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, IGHD3
External IDs	OMIM: 300300 MGI: 88216 HomoloGene: 30953 GeneCards: BTK
Gene location (Human) Chr. X chromosome (human) [1] Band Xq22.1 Start 101,349,338 bp [1] End 101,390,796 bp [1]
Gene location (Mouse) Chr. X chromosome (mouse) [2] Band X E3|X 56.18 cM Start 133,443,085 bp [2] End 133,484,319 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in monocyte spleen bone marrow cells lymph node blood appendix right lung upper lobe of left lung rectum gallbladder Top expressed in spleen blood bone marrow secondary oocyte right lobe of liver pharynx body of femur morula subcutaneous adipose tissue yolk sac More reference expression data BioGPS More reference expression data
Gene ontology Molecular function metal ion binding nucleotide binding lipid binding signaling 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 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 population 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 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: 133.44 – 133.48 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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.

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

Involvement of BTK in B cell receptor signaling

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. ^[8]

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. ^[9] 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). ^[10] At least 400 mutations of the BTK gene have been identified. Of these, at least 212 are considered to be disease-causing mutations. ^[11]

BTK inhibitors

Approved drugs that inhibit BTK:

• Ibrutinib (Imbruvica), a selective Bruton's tyrosine kinase inhibitor.
• Acalabrutinib (Calquence), approved in October 2017 ^[12] for relapsed mantle cell lymphoma.
• Zanubrutinib (Brukinsa) for mantle cell lymphoma, chronic lymphocytic leukemia (CLL), or small lymphocytic lymphoma (SLL). ^[13] It can be taken by mouth. ^{[14] [15]}
• Tirabrutinib (Velexbru), approved in March 2020, in Japan, for the treatment of recurrent or refractory primary central nervous system lymphoma. ^[16]
• Pirtobrutinib (Jaypirca), a reversible (non-covalent) inhibitor of BTK, for mantle cell lymphoma. ^{[17] [18]}
• Orelabrutinib, approved in China for patients with mantle cell lymphoma (MCL) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), who have received at least one treatment in the past. ^[19]

Various drugs that inhibit BTK are in clinical trials: ^[20]

• Phase 3:
  • Acalabrutinib, for relapsed chronic lymphocytic leukemia, 95% overall remission reported.
  • Evobrutinib for multiple sclerosis. ^{[21] [22] [23]}
  • Tolebrutinib, for multiple sclerosis. ^{[24] [25]}
  • Remibrutinib, for multiple sclerosis. ^[26]
  • Fenebrutinib (RG7845) for multiple sclerosis. ^{[27] [28]}
• Phase 2:
  • ABBV-105 for systemic lupus erythematosus (SLE) ^[29]
  • Fenebrutinib (GDC-0853) for rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis and chronic spontaneous urticaria. ^[30]
• Phase 1:
  • Tirabrutinib, for non-Hodgkin lymphoma and/or CLL. ^[31] Renamed GS-4059 and now in trial NCT02457598. ^[32]
  • Spebrutinib (AVL-292, CC-292) ^[33]
  • HM71224, for autoimmune diseases, under development by Hanmi Pharmaceutical and Lilly as of 2015 ^[34]
  • Luxeptinib (CG-806), for CLL, SLL, non-Hodgkin lymphoma, acute myeloid leukaemia, and myelodysplastic syndromes (Phase I Trial; Phase I Trial). The inhibitor targets multiple kinase pathways, including BTK and FLT3. ^[35]

Discovery

Bruton's tyrosine kinase was discovered in 1993 and is named for Ogden Bruton, who first described XLA in 1952. ^[10]

Interactions

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

• ARID3A ^[36]
• BLNK (SLP-65), ^{[37] [38]}
• CAV1, ^[39]
• GNAQ, ^[40]
• GTF2I, ^{[41] [42] [43]}
• PLCG2, ^{[37] [44]}
• PRKD1, ^[45] and
• SH3BP5. ^{[46] [47]}

