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
External IDs	OMIM: 300300 MGI: 88216 HomoloGene: 30953 GeneCards: BTK
Targeted by Drug
ibrutinib[1]
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 • protein binding • protein tyrosine kinase activity Cellular component • cytoplasm • nucleus • intracellular membrane-bounded organelle • 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 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 Sources:Amigo / QuickGO
RNA expression pattern
More reference expression data
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_000052.1 NP_001274273.1 NP_001274274.1	NP_038510.2
Location (UCSC)	Chr X: 101.35 – 101.39 Mb	Chr X: 134.54 – 134.58 Mb
PubMed search	[2]	[3]
Wikidata

Bruton's tyrosine kinase (abbreviated Btk or BTK) also known as tyrosine-protein kinase BTK is an enzyme that in humans is encoded by the BTK gene. BTK is a kinase that plays a crucial role in B-cell development.

Function

BTK plays a crucial role in B cell maturation as well as mast cell activation through the high-affinity IgE receptor.^[4]

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.^[4]

Clinical significance

Mutations in the BTK gene are implicated in the primary immunodeficiency disease X-linked agammaglobulinemia (Bruton's agammaglobulinemia); sometimes abbreviated to XLA. 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.^[5] At least 400 mutations of the BTK gene have been identified.

BTK inhibitors

Approved drugs that inhibit BTK :

• Ibrutinib (PCI-32765), a selective Bruton's tyrosine kinase inhibitor.^[4]

Various drugs that inhibit BTK are in clinical trials:^[6]

• Phase 3:
  • Acalabrutinib, for relapsed CLL, 95% overall remission reported.
• Phase 2:
• Phase 1:
  • ONO-4059 for Non-Hodgkin's Lymphoma and/or CLL.^[7] Renamed GS-4059 and now in trial NCT02457598.^[8]
  • spebrutinib (AVL-292, CC-292) ^[9]
  • BGB-3111 for CLL.^[8] It can be taken orally.^[10]

Discovery

Bruton's tyrosine kinase was discovered in 1993 and is named for Ogden Bruton, who first described XLA in 1952.^[5]

Interactions

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

See also

• Ibrutinib (PCI-32765), a selective Bruton's tyrosine kinase inhibitor

References

Further reading

External links

• GeneReviews/NCBI/NIH/UW entry on X-Linked or Brunton's Agammaglobulinemia
• UMich Orientation of Proteins in Membranes protein/pdbid-1bwn
• Bruton's tyrosine kinase at the US National Library of Medicine Medical Subject Headings (MeSH)

PDB gallery
1aww: SH3 DOMAIN FROM BRUTON'S TYROSINE KINASE, NMR, 42 STRUCTURES  1awx: SH3 DOMAIN FROM BRUTON'S TYROSINE KINASE, NMR, MINIMIZED AVERAGE STRUCTURE  1b55: PH DOMAIN FROM BRUTON'S TYROSINE KINASE IN COMPLEX WITH INOSITOL 1,3,4,5-TETRAKISPHOSPHATE  1btk: PH DOMAIN AND BTK MOTIF FROM BRUTON'S TYROSINE KINASE MUTANT R28C  1bwn: PH DOMAIN AND BTK MOTIF FROM BRUTON'S TYROSINE KINASE MUTANT E41K IN COMPLEX WITH INS(1,3,4,5)P4  1k2p: Crystal structure of Bruton's tyrosine kinase domain  1qly: NMR STUDY OF THE SH3 DOMAIN FROM BRUTON'S TYROSINE KINASE, 20 STRUCTURES  2ge9: Solution Structures of the SH2 domain of Bruton's Tyrosine Kinase