ID:BTK_HUMAN DESCRIPTION: RecName: Full=Tyrosine-protein kinase BTK; EC=2.7.10.2; AltName: Full=Agammaglobulinaemia tyrosine kinase; Short=ATK; AltName: Full=B-cell progenitor kinase; Short=BPK; AltName: Full=Bruton tyrosine kinase; FUNCTION: Non-receptor tyrosine kinase 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. BTK acts as a platform to bring together a diverse array of signaling proteins and is implicated in cytokine receptor signaling pathways. 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. BTK 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 BTK. BTK is required for the formation of functional ARID3A DNA-binding complexes. There is however no evidence that BTK itself binds directly to DNA. BTK has a dual role in the regulation of apoptosis. CATALYTIC ACTIVITY: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate. COFACTOR: Binds 1 zinc ion per subunit. ENZYME REGULATION: 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. SUBUNIT: 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. INTERACTION: Self; NbExp=2; IntAct=EBI-624835, EBI-624835; P78347:GTF2I; NbExp=5; IntAct=EBI-624835, EBI-359622; P21145:MAL; NbExp=5; IntAct=EBI-624835, EBI-3932027; Q04759:PRKCQ; NbExp=2; IntAct=EBI-624835, EBI-374762; O60239:SH3BP5; NbExp=4; IntAct=EBI-624835, EBI-624860; 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 CRM1. TISSUE SPECIFICITY: Predominantly expressed in B-lymphocytes. 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. PTM: 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. DISEASE: Defects in BTK 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. DISEASE: Defects in BTK may be the cause of X-linked hypogammaglobulinemia and isolated growth hormone deficiency (XLA- IGHD) [MIM:307200]; also known as agammaglobulinemia and isolated growth hormone deficiency or Fleisher syndrome or isolated growth hormone deficiency type 3 (IGHD3). In rare cases XLA is inherited together with isolated growth hormone deficiency (IGHD). SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein kinase family. TEC subfamily. SIMILARITY: Contains 1 Btk-type zinc finger. SIMILARITY: Contains 1 PH domain. SIMILARITY: Contains 1 protein kinase domain. SIMILARITY: Contains 1 SH2 domain. SIMILARITY: Contains 1 SH3 domain. WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/BTKID851chXq22.html"; WEB RESOURCE: Name=BTKbase; Note=BTK mutation db; URL="http://bioinf.uta.fi/BTKbase/"; WEB RESOURCE: Name=GeneReviews; URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/BTK";
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on Q06187
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Biological Process: GO:0001805 positive regulation of type III hypersensitivity GO:0001812 positive regulation of type I hypersensitivity GO:0001818 negative regulation of cytokine production GO:0002250 adaptive immune response GO:0002344 B cell affinity maturation GO:0002376 immune system process GO:0002553 histamine secretion by mast cell GO:0002721 regulation of B cell cytokine production GO:0002755 MyD88-dependent toll-like receptor signaling pathway GO:0002902 regulation of B cell apoptotic process GO:0006351 transcription, DNA-templated GO:0006355 regulation of transcription, DNA-templated GO:0006468 protein phosphorylation GO:0006915 