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

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.^[1]

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.^[1]

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.^[2] 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.^[1]

Various drugs that inhibit BTK are in clinical trials:^[3]

• Phase 3:
  • Acalabrutinib, for relapsed CLL, 95% overall remission reported.
• Phase 2:
• Phase 1:
  • ONO-4059 for Non-Hodgkin's Lymphoma and/or CLL.^[4] Renamed GS-4059 and now in trial NCT02457598.^[5]
  • spebrutinib (AVL-292, CC-292) ^[6]
  • BGB-3111 for CLL.^[5]

Discovery

Bruton's tyrosine kinase was discovered in 1993 and is named for Ogden Bruton, who first described XLA in 1952.^[2]

Interactions

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

• ARID3A^[7]
• BLNK,^[8][9]
• CAV1,^[10]
• GNAQ,^[11]
• GTF2I,^[12][13][14]
• PLCG2,^[8][15]
• PRKD1,^[16] and
• SH3BP5.^[17][18]

See also

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

References

1. Seda V, Mraz M (Mar 2015). "B-cell receptor signalling and its crosstalk with other pathways in normal and malignant cells". European Journal of Haematology 94 (3): 193–205. doi:10.1111/ejh.12427. PMID 25080849.
2. X-Linked Agammaglobulinemia Patient and Family Handbook for The Primary Immune Diseases. Third Edition. 2001. Published by the Immune Deficiency Foundation.
3. Astra Signals A Late Run On BTK Inhibition. Dec 2015
4. Clinical trial number NCT01659255 for "ONO-4059 Phase I Dose-escalation Study to Investigate the Safety and Tolerability of ONO-4059 Given as Monotherapy in Patients With Relapsed/Refractory Non-Hodgkin's Lymphoma and/or Chronic Lymphocytic Leukaemi" at ClinicalTrials.gov
5. Novel BTK, PI3K Inhibitors on Horizon for Relapsed CLL. March 2016
6. Clinical trial number NCT01351935 for "Escalating Dose Study in Subjects With Relapsed or Refractory B Cell Non-Hodgkin Lymphoma, Chronic Lymphocytic Leukemia, and Waldenstrom's Macroglobulinemia" at ClinicalTrials.gov
7. Nixon JC, Rajaiya JB, Ayers N, Evetts S, Webb CF (March 2004). "The transcription factor, Bright, is not expressed in all human B lymphocyte subpopulations". Cell. Immunol. 228 (1): 42–53. doi:10.1016/j.cellimm.2004.03.004. PMID 15203319.
8. Yasuda T, Tezuka T, Maeda A, Inazu T, Yamanashi Y, Gu H, Kurosaki T, Yamamoto T (July 2002). "Cbl-b positively regulates Btk-mediated activation of phospholipase C-gamma2 in B cells". J. Exp. Med. 196 (1): 51–63. doi:10.1084/jem.20020068. PMC 2194016. PMID 12093870.
9. Hashimoto S, Iwamatsu A, Ishiai M, Okawa K, Yamadori T, Matsushita M, Baba Y, Kishimoto T, Kurosaki T, Tsukada S (October 1999). "Identification of the SH2 domain binding protein of Bruton's tyrosine kinase as BLNK--functional significance of Btk-SH2 domain in B-cell antigen receptor-coupled calcium signaling". Blood 94 (7): 2357–64. PMID 10498607.
10. Vargas L, Nore BF, Berglof A, Heinonen JE, Mattsson PT, Smith CI, Mohamed AJ (March 2002). "Functional interaction of caveolin-1 with Bruton's tyrosine kinase and Bmx". J. Biol. Chem. 277 (11): 9351–7. doi:10.1074/jbc.M108537200. PMID 11751885.
11. Ma YC, Huang XY (October 1998). "Identification of the binding site for Gqalpha on its effector Bruton's tyrosine kinase". Proc. Natl. Acad. Sci. U.S.A. 95 (21): 12197–201. doi:10.1073/pnas.95.21.12197. PMC 22808. PMID 9770463.
12. Sacristán C, Tussié-Luna MI, Logan SM, Roy AL (February 2004). "Mechanism of Bruton's tyrosine kinase-mediated recruitment and regulation of TFII-I". J. Biol. Chem. 279 (8): 7147–58. doi:10.1074/jbc.M303724200. PMID 14623887.
13. Novina CD, Kumar S, Bajpai U, Cheriyath V, Zhang K, Pillai S, Wortis HH, Roy AL (July 1999). "Regulation of nuclear localization and transcriptional activity of TFII-I by Bruton's tyrosine kinase". Mol. Cell. Biol. 19 (7): 5014–24. doi:10.1128/mcb.19.7.5014. PMC 84330. PMID 10373551.
14. Yang W, Desiderio S (January 1997). "BAP-135, a target for Bruton's tyrosine kinase in response to B cell receptor engagement". Proc. Natl. Acad. Sci. U.S.A. 94 (2): 604–9. doi:10.1073/pnas.94.2.604. PMC 19560. PMID 9012831.
15. Guo B, Kato RM, Garcia-Lloret M, Wahl MI, Rawlings DJ (August 2000). "Engagement of the human pre-B cell receptor generates a lipid raft-dependent calcium signaling complex". Immunity 13 (2): 243–53. doi:10.1016/s1074-7613(00)00024-8. PMID 10981967.
16. Johannes FJ, Hausser A, Storz P, Truckenmüller L, Link G, Kawakami T, Pfizenmaier K (November 1999). "Bruton's tyrosine kinase (Btk) associates with protein kinase C mu". FEBS Lett. 461 (1-2): 68–72. doi:10.1016/S0014-5793(99)01424-6. PMID 10561498.
17. Matsushita M, Yamadori T, Kato S, Takemoto Y, Inazawa J, Baba Y, Hashimoto S, Sekine S, Arai S, Kunikata T, Kurimoto M, Kishimoto T, Tsukada S (April 1998). "Identification and characterization of a novel SH3-domain binding protein, Sab, which preferentially associates with Bruton's tyrosine kinase (BtK)". Biochem. Biophys. Res. Commun. 245 (2): 337–43. doi:10.1006/bbrc.1998.8420. PMID 9571151.
18. Yamadori T, Baba Y, Matsushita M, Hashimoto S, Kurosaki M, Kurosaki T, Kishimoto T, Tsukada S (May 1999). "Bruton's tyrosine kinase activity is negatively regulated by Sab, the Btk-SH3 domain-binding protein". Proc. Natl. Acad. Sci. U.S.A. 96 (11): 6341–6. doi:10.1073/pnas.96.11.6341. PMC 26883. PMID 10339589.

Further reading

• Ochs HD, Aruffo A (1993). "Advances in X-linked immunodeficiency diseases". Curr. Opin. Pediatr. 5 (6): 684–91. doi:10.1097/00008480-199312000-00008. PMID 7907259.
• Uckun FM (1998). "Bruton's tyrosine kinase (BTK) as a dual-function regulator of apoptosis". Biochem. Pharmacol. 56 (6): 683–91. doi:10.1016/S0006-2952(98)00122-1. PMID 9751072.
• Tsubata T, Wienands J (2001). "B cell signaling. Introduction". Int. Rev. Immunol. 20 (6): 675–8. doi:10.3109/08830180109045584. PMID 11913944.
• Etzioni A (2002). "Novel aspects of hypogammaglobulinemic states". Isr. Med. Assoc. J. 4 (4): 294–7. PMID 12001708.
• Niiro H, Clark EA (2003). "Branches of the B cell antigen receptor pathway are directed by protein conduits Bam32 and Carma1". Immunity 19 (5): 637–40. doi:10.1016/S1074-7613(03)00303-0. PMID 14614850.
• Carpenter CL (2004). "Btk-dependent regulation of phosphoinositide synthesis". Biochem. Soc. Trans. 32 (Pt 2): 326–9. doi:10.1042/BST0320326. PMID 15046600.
• Hendriks RW, Kersseboom R (2006). "Involvement of SLP-65 and Btk in tumor suppression and malignant transformation of pre-B cells". Semin. Immunol. 18 (1): 67–76. doi:10.1016/j.smim.2005.10.002. PMID 16300960.

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)