Names & Taxonomy

Uniprot ID:
Q06187
Entry Name:
BTK_HUMAN
Status:
reviewed
Protein Names:
Tyrosine-protein kinase BTK (EC 2.7.10.2) (Agammaglobulinemia tyrosine kinase) (ATK) (B-cell progenitor kinase) (BPK) (Bruton tyrosine kinase)
Gene Names:
BTK AGMX1 ATK BPK
Gene Names Primary:
BTK
Organism:
Homo sapiens (Human)

Structure

Length:
659
Sequence:
MAAVILESIFLKRSQQKKKTSPLNFKKRLFLLTVHKLSYYEYDFERGRRGSKKGSIDVEKITCVETVVPEKNPPPERQIPRRGEESSEMEQISIIERFPYPFQVVYDEGPLYVFSPTEELRKRWIHQLKNVIRYNSDLVQKYHPCFWIDGQYLCCSQTAKNAMGCQILENRNGSLKPGSSHRKTKKPLPPTPEEDQILKKPLPPEPAAAPVSTSELKKVVALYDYMPMNANDLQLRKGDEYFILEESNLPWWRARDKNGQEGYIPSNYVTEAEDSIEMYEWYSKHMTRSQAEQLLKQEGKEGGFIVRDSSKAGKYTVSVFAKSTGDPQGVIRHYVVCSTPQSQYYLAEKHLFSTIPELINYHQHNSAGLISRLKYPVSQQNKNAPSTAGLGYGSWEIDPKDLTFLKELGTGQFGVVKYGKWRGQYDVAIKMIKEGSMSEDEFIEEAKVMMNLSHEKLVQLYGVCTKQRPIFIITEYMANGCLLNYLREMRHRFQTQQLLEMCKDVCEAMEYLESKQFLHRDLAARNCLVNDQGVVKVSDFGLSRYVLDDEYTSSVGSKFPVRWSPPEVLMYSKFSSKSDIWAFGVLMWEIYSLGKMPYERFTNSETAEHIAQGLRLYRPHLASEKVYTIMYSCWHEKADERPTFKILLSNILDVMDEES
Proteomes:
UP000005640

Subcellular location

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.

Function

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 -L-tyrosine = ADP + a -L-tyrosine phosphate.
Cofactor:
COFACTOR: Name=Zn(2+); Xref=ChEBI:CHEBI:29105; ; Note=Binds 1 zinc ion per subunit.;
Enzyme Regulation:
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.
Active Site:
ACT_SITE 521 521 Proton acceptor.
Cross Reference Drug Bank:
DB09053
Gene Ontology Go:
cytoplasm
cytoplasmic vesicle
cytosol
extrinsic component of cytoplasmic side of plasma membrane
intracellular membrane-bounded organelle
membrane raft
nucleus
plasma membrane
ATP binding
identical protein binding
metal ion binding
non-membrane spanning protein tyrosine kinase activity
phosphatidylinositol-3,4,5-trisphosphate binding
protein tyrosine kinase activity
adaptive immune response
apoptotic signaling pathway
B cell activation
B cell receptor signaling pathway
calcium-mediated signaling
cell differentiation
cell maturation
Fc-epsilon receptor signaling pathway
I-kappaB kinase/NF-kappaB signaling
innate immune response
intracellular signal transduction
mesoderm development
MyD88-dependent toll-like receptor signaling pathway
negative regulation of cytokine production
peptidyl-tyrosine autophosphorylation
peptidyl-tyrosine phosphorylation
positive regulation of B cell differentiation
positive regulation of NF-kappaB transcription factor activity
protein phosphorylation
regulation of B cell apoptotic process
regulation of B cell cytokine production
regulation of cell proliferation
toll-like receptor 2 signaling pathway
toll-like receptor 4 signaling pathway
toll-like receptor signaling pathway
toll-like receptor TLR1:TLR2 signaling pathway
toll-like receptor TLR6:TLR2 signaling pathway
transcription, DNA-templated
transmembrane receptor protein tyrosine kinase signaling pathway
Gene Ontology Biological Process:
adaptive immune response
apoptotic signaling pathway
B cell activation
B cell receptor signaling pathway
calcium-mediated signaling
cell differentiation
cell maturation
Fc-epsilon receptor signaling pathway
I-kappaB kinase/NF-kappaB signaling
innate immune response
intracellular signal transduction
mesoderm development
MyD88-dependent toll-like receptor signaling pathway
negative regulation of cytokine production
peptidyl-tyrosine autophosphorylation
peptidyl-tyrosine phosphorylation
positive regulation of B cell differentiation
positive regulation of NF-kappaB transcription factor activity
protein phosphorylation
regulation of B cell apoptotic process
regulation of B cell cytokine production
regulation of cell proliferation
toll-like receptor 2 signaling pathway
toll-like receptor 4 signaling pathway
toll-like receptor signaling pathway
toll-like receptor TLR1:TLR2 signaling pathway
toll-like receptor TLR6:TLR2 signaling pathway
transcription, DNA-templated
transmembrane receptor protein tyrosine kinase signaling pathway
Gene Ontology Molecular Function:
ATP binding
identical protein binding
metal ion binding
non-membrane spanning protein tyrosine kinase activity
phosphatidylinositol-3,4,5-trisphosphate binding
protein tyrosine kinase activity
Gene Ontology Cellular Component:
cytoplasm
cytoplasmic vesicle
cytosol
extrinsic component of cytoplasmic side of plasma membrane
intracellular membrane-bounded organelle
membrane raft
nucleus
plasma membrane
Keywords:
3D-structure
ATP-binding
Acetylation
Adaptive immunity
Alternative promoter usage
Apoptosis
Cell membrane
Complete proteome
Cytoplasm
Direct protein sequencing
Disease mutation
Immunity
Innate immunity
Kinase
Lipid-binding
Membrane
Metal-binding
Nucleotide-binding
Nucleus
Phosphoprotein
Polymorphism
Reference proteome
SH2 domain
SH3 domain
Transcription
Transcription regulation
Transferase
Tyrosine-protein kinase
Zinc
Zinc-finger
Interacts With:
Itself; Q99856; Q8WV28; P78347; P08238; P21145; Q04759; O60239; P42768

Publication

PubMed ID:
8380905 8090769 7927535 7880320 7626884 14702039 15772651 15489334 8425221 12573241 8013627 8070576 8630736 9012831 9571151 10196179 10339589 10602036 11016936 11598012 11606584 11577348 11751885 15375214 16644721 16517732 16738337 16415872 17932028 19807924 9751072 19290921 19369195 21269460 23913792 25944712 9218782 9485443 10196129 10826882 11527964 16969585 20052711 21280133 8594569 9016530 8162056 8162018 7849697 7849721 7809124 7849006 7711734 7633420 7633429 8634718 7627183 7897635 8723128 8695804 8834236 9280283 9260159 9545398 9445504 10220140 10678660 10612838 17344846 24869598 24869597 25189416