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BTK

Official Full Name
Bruton tyrosine kinase
Organism
Homo sapiens
GeneID
695
Background
The protein encoded by this gene plays a crucial role in B-cell development. Mutations in this 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. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2013]
Synonyms
AT; ATK; BPK; XLA; IMD1; AGMX1; IGHD3; PSCTK1;
Bio Chemical Class
Kinase
Protein Sequence
MAAVILESIFLKRSQQKKKTSPLNFKKRLFLLTVHKLSYYEYDFERGRRGSKKGSIDVEKITCVETVVPEKNPPPERQIPRRGEESSEMEQISIIERFPYPFQVVYDEGPLYVFSPTEELRKRWIHQLKNVIRYNSDLVQKYHPCFWIDGQYLCCSQTAKNAMGCQILENRNGSLKPGSSHRKTKKPLPPTPEEDQILKKPLPPEPAAAPVSTSELKKVVALYDYMPMNANDLQLRKGDEYFILEESNLPWWRARDKNGQEGYIPSNYVTEAEDSIEMYEWYSKHMTRSQAEQLLKQEGKEGGFIVRDSSKAGKYTVSVFAKSTGDPQGVIRHYVVCSTPQSQYYLAEKHLFSTIPELINYHQHNSAGLISRLKYPVSQQNKNAPSTAGLGYGSWEIDPKDLTFLKELGTGQFGVVKYGKWRGQYDVAIKMIKEGSMSEDEFIEEAKVMMNLSHEKLVQLYGVCTKQRPIFIITEYMANGCLLNYLREMRHRFQTQQLLEMCKDVCEAMEYLESKQFLHRDLAARNCLVNDQGVVKVSDFGLSRYVLDDEYTSSVGSKFPVRWSPPEVLMYSKFSSKSDIWAFGVLMWEIYSLGKMPYERFTNSETAEHIAQGLRLYRPHLASEKVYTIMYSCWHEKADERPTFKILLSNILDVMDEES
Open
Disease
Acute myeloid leukaemia, Atopic eczema, Autoimmune disease, B-cell lymphoma, Diabetes mellitus, Diffuse large B-cell lymphoma, Follicular lymphoma, Lupus erythematosus, Malignant haematopoietic neoplasm, Mature B-cell leukaemia, Mature B-cell lymphoma, Multiple sclerosis, Pancreatic cancer, Pemphigus, Rheumatoid arthritis, Solid tumour/cancer, Spontaneous urticaria
Approved Drug
4 +
Clinical Trial Drug
35 +
Discontinued Drug
1 +

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Detailed Information

Crucially for B cell growth, differentiation, and signaling is BTK, a non-receptor tyrosine kinase. An antigen attaching to the B-cell antigen receptor (BCR starts a series of signaling reactions that finally result in B-cell activation. BTK phosphorylates phospholipase C-gamma 2 (PLCG2) at many places upon BCR interaction, therefore starting a downstream signaling cascade that mobilizes calcium ions and activates members of the protein kinase C (PKC) family. Close coordination of this phosphorylation process with the adaptor protein B-cell linker protein (BLNK) establishes BTK as a fundamental signaling center for B-cell activation and activity.

BTK and Cytokine Signaling

Beyond its role in B-cell signaling, BTK is also implicated in various cytokine receptor signaling pathways, particularly within the Toll-like receptor (TLR) pathway. TLRs serve as a primary surveillance mechanism for detecting pathogens, thus playing a pivotal role in both innate and adaptive immunity. BTK is crucial in regulating TLR9 activation in splenic B-cells, where it induces tyrosine phosphorylation of TIRAP, facilitating its degradation and subsequent downstream signaling.

Transcriptional Regulation

BTK's impact reaches into transcriptional control, in which it activates important transcription factors like NF-kappa-B, therefore controlling the expression of several immune-related genes. BTK's regulating ability in B-cell growth and function is highlighted by interactions with other transcriptional targets like ARID3A and NFAT. Though direct proof of BTK binding to DNA is lacking, it is essential for the creation of DNA-binding complexes required for the regulation of gene expression.

