Bruton's tyrosine kinase

Bruton agammaglobulinemia tyrosine kinase
PH domain of Bruton's tyrosine kinase dimer with bound lipids. Blue plane shows hydrocarbon boundary of the lipid bilayer
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
Identifiers
Symbols	BTK ; AGMX1; AT; ATK; BPK; IMD1; PSCTK1; XLA
External IDs	OMIM: 300300 MGI: 88216 HomoloGene: 30953 ChEMBL: 5251 GeneCards: BTK Gene
EC number	2.7.10.2
Gene ontology Molecular function • protein tyrosine kinase activity • non-membrane spanning protein tyrosine kinase activity • receptor binding • protein binding • ATP binding • phosphatidylinositol-3,4,5-trisphosphate binding • identical protein binding • metal ion binding Cellular component • nucleus • cytoplasm • cytosol • plasma membrane • extrinsic component of cytoplasmic side of plasma membrane • cytoplasmic vesicle • intracellular membrane-bounded organelle • membrane raft Biological process • negative regulation of cytokine production • toll-like receptor signaling pathway • adaptive immune response • regulation of B cell cytokine production • MyD88-dependent toll-like receptor signaling pathway • regulation of B cell apoptotic process • transcription, DNA-templated • protein phosphorylation • transmembrane receptor protein tyrosine kinase signaling pathway • I-kappaB kinase/NF-kappaB signaling • mesoderm development • peptidyl-tyrosine phosphorylation • calcium-mediated signaling • cell differentiation • toll-like receptor 2 signaling pathway • toll-like receptor 4 signaling pathway • intracellular signal transduction • peptidyl-tyrosine autophosphorylation • Fc-epsilon receptor signaling pathway • toll-like receptor TLR1:TLR2 signaling pathway • toll-like receptor TLR6:TLR2 signaling pathway • B cell activation • regulation of cell proliferation • innate immune response • positive regulation of B cell differentiation • cell maturation • T cell receptor signaling pathway • B cell receptor signaling pathway • positive regulation of NF-kappaB transcription factor activity • apoptotic signaling pathway 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_000061	NM_013482
RefSeq (protein)	NP_000052	NP_038510
Location (UCSC)	Chr X: 101.35 – 101.39 Mb	Chr X: 134.54 – 134.58 Mb
PubMed search	[1]	[2]

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.

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.

Clinical significance

Mutations in the BTK gene are implicated in the primary immunodeficiency disease X-linked agammaglobulinemia (Bruton's agammaglobulinemia). 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. 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.

Various drugs that inhibit BTK are in clinical trials:

• Phase 3:
  • Acalabrutinib, for relapsed CLL, 95% overall remission reported.
• Phase 2:
• Phase 1:
  • ONO-4059 for Non-Hodgkin's Lymphoma and/or CLL.
  • spebrutinib (AVL-292, CC-292)

Discovery

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

Interactions

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

• ARID3A
• BLNK,
• CAV1,
• GNAQ,
• GTF2I,
• PLCG2,
• PRKD1, and
• SH3BP5.

See also

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

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)