apoptotic process GO:0007169 transmembrane receptor protein tyrosine kinase signaling pathway GO:0007249 I-kappaB kinase/NF-kappaB signaling GO:0007498 mesoderm development GO:0010033 response to organic substance GO:0016310 phosphorylation GO:0018108 peptidyl-tyrosine phosphorylation GO:0019722 calcium-mediated signaling GO:0030889 negative regulation of B cell proliferation GO:0034614 cellular response to reactive oxygen species GO:0035556 intracellular signal transduction GO:0038083 peptidyl-tyrosine autophosphorylation GO:0038095 Fc-epsilon receptor signaling pathway GO:0042113 B cell activation GO:0042127 regulation of cell proliferation GO:0045087 innate immune response GO:0045579 positive regulation of B cell differentiation GO:0046777 protein autophosphorylation GO:0048469 cell maturation GO:0050853 B cell receptor signaling pathway GO:0051092 positive regulation of NF-kappaB transcription factor activity GO:0071226 cellular response to molecule of fungal origin GO:0097190 apoptotic signaling pathway GO:0098761 cellular response to interleukin-7
KF241986 - Homo sapiens truncated Bruton agammaglobulinemia tyrosine kinase (BTK) mRNA, complete cds. AK057105 - Homo sapiens cDNA FLJ32543 fis, clone SMINT2000538, highly similar to Tyrosine-protein kinase BTK (EC 2.7.10.2). X58957 - H.sapiens atk mRNA for agammaglobulinaemia tyrosine kinase. AM051281 - Homo sapiens partial mRNA for dominant-negative kinase-deficient Brutons tyrosine kinase isoform 7 (BTK kinase deficient isoform 7 gene), cell type TEL-AML1+ leukemia cells. BC109079 - Homo sapiens Bruton agammaglobulinemia tyrosine kinase, mRNA (cDNA clone MGC:126261 IMAGE:40034287), complete cds. BC109080 - Homo sapiens Bruton agammaglobulinemia tyrosine kinase, mRNA (cDNA clone MGC:126262 IMAGE:40034289), complete cds. JD101417 - Sequence 82441 from Patent EP1572962. AM051275 - Homo sapiens partial mRNA for dominant-negative kinase-deficient Brutons tyrosine kinase isoform 1 (BTK kinase deficient isoform 1 gene), cell type BCR-ABL1+ and MLL-AF4+ leukemia cells. AM051276 - Homo sapiens partial mRNA for dominant-negative kinase-deficient Brutons tyrosine kinase isoform 2 (BTK kinase deficient isoform 2 gene), cell type MLL-AF4+ leukemia cells. AM051277 - Homo sapiens partial mRNA for dominant-negative kinase-deficient Brutons tyrosine kinase isoform 3 (BTK kinase deficient isoform 3 gene), cell type MLL-AF4+ leukemia cells. AM051278 - Homo sapiens partial mRNA for dominant-negative kinase-deficient Brutons tyrosine kinase isoform 4 (BTK kinase deficient isoform 4 gene), cell type BCR-ABL1+ leukemia cells. AM051279 - Homo sapiens partial mRNA for dominant-negative kinase-deficient Brutons tyrosine kinase isoform 5 (BTK kinase deficient isoform 5 gene), cell type BCR-ABL1+ leukemia cells. AM051280 - Homo sapiens partial mRNA for dominant-negative kinase-deficient Brutons tyrosine kinase isoform 6 (BTK kinase deficient isoform 6 gene), cell type BCR-ABL1+ leukemia cells. AM051282 - Homo sapiens partial mRNA for dominant-negative kinase-deficient Brutons tyrosine kinase isoform 8 (BTK kinase deficient isoform 8 gene), cell type TEL-AML1+ leukemia cells. AM051283 - Homo sapiens partial mRNA for dominant-negative kinase-deficient Brutons tyrosine kinase isoform 9 (BTK kinase deficient isoform 9 gene), cell type