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 JA, Punt J, Stranford SA, Jones PP (2013). Kuby Immunology (7th ed.). New York: W.H. Freeman. p. 93. ISBN   978-14641-3784-6.
7. Turner H, Kinet JP (November 1999). "Signalling through the high-affinity IgE receptor Fc epsilonRI". Nature. 402 (6760 Suppl): B24–B30. doi: 10.1038/35037021 . PMID   10586892.
8. Lowe J, Joseph RE, Andreotti AH (1 January 2022). "Conformational switches that control the TEC kinase - PLCγ signaling axis". Journal of Structural Biology. 6: 100061. doi:10.1016/j.yjsbx.2022.100061. PMC   8803661 . PMID   35128378.
9. Geier CB, Sauerwein KM, Leiss-Piller A, Zmek I, Fischer MB, Eibl MM, et al. (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.
10. X-Linked Agammaglobulinemia Patient and Family Handbook for The Primary Immune Diseases. Third Edition. 2001. Published by the Immune Deficiency Foundation.
11. Šimčíková D, Heneberg P (December 2019). "Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases". Scientific Reports. 9 (1): 18577. Bibcode:2019NatSR...918577S. doi:10.1038/s41598-019-54976-4. PMC   6901466 . PMID   31819097.
12. "FDA approves new treatment for adults with mantle cell lymphoma". Food and Drug Administration . 24 March 2020.
13. "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.
14. BeiGene Announces Initiation of a Combination Trial of the BTK Inhibitor BGB-3111 with the PD-1 Antibody BGB-A317. June 2016
15. "FDA approves zanubrutinib for chronic lymphocytic leukemia or small lymphocytic lymphoma". U.S. Food and Drug Administration (FDA). 19 January 2023. Retrieved 26 January 2023.
16. Dhillon S (June 2020). "Tirabrutinib: First Approval". Drugs. 80 (8): 835–840. doi:10.1007/s40265-020-01318-8. PMID   32382949. S2CID   218531327.
17. "FDA grants accelerated approval to pirtobrutinib for relapsed or refractory mantle cell lymphoma". U.S. Food and Drug Administration (FDA). 27 January 2023.
18. Mato AR, Shah NN, Jurczak W, Cheah CY, Pagel JM, Woyach JA, et al. (March 2021). "Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study". Lancet. 397 (10277): 892–901. doi:10.1016/S0140-6736(21)00224-5. PMID   33676628. S2CID   232116910.
19. Dhillon S (2021). "Orelabrutinib: First Approval". Drugs. 81 (4): 503–507. doi:10.1007/s40265-021-01482-5.
20. Alu A, Lei H, Han X, Wei Y, Wei X (October 2022). "BTK inhibitors in the treatment of hematological malignancies and inflammatory diseases: mechanisms and clinical studies". Journal of Hematology & Oncology. 15 (1): 138. doi: 10.1186/s13045-022-01353-w . PMC   9526392 . PMID   36183125.
21. Montalban X, Arnold DL, Weber MS, Staikov I, Piasecka-Stryczynska K, Willmer J, et al. (June 2019). "Placebo-Controlled Trial of an Oral BTK Inhibitor in Multiple Sclerosis". The New England Journal of Medicine. 380 (25): 2406–2417. doi: 10.1056/NEJMoa1901981 . PMID   31075187.
22. Clinical trial number NCT02975349 for "A Study of Efficacy and Safety of M2951 in Subjects With Relapsing Multiple Sclerosis" at ClinicalTrials.gov
23. Clinical trial number NCT04032171 for "A Phase III, Multicenter, Randomized, Parallel Group, Double Blind, Double Dummy, Active Controlled Study of Evobrutinib Compared With an Interferon Beta 1a (Avonex®), in Participants With RMS to Evaluate Efficacy and Safety " at ClinicalTrials.gov
24. Dolgin E (January 2021). "BTK blockers make headway in multiple sclerosis". Nature Biotechnology. 39 (1): 3–5. doi: 10.1038/s41587-020-00790-7 . PMID   33432223.
25. Clinical trial number NCT04742400 for "A Phase 2 Clinical Trial of Tolebrutinib, a Brain-penetrant Bruton s Tyrosine Kinase Inhibitor, for the Modulation of Chronically Inflamed White Matter Lesions in Multiple Sclerosis" at ClinicalTrials.gov
26. Wexler M (21 June 2022). "Remibrutinib for Multiple Sclerosis". BioNews, Inc.
27. "Genentech: Our Pipeline". www.gene.com. Retrieved 5 June 2023.
