ブルトン型チロシンキナーゼ Tyrosine-protein kinase BTK

https://www.uniprot.org/uniprotkb/Q06187/entry

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).

Activity 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.