TEL-AML1+ leukemia cells. AM051285 - Homo sapiens partial mRNA for dominant-negative kinase-deficient Brutons tyrosine kinase isoform 11 (BTK kinase deficient isoform 11 gene), cell type E2A-PBX1+ leukemia cells. AM051286 - Homo sapiens partial mRNA for dominant-negative kinase-deficient Brutons tyrosine kinase isoform 12 (BTK kinase deficient isoform 12 gene), cell type E2A-PBX1+ leukemia cells. AM051284 - Homo sapiens partial mRNA for dominant-negative kinase-deficient Brutons tyrosine kinase isoform 10 (BTK kinase deficient isoform 10 gene), cell type TEL-AML1+ leukemia cells. AK309851 - Homo sapiens cDNA, FLJ99892. AF153364 - Homo sapiens Bruton's tyrosine kinase mRNA, complete cds. AF153756 - Homo sapiens Bruton's tyrosine kinase mRNA, complete cds. AF153757 - Homo sapiens Bruton's tyrosine kinase mRNA, complete cds. AF153758 - Homo sapiens Bruton's tyrosine kinase mRNA, complete cds. AF153759 - Homo sapiens Bruton's tyrosine kinase mRNA, complete cds. AF153760 - Homo sapiens Bruton's tyrosine kinase mRNA, complete cds. AF153761 - Homo sapiens Bruton's tyrosine kinase mRNA, complete cds. AF153762 - Homo sapiens Bruton's tyrosine kinase mRNA, complete cds. AF153764 - Homo sapiens Bruton's tyrosine kinase mRNA, partial cds. AK314382 - Homo sapiens cDNA, FLJ95155, highly similar to Homo sapiens Bruton agammaglobulinemia tyrosine kinase (BTK), mRNA. KJ890786 - Synthetic construct Homo sapiens clone ccsbBroadEn_00180 BTK gene, encodes complete protein. KR711531 - Synthetic construct Homo sapiens clone CCSBHm_00025588 BTK (BTK) mRNA, encodes complete protein. KR711532 - Synthetic construct Homo sapiens clone CCSBHm_00025631 BTK (BTK) mRNA, encodes complete protein. KR711533 - Synthetic construct Homo sapiens clone CCSBHm_00025709 BTK (BTK) mRNA, encodes complete protein. KR711534 - Synthetic construct Homo sapiens clone CCSBHm_00025787 BTK (BTK) mRNA, encodes complete protein. AJ888376 - Homo sapiens partial mRNA for tyrosine-protein kinase BTK isoform 65 (BTK gene), tissue type BCR-ABL1+ pre-B lymphoblastic leukemia. AJ888379 - Homo sapiens partial mRNA for tyrosine-protein kinase BTK isoform (lacking exon 13 to 17) (BTK gene), tissue type BCR-ABL1+ pre-B lymphoblastic leukemia. AJ888380 - Homo sapiens partial mRNA for tyrosine-protein kinase BTK isoform (lacking exon 15 to 18) (BTK gene), tissue type BCR-ABL1+ pre-B lymphoblastic leukemia. AB590081 - Synthetic construct DNA, clone: pFN21AE0996, Homo sapiens BTK gene for Bruton agammaglobulinemia tyrosine kinase, without stop codon, in Flexi system. AJ888378 - Homo sapiens partial mRNA for tyrosine-protein kinase BTK isoform 52 (BTK gene), tissue type BCR-ABL1+ pre-B lymphoblastic leukemia. AJ888381 - Homo sapiens partial mRNA for tyrosine-protein kinase BTK isoform (lacking exon 14) (BTK gene), tissue type BCR-ABL1+ pre-B lymphoblastic leukemia. AJ888377 - Homo sapiens partial mRNA for tyrosine-protein kinase BTK isoform 51 (BTK gene), tissue type BCR-ABL1+ pre-B lymphoblastic leukemia. AK225577 - Homo sapiens mRNA for Bruton agammaglobulinemia tyrosine kinase variant, clone: LNG09949. AF153763 - Homo sapiens Bruton's tyrosine kinase mRNA, partial cds. DL491428 - Novel nucleic acids. AF153755 - Homo sapiens Bruton's tyrosine kinase mRNA, partial cds. JD284811 - Sequence 265835 from Patent EP1572962.