28. Clinical trial number NCT04544449 for "A Phase III Multicenter, Randomized, Double-Blind, Double-Dummy, Parallel-Group Study to Evaluate the Efficacy and Safety of Fenebrutinib Compared With Ocrelizumab in Adult Patients With Primary Progressive Multiple Sclerosis" at ClinicalTrials.gov
29. Clinical trial number NCT03978520 for "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" at ClinicalTrials.gov
30. "Genentech: Our Pipeline". www.gene.com. Retrieved 10 October 2020.
31. 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
32. "Novel BTK, PI3K Inhibitors on Horizon for Relapsed CLL. March 2016". Archived from the original on 5 April 2016. Retrieved 22 March 2016.
33. 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
34. Garde D (19 March 2015). "Lilly inks a $690M deal to get its hands on an autoimmune drug". FierceBiotech.
35. Rice WG, Howell SB, Zhang H, Rastgoo N, Local A, Kurtz SE, et al. (July 2022). "Luxeptinib (CG-806) Targets FLT3 and Clusters of Kinases Operative in Acute Myeloid Leukemia". Molecular Cancer Therapeutics. 21 (7): 1125–1135. doi:10.1158/1535-7163.MCT-21-0832. PMC   9256809 . PMID   35499387.
36. 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". Cellular Immunology. 228 (1): 42–53. doi:10.1016/j.cellimm.2004.03.004. PMID   15203319.
37. Yasuda T, Tezuka T, Maeda A, Inazu T, Yamanashi Y, Gu H, et al. (July 2002). "Cbl-b positively regulates Btk-mediated activation of phospholipase C-gamma2 in B cells". The Journal of Experimental Medicine. 196 (1): 51–63. doi:10.1084/jem.20020068. PMC   2194016 . PMID   12093870.
38. Hashimoto S, Iwamatsu A, Ishiai M, Okawa K, Yamadori T, Matsushita M, et al. (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): 2357–2364. doi:10.1182/blood.V94.7.2357.419k40_2357_2364. PMID   10498607. S2CID   21014231.
39. Vargas L, Nore BF, Berglof A, Heinonen JE, Mattsson PT, Smith CI, et al. (March 2002). "Functional interaction of caveolin-1 with Bruton's tyrosine kinase and Bmx". The Journal of Biological Chemistry. 277 (11): 9351–9357. doi: 10.1074/jbc.M108537200 . PMID   11751885.
40. Ma YC, Huang XY (October 1998). "Identification of the binding site for Gqalpha on its effector Bruton's tyrosine kinase". Proceedings of the National Academy of Sciences of the United States of America. 95 (21): 12197–12201. Bibcode:1998PNAS...9512197M. doi: 10.1073/pnas.95.21.12197 . PMC   22808 . PMID   9770463.
41. Sacristán C, Tussié-Luna MI, Logan SM, Roy AL (February 2004). "Mechanism of Bruton's tyrosine kinase-mediated recruitment and regulation of TFII-I". The Journal of Biological Chemistry. 279 (8): 7147–7158. doi: 10.1074/jbc.M303724200 . PMID   14623887.
42. Novina CD, Kumar S, Bajpai U, Cheriyath V, Zhang K, Pillai S, et al. (July 1999). "Regulation of nuclear localization and transcriptional activity of TFII-I by Bruton's tyrosine kinase". Molecular and Cellular Biology. 19 (7): 5014–5024. doi:10.1128/mcb.19.7.5014. PMC   84330 . PMID   10373551.
43. Yang W, Desiderio S (January 1997). "BAP-135, a target for Bruton's tyrosine kinase in response to B cell receptor engagement". Proceedings of the National Academy of Sciences of the United States of America. 94 (2): 604–609. Bibcode:1997PNAS...94..604Y. doi: 10.1073/pnas.94.2.604 . PMC   19560 . PMID   9012831.
44. 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): 243–253. doi: 10.1016/s1074-7613(00)00024-8 . PMID   10981967.
45. Johannes FJ, Hausser A, Storz P, Truckenmüller L, Link G, Kawakami T, et al. (November 1999). "Bruton's tyrosine kinase (Btk) associates with protein kinase C mu". FEBS Letters. 461 (1–2): 68–72. doi:10.1016/S0014-5793(99)01424-6. PMID   10561498. S2CID   86153017.
46. Matsushita M, Yamadori T, Kato S, Takemoto Y, Inazawa J, Baba Y, et al. (April 1998). "Identification and characterization of a novel SH3-domain binding protein, Sab, which preferentially associates with Bruton's tyrosine kinase (BtK)". Biochemical and Biophysical Research Communications. 245 (2): 337–343. doi:10.1006/bbrc.1998.8420. PMID   9571151.
47. Yamadori T, Baba Y, Matsushita M, Hashimoto S, Kurosaki M, Kurosaki T, et al. (May 1