Bruton's tyrosine kinase

BTK
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1AWW, 1AWX, 1B55, 1BTK, 1BWN, 1K2P, 1QLY, 2GE9, 2Z0P, 3GEN, 3K54, 3OCS, 3OCT, 3P08, 3PIX, 3PIY, 3PIZ, 3PJ1, 3PJ2, 3PJ3, 4NWM, 4OT5, 4OT6, 4OTF, 4OTQ, 4OTR, 4RFY, 4RFZ, 4RG0, 4YHF, 4Z3V, 4ZLY, 4ZLZ, 5BPY, 5BQ0, 5FBN, 4RX5, 5FBO
Identifiers
Aliases	BTK, AGMX1, AT, ATK, BPK, IMD1, PSCTK1, XLA, Bruton tyrosine kinase, IGHD3
External IDs	OMIM: 300300 MGI: 88216 HomoloGene: 30953 GeneCards: BTK
Gene location (Human) Chr. X chromosome (human)[1] Band Xq22.1 Start 101,349,338 bp[1] End 101,390,796 bp[1]
Gene location (Mouse) Chr. X chromosome (mouse)[2] Band X E3|X 56.18 cM Start 133,443,085 bp[2] End 133,484,319 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in monocyte spleen bone marrow cells lymph node blood appendix right lung upper lobe of left lung rectum gallbladder Top expressed in spleen blood bone marrow secondary oocyte right lobe of liver pharynx body of femur morula subcutaneous adipose tissue yolk sac More reference expression data BioGPS More reference expression data
Gene ontology Molecular function metal ion binding nucleotide binding lipid binding signaling receptor binding identical protein binding protein kinase activity transferase activity kinase activity phosphatidylinositol-3,4,5-trisphosphate binding non-membrane spanning protein tyrosine kinase activity ATP binding protein binding protein tyrosine kinase activity Cellular component cytoplasm nucleus membrane membrane raft extrinsic component of cytoplasmic side of plasma membrane cytoplasmic vesicle cytosol plasma membrane perinuclear region of cytoplasm mast cell granule Biological process transmembrane receptor protein tyrosine kinase signaling pathway mesoderm development intracellular signal transduction peptidyl-tyrosine autophosphorylation B cell activation positive regulation of NF-kappaB transcription factor activity transcription, DNA-templated positive regulation of B cell differentiation B cell receptor signaling pathway Fc-epsilon receptor signaling pathway regulation of cell population proliferation adaptive immune response apoptotic process peptidyl-tyrosine phosphorylation protein phosphorylation negative regulation of cytokine production MyD88-dependent toll-like receptor signaling pathway apoptotic signaling pathway calcium-mediated signaling I-kappaB kinase/NF-kappaB signaling innate immune response regulation of transcription, DNA-templated cell maturation immune system process regulation of B cell cytokine production regulation of B cell apoptotic process phosphorylation histamine secretion by mast cell response to organic substance positive regulation of type III hypersensitivity protein autophosphorylation cellular response to reactive oxygen species cellular response to molecule of fungal origin positive regulation of type I hypersensitivity B cell affinity maturation negative regulation of B cell proliferation cellular response to interleukin-7 T cell receptor signaling pathway G protein-coupled receptor signaling pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 695 12229 Ensembl ENSG00000010671 ENSMUSG00000031264 UniProt Q06187 P35991 RefSeq (mRNA) NM_001287345 NM_000061 NM_001287344 NM_013482 RefSeq (protein) NP_000052 NP_001274273 NP_001274274 NP_038510 Location (UCSC) Chr X: 101.35 – 101.39 Mb Chr X: 133.44 – 133.48 Mb PubMed search [3] [4]
Wikidata
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Bruton's tyrosine kinase (abbreviated Btk or BTK), also known as tyrosine-protein kinase BTK, is a tyrosine kinase that is encoded by the BTK gene in humans. BTK plays a crucial role in B cell development.

Structure

BTK contains five different protein interaction domains. These domains include an amino terminal pleckstrin homology (PH) domain, a proline-rich TEC homology (TH) domain, SRC homology (SH) domains SH2 and SH3, as well as a protein kinase domain with tyrosine phosphorylation activity.^[5]

Part of the TH domain is folded against the PH domain while the rest is intrinsically disordered.

Function

BTK plays a crucial role in B cell development as it is required for transmitting signals from the pre-B cell receptor that forms after successful immunoglobulin heavy chain rearrangement.^[6] It also has a role in mast cell activation through the high-affinity IgE receptor.^[7]

Btk contains a PH domain that binds phosphatidylinositol (3,4,5)-trisphosphate (PIP3). PIP3 binding induces Btk to phosphorylate phospholipase C, which in turn hydrolyzes PIP₂, a phosphatidylinositol, into two second messengers, inositol triphosphate (IP3) and diacylglycerol (DAG), which then go on to modulate the activity of downstream proteins during B-cell signalling.^[8]

Clinical significance

Mutations in the BTK gene are implicated in the primary immunodeficiency disease X-linked agammaglobulinemia (Bruton's agammaglobulinemia); sometimes abbreviated to XLA and selective IgM deficiency.^[9] Patients with XLA have normal pre-B cell populations in their bone marrow but these cells fail to mature and enter the circulation. The Btk gene is located on the X chromosome (Xq21.3-q22).^[10] At least 400 mutations of the BTK gene have been identified. Of these, at least 212 are considered to be disease-causing mutations.^[11]

BTK inhibitors

Approved drugs that inhibit BTK:

• Ibrutinib (Imbruvica), a selective Bruton's tyrosine kinase inhibitor.
• Acalabrutinib (Calquence), approved in October 2017^[12] for relapsed mantle cell lymphoma and in October 2019 for Chronic lymphocytic leukemia (CLL) and Small lymphocytic lymphoma (SLL)
• Zanubrutinib (Brukinsa) for mantle cell lymphoma, chronic lymphocytic leukemia (CLL), or small lymphocytic lymphoma (SLL).^[13] It can be taken by mouth.^[14][15]
• Tirabrutinib (Velexbru), approved in March 2020, in Japan, for the treatment of recurrent or refractory primary central nervous system lymphoma.^[16]
• Pirtobrutinib (Jaypirca), a reversible (non-covalent) inhibitor of BTK, for mantle cell lymphoma.^[17][18]
• Orelabrutinib, approved in China for patients with mantle cell lymphoma (MCL) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), who have received at least one treatment in the past.^[19]

Various drugs that inhibit BTK are in clinical trials:^[20]

• Phase 3:
  • Evobrutinib for multiple sclerosis.^[21][22][23]
  • Tolebrutinib, for multiple sclerosis.^[24][25]
  • Remibrutinib, for multiple sclerosis.^[26]
  • Fenebrutinib (RG7845) for multiple sclerosis.^[27][28]
• Phase 2:
  • ABBV-105 for systemic lupus erythematosus (SLE)^[29]
  • Fenebrutinib (GDC-0853) for rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis and chronic spontaneous urticaria.^[30]
• Phase 1:
  • Tirabrutinib, for non-Hodgkin lymphoma and/or CLL.^[31] Renamed GS-4059 and now in trial NCT02457598.^[32]
  • Spebrutinib (AVL-292, CC-292) ^[33]
  • HM71224, for autoimmune diseases, under development by Hanmi Pharmaceutical and Lilly as of 2015^[34]
  • Luxeptinib (CG-806), for CLL, SLL, non-Hodgkin lymphoma, acute myeloid leukaemia, and myelodysplastic syndromes (Phase I Trial; Phase I Trial). The inhibitor targets multiple kinase pathways, including BTK and FLT3.^[35]

Discovery

Bruton's tyrosine kinase was discovered in 1993 and is named for Ogden Bruton, who first described XLA in 1952.^[10]

Interactions

Bruton's tyrosine kinase has been shown to interact with:

References

Further reading

External links

• GeneReviews/NCBI/NIH/UW entry on X-Linked or Brunton's Agammaglobulinemia
• Bruton's+tyrosine+kinase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Human BTK genome location and BTK gene details page in the UCSC Genome Browser.
• Overview of all the structural information available in the PDB for UniProt: Q06187 (Tyrosine-protein kinase BTK) at the PDBe-KB.