Biochemical and Signaling Pathways
BioCarta from NCI Cancer Genome Anatomy Project h_bcrPathway - BCR Signaling Pathway h_ptdinsPathway - Phosphoinositides and their downstream targets. h_fcer1Pathway - Fc Epsilon Receptor I Signaling in Mast Cells
Reactome (by CSHL, EBI, and GO)
Protein Q06187 (Reactome details) participates in the following event(s):
R-HSA-2424481 Recruitment of VAV and BTK to p-SLP-76 R-HSA-2559414 Activated TLR2/4:MAL interacts with BTK R-HSA-166072 MyD88 forms a complex with MAL:activated TLR2/4 R-HSA-2201322 MAL is phosphorylated by BTK R-HSA-2424484 Phosphorylation of BTK by p-SYK R-HSA-2424486 Phosphorylation and activation of VAV2/VAV3 by SYK R-HSA-2730885 Recruitment of TEC kinases to p-SLP-76 R-HSA-2424487 Phosphorylation of PLC-gamma by p-BTK/p-SYK R-HSA-2424485 Release of p-PLCG1 R-HSA-937079 MyD88 oligomerization within the complex of activated TLR:Mal:MyD88 R-HSA-166082 IRAK4 binds to the activated TLR receptor:Mal:MyD88 complex R-HSA-2424476 Activation of RAC1 by VAV2/3 R-HSA-2730833 Phosphorylation of TEC kinases by p-SYK R-HSA-2197698 Phosphorylation of WASP/N-WASP R-HSA-2730888 Phosphorylation of PLC-gamma R-HSA-2730858 Autophosphorylation of BTK/ITK R-HSA-937022 IRAK4 autophosphorylation in the complex with activated TLR:MyD88:Mal R-HSA-166091 IRAK1 or IRAK2 binds to the activated IRAK4 :activated TLR:MyD88:Mal complex R-HSA-166362 Dissociation of hp-IRAK1:TRAF6 from the activated TLR:oligo-Myd88:Mal:p-IRAK4 complex R-HSA-2262775 Dissociation of p-IRAK2:TRAF6 from the activated TLR:oligo-Myd88:Mal:p-IRAK4 complex R-HSA-1112666 BLNK (SLP-65) Signalosome hydrolyzes phosphatidyinositol bisphosphate forming diacylglycerol and inositol-1,4,5-trisphosphate R-HSA-2730847 Hydrolysis of PIP2 by PLCG R-HSA-166286 Multiple IRAK1 autophosphorylation steps R-HSA-166284 Second phosphorylation of IRAK1 by IRAK4 bound to activated TLR:MyD88:Mal R-HSA-166119 First phosphorylation of IRAK1 by IRAK4 bound to activated TLR:MyD88:Mal R-HSA-166363 TRAF6 binds to hp- IRAK1 R-HSA-937059 Phosphorylation of IRAK2 bound to the activated IRAK4:MyD88 oligomer:Mal:activated TLR complex R-HSA-2262777 TRAF6 binds to p-IRAK2 R-HSA-983695 Antigen activates B Cell Receptor (BCR) leading to generation of second messengers R-HSA-2424491 DAP12 signaling R-HSA-166058 MyD88:Mal cascade initiated on plasma membrane R-HSA-5602498 MyD88 deficiency (TLR2/4) R-HSA-2871809 FCERI mediated Ca+2 mobilization R-HSA-983705 Signaling by the B Cell Receptor (BCR) R-HSA-2172127 DAP12 interactions R-HSA-166016 Toll Like Receptor 4 (TLR4) Cascade R-HSA-168179 Toll Like Receptor TLR1:TLR2 Cascade R-HSA-168188 Toll Like Receptor TLR6:TLR2 Cascade R-HSA-5603041 IRAK4 deficiency (TLR2/4) R-HSA-5602358 Diseases associated with the TLR signaling cascade R-HSA-2454202 Fc epsilon receptor (FCERI) signaling R-HSA-2029482 Regulation of actin dynamics for phagocytic cup formation R-HSA-5663213 RHO GTPases Activate WASPs and WAVEs R-HSA-1280218 Adaptive Immune System R-HSA-168249 Innate Immune System R-HSA-168898 Toll-Like Receptors Cascades R-HSA-181438 Toll Like Receptor 2 (TLR2) Cascade R-HSA-5260271 Diseases of Immune System R-HSA-2029480 Fcgamma receptor (FCGR) dependent phagocytosis R-HSA-195258 RHO GTPase Effectors R-HSA-168256 Immune System R-HSA-1643685 Disease R-HSA-194315 Signaling by Rho GTPases R-HSA-162582 Signal Transduction
US Server
Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