Role in Apoptosis

Fascinatingly, BTK displays its complex involvement in cellular processes beyond basic signalling and serves two purposes in the regulation of death. Understanding BTK's arrangement of these functions may assist one to grasp its probable therapy targets for various diseases.

Structural Insights

Since BTK's 1990s discovery, structural elements of the work have been extensively examined. Part of the Tec family of kinases, BTK has two SRC homology domains (SH2 and SH3), a kinase domain, an N-terminal pleckstrin homology (PH) domain, and a TEC homology domain. Unlike SRC kinases, BTK lives mostly in the cytoplasm and translocates to the membrane upon activation—a process driven by PIP3 production. BTK activation depends on phosphorylation at the 551 location of the kinase domain; other kinases such as SYK and SRC may help to mediate this process.

BCR Signaling Pathway

BTK is positioned downstream of the antigen receptor within the BCR signaling pathway, where it is essential for B-cell activation. A sequence of phosphorylation events follows upon BCR activation, including phosphorylation of PLCG2, necessary for producing second messengers controlling downstream signaling pathways. BTK's significance in B-cell maturation and function is shown by its capacity to create a positive feedback loop by means of interactions with other kinases.

Figure 1 illustrates the multiple roles of Bruton tyrosine kinase (BTK) in regulating innate immune responses, including its involvement in chemokine signaling, Fc receptor activation, Toll-like receptor pathways, and inflammasome assembly.Figure 1. Roles of Bruton's tyrosine kinase (BTK) in innate immunity. (McDonald C, et al., 2021)

Toll-Like Receptor Interactions

Pathogen-associated molecular patterns (PAMPs) rely on toll-like receptors (TLRs) to be recognized as such. Effective immune responses depend on the interaction of BCR and TLR signaling pathways. BTK's participation in TLR signaling—especially via its interaction with MYD88—emphasizes its function in connecting innate and adaptive immunity. Recent research points to BTK as a possible target for therapeutic approaches as abnormalities in TLR signaling may lead to diseases such as chronic lymphocytic leukemia (CLL).

Chemokine Receptor Signaling

Crucially for B-cell trafficking and function, BTK also engages in chemokine receptor signaling pathways. BTK's function in controlling B-cell migration from peripheral blood to lymphoid tissues is best shown by the stimulation of CXCR4 by S DF-1. Moreover, BTK expression has been connected to abnormalities in actin remodeling, thus highlighting the many character of its signaling channels.

Nuclear Functions of BTK

Though mostly a cytoplasmic protein, BTK is found in limited amounts inside the nucleus where it acts as a transcriptionally regulating agent. Though various proteins are modulators of BTK's nucleocytoplasmic shuttling, the mechanisms controlling this process are still unknown. The nuclear presence of BTK has been connected to TNF expression control, suggesting possible paths for anti-inflammatory treatments via TLR signaling modification.

BTK and Immune Cell Function

Apart from their functions in B-cells, BTK is also expressed in other immune cells including dendritic cells, macrophages, and mast cells. From pathogen eradication to regulation of inflammatory processes, this wide expression profile shows its participation in many aspects of the immune response. The functional adaptability of BTK emphasizes its importance as a target for therapeutic approaches meant to boost immune responses or reduce autoimmune disorders.

References:

  1. McDonald C, Xanthopoulos C, Kostareli E. The role of Bruton's tyrosine kinase in the immune system and disease. Immunology. 2021;164(4):722-736. doi:10.1111/imm.13416
  2. Mohamed AJ, Yu L, Bäckesjö CM, et al. Bruton's tyrosine kinase (Btk): function, regulation, and transformation with special emphasis on the PH domain. Immunol Rev. 2009;228(1):58-73.
  3. Churcher I. Protac-Induced Protein Degradation in Drug Discovery: Breaking the Rules or Just Making New Ones?. J Med Chem. 2018;61(2):444-452.
  4. Hanley SE, Cooper KF. Sorting Nexins in Protein Homeostasis. Cells. 2020;10(1):17.
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