causes Bruton tyrosine kinase activation. As a negative feedback mechanism to fine-tune BCR signaling, activated PRKCB down-modulates Bruton tyrosine kinase 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 Bruton tyrosine kinase. LFM-13A is a specific inhibitor of BTK. Dasatinib, a cancer drug acting as a tyrosine kinase inhibitor, also blocks Bruton tyrosine kinase activity.

General information above from UniProt

Function for Bruton tyrosine kinase Protein

UniProtKB:

Bruton tyrosine kinase, Non-receptor tyrosine kinase is indispensable for B lymphocyte development, differentiation and signaling. Binding of antigen to the B-cell antigen receptor (BCR) triggers signaling that ultimately leads to B-cell activation. After BCR engagement and activation at the plasma membrane, phosphorylates PLCG2 at several sites, igniting the downstream signaling pathway through calcium mobilization, followed by activation of the protein kinase C (PKC) family members. PLCG2 phosphorylation is performed in close cooperation with the adapter protein B-cell linker protein BLNK. Bruton tyrosine kinase acts as a platform to bring together a diverse array of signaling proteins and is implicated in cytokine receptor signaling pathways. Bruton tyrosine kinase plays an important role in the function of immune cells of innate as well as adaptive immunity, as a component of the Toll-like receptors (TLR) pathway. The TLR pathway acts as a primary surveillance system for the detection of pathogens and are crucial to the activation of host defense. Especially, is a critical molecule in regulating TLR9 activation in splenic B-cells. Within the TLR pathway, induces tyrosine phosphorylation of TIRAP which leads to TIRAP degradation. Bruton tyrosine kinase plays also a critical role in transcription regulation. Induces the activity of NF-kappa-B, which is involved in regulating the expression of hundreds of genes. BTK is involved on the signaling pathway linking TLR8 and TLR9 to NF-kappa-B. Transiently phosphorylates transcription factor GTF2I on tyrosine residues in response to BCR. GTF2I then translocates to the nucleus to bind regulatory enhancer elements to modulate gene expression. ARID3A and NFAT are other transcriptional target of Bruton tyrosine kinase. BTK is required for the formation of functional ARID3A DNA-binding complexes. There is however no evidence that BTK itself binds directly to DNA. Bruton tyrosine kinase has a dual role in the regulation of apoptosis.

Genatlas:

• Bruton tyrosine kinase is non receptor tyrosine kinase
• coupling activated immunoreceptors to downstream signaling events
• Bruton tyrosine kinase plays a crucial roles in the differentiation and activation of B and myeloid cells
• Bruton tyrosine kinase has negative regulatory functions in dendritic cells, mediated mainly through autocrine secretion of IL10 and subsequent activation of STAT3
• Bruton tyrosine kinase is required for NFkappaB activation, participating in the pathway to increased phosphorylation of RELA on serine 536 activated by TLR8 and TLR9 (Pubmed 17932028)
• is required for the initial loss of tolerance to DNA and the subsequent production of pathogenic autoantibodies once tolerance is breached (Pubmed 18849077)
• Bruton tyrosine kinase plays a central role in signal transduction pathways regulating survival, activation, proliferation, and differentiation of B-lineage lymphoid cells (Pubmed 19206206)
• Bruton tyrosine kinase signaling is crucial for optimal actin cytoskeletal organization and lacunar resorption in isolated osteoclasts (Pubmed 20715177)
• Bruton tyrosine kinase is essential for B cell development and function and also appears to be important for myeloid cells (Pubmed 21063022)
• Bruton tyrosine kinase is the important regulator of neutrophilic granulocyte maturation and function (Pubmed 21063022)

Phenotype Information for Bruton tyrosine kinase

• Gene/Locus: BTK, AGMX1, IMD1, XLA, AT
• Phenotype: Agammaglobulinemia and isolated hormone deficiency
  Agammaglobulinemia, X-linked 1