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

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 kinase domain with enzymatic activity.[5]

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.

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.[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 inhibitors

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]

Discovery

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

Interactions

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

• ARID3A[22]
• BLNK,[23][24]
• CAV1,[25]
• GNAQ,[26]
• GTF2I,[27][28][29]
• PLCG2,[23][30]
• PRKD1,[31] and
• SH3BP5.[32][33]

See also

• Ibrutinib (PCI-32765)
• Acalabrutinib

References

1. GRCh38: Ensembl release 89: ENSG00000010671 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000031264 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Pal Singh S, Dammeijer F, Hendriks RW (February 2018). "Role of Bruton's tyrosine kinase in B cells and malignancies". Molecular Cancer. 17 (1): 57. doi:10.1186/s12943-018-0779-z. PMC 5817726. PMID 29455639.
6. Owen, Judith A.; Punt, Jenni; Stranford, Sharon A.; Jones, Patricia P. (2013). Kuby Immunology (7th ed.). New York: W.H. Freeman. p. 93. ISBN 978-14641-3784-6.
7. Turner, Helen; Kinet, Jean-Pierre (November 1999). "Signalling through the high-affinity IgE receptor FcεRI". Nature. 402 (S6760): 24–30. doi:10.1038/35037021. PMID 10586892.
8. Christoph, Geier (18 August 2018). "Hypomorphic Mutations in the BCR Signalosome Lead to Selective Immunoglobulin M Deficiency and Impaired B-cell Homeostasis". Frontiers in Immunology. 9: 2984. doi:10.3389/fimmu.2018.02984. PMC 6305442. PMID 30619340.
9. X-Linked Agammaglobulinemia Patient and Family Handbook for The Primary Immune Diseases. Third Edition. 2001. Published by the Immune Deficiency Foundation.
10. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm583076.htm
11. "FDA approves therapy to treat patients with relapsed and refractory mantle cell lymphoma supported by clinical trial results showing high response rate of tumor shrinkage". U.S. Food and Drug Administration (FDA) (Press release). 14 November 2019. Retrieved 15 November 2019.
12. BeiGene Announces Initiation of a Combination Trial of the BTK Inhibitor BGB-3111 with the PD-1 Antibody BGB-A317. June 2016
13. Astra Signals A Late Run On BTK Inhibition. Dec 2015
14. Montalban X, Arnold DL, Weber MS, et al. (June 2019). "Placebo-Controlled Trial of an Oral BTK Inhibitor in Multiple Sclerosis". N. Engl. J. Med. 380 (25): 2406–2417. doi:10.1056/NEJMoa1901981. PMID 31075187.
15. "A Study of Efficacy and Safety of M2951 in Subjects With Relapsing Multiple Sclerosis". ClinicalTrials.gov. 29 November 2016. Retrieved 28 March 2020.
16. "A Study to Investigate the Safety and Efficacy of ABBV-105 and Upadacitinib Given Alone or in Combination in Participants With Moderately to Severely Active Systemic Lupus Erythematosus - Full Text View - ClinicalTrials.gov". clinicaltrials.gov. Retrieved 2019-10-08.
17. "Genentech: Our Pipeline". www.gene.com. Retrieved 2020-10-10.
18. 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
19. "Novel BTK, PI3K Inhibitors on Horizon for Relapsed CLL. March 2016". Archived from the original on 2016-04-05. Retrieved 2016-03-22.
20. 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
21. Garde, Damian (March 19, 2015). "Lilly inks a $690M deal to get its hands on an autoimmune drug". FierceBiotech.
22. 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.
23. 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.
24. 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. doi:10.1182/blood.V94.7.2357.419k40_2357_2364. PMID 10498607.
25. 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.
26. 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.
27. 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.
28. 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.
29. 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.
30. 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.
31. 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.
32. 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.
33. 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. S2CID 41318916.
• 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
• Bruton's+tyrosine+kinase at the US 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.