Bruton's tyrosine kinase

 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.

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 101,349,447 bp[1] End 101,390,796 bp[1]
Gene location (Mouse) Chr. X chromosome (mouse)[2] Band X E3|X 56.18 cM Start 134,542,336 bp[2] End 134,583,570 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • metal ion binding • nucleotide binding • lipid binding • 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 • GO:0001948 protein binding • protein tyrosine kinase activity Cellular component • cytoplasm • cell nucleus • membrane • membrane raft • extrinsic component of cytoplasmic side of plasma membrane • cytoplasmic vesicle • cytosol • cell membrane • perinuclear region of cytoplasm • mast cell granule Biological process • transmembrane receptor protein tyrosine kinase signaling pathway • mesoderm development • GO:0007243 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 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 system • 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 • 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: 134.54 – 134.58 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

StructureEdit

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 kinase domain with enzymatic activity.^[5]

FunctionEdit

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.^{[citation needed]}

Clinical significanceEdit

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.^[8] 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).^[9] At least 400 mutations of the BTK gene have been identified.

BTK inhibitorsEdit

Approved drugs that inhibit BTK:

• Ibrutinib (PCI-32765), a selective Bruton's tyrosine kinase inhibitor.
• Acalabrutinib, approved in October 2017^[10] for relapsed mantle cell lymphoma
• Zanubrutinib for mantle cell lymphoma.^[11] It can be taken orally.^[12]

Various drugs that inhibit BTK are in clinical trials:^[13]

• Phase 3:
  • Acalabrutinib, for relapsed chronic lymphocytic leukemia (CLL), 95% overall remission reported.
• Phase 2:
  • Evobrutinib for multiple sclerosis.^[14][15]
  • ABBV-105 for systemic lupus erythematosus (SLE)^[16]
  • Fenebrutinib (GDC-0853, RG7845) for rheumatoid arthritis, systemic lupus erythematosus and chronic spontaneous urticaria.^[17]
• Phase 1:
  • ONO-4059 for non-Hodgkin lymphoma and/or CLL.^[18] Renamed GS-4059 and now in trial NCT02457598.^[19]
  • Spebrutinib (AVL-292, CC-292) ^[20]
  • HM71224 for autoimmune diseases, under development by Hanmi Pharmaceutical and Lilly as of 2015^[21]

DiscoveryEdit

Bruton's tyrosine kinase was discovered in 1993 and is named for Ogden Bruton, who first described XLA in 1952.^[9]

This article uses material from the Wikipedia article  Metasyntactic variable, which is released under the  Creative Commons Attribution-ShareAlike 3.0 Unported License.