Recombinant Human Tyrosine-protein kinase BTK (BTK)

Function

Non-receptor tyrosine kinase indispensable for B lymphocyte development, differentiation and signaling (PubMed:19290921). Binding of antigen to the B-cell antigen receptor (BCR) triggers signaling that ultimately leads to B-cell activation (PubMed:19290921). 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 (PubMed:11606584). PLCG2 phosphorylation is performed in close cooperation with the adapter protein B-cell linker protein BLNK (PubMed:11606584). BTK acts as a platform to bring together a diverse array of signaling proteins and is implicated in cytokine receptor signaling pathways (PubMed:16517732, PubMed:17932028). 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 (PubMed:16517732). The TLR pathway acts as a primary surveillance system for the detection of pathogens and are crucial to the activation of host defense (PubMed:16517732). Especially, is a critical molecule in regulating TLR9 activation in splenic B-cells (PubMed:16517732, PubMed:17932028). Within the TLR pathway, induces tyrosine phosphorylation of TIRAP which leads to TIRAP degradation (PubMed:16415872). BTK also plays a critical role in transcription regulation (PubMed:19290921). Induces the activity of NF-kappa-B, which is involved in regulating the expression of hundreds of genes (PubMed:19290921). BTK is involved on the signaling pathway linking TLR8 and TLR9 to NF-kappa-B (PubMed:19290921). Acts as an activator of NLRP3 inflammasome assembly by mediating phosphorylation of NLRP3 (PubMed:34554188). Transiently phosphorylates transcription factor GTF2I on tyrosine residues in response to BCR (PubMed:9012831). GTF2I then translocates to the nucleus to bind regulatory enhancer elements to modulate gene expression (PubMed:9012831). ARID3A and NFAT are other transcriptional target of BTK (PubMed:16738337). BTK is required for the formation of functional ARID3A DNA-binding complexes (PubMed:16738337). There is however no evidence that BTK itself binds directly to DNA (PubMed:16738337). BTK has a dual role in the regulation of apoptosis (PubMed:9751072). Plays a role in STING1-mediated induction of type I interferon (IFN) response by phosphorylating DDX41 (PubMed:25704810)

Subcellular Location

Cytoplasm; Cell membrane (Peripheral membrane protein); Nucleus; Membrane raft

Disease Association

X-linked agammaglobulinemia (XLA) : 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. [The disease is caused by variants affecting the gene represented in this entry] | Growth hormone deficiency, isolated, 3, with agammaglobulinemia (IGHD3) : An X-linked recessive disorder characterized by growth hormone deficiency, short stature, delayed bone age, agammaglobulinemia with markedly reduced numbers of B cells, and good response to treatment with growth hormone. [The disease may be caused by variants affecting the gene represented in this entry]

Tissue Specificity

Predominantly expressed in B-lymphocytes

Subunit

Part of a complex composed of EEIG1, TNFRSF11A/RANK, PLCG2, GAB2, TEC and BTK; complex formation increases in the presence of TNFSF11/RANKL (By similarity). 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. Interacts with MPL/TPOR (PubMed:24607955). Interacts with STAC2; this interaction affects association with PLCG2 and subsequent PLCG2 phosphorylation (By similarity)

• Vetrie D. et al. The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases. — Nature (1993)
• Vetrie D. et al. PubMed: CI-DCI5D3MUL42TD — Nature (1993)
• Ohta Y. et al. Genomic organization and structure of Bruton agammaglobulinemia tyrosine kinase: localization of mutations associated with varied clinical presentations and course in X chromosome-linked agammaglobulinemia. — Proc. Natl. Acad. Sci. U.S.A. (1994)
• Rohrer J. et al. The genomic structure of human BTK, the defective gene in X-linked agammaglobulinemia. — Immunogenetics (1994)
• Hagemann T.L. et al. Genomic organization of the Btk gene and exon scanning for mutations in patients with X-linked agammaglobulinemia. — Hum. Mol. Genet. (1994)
• Oeltjen J.C. et al. Sixty-nine kilobases of contiguous human genomic sequence containing the alpha-galactosidase A and Bruton's tyrosine kinase loci. — Mamm. Genome (1995)
• Ota T. et al. Complete sequencing and characterization of 21,243 full-length human cDNAs. — Nat. Genet. (2004)
• Ross M.T. et al. The DNA sequence of the human X chromosome. — Nature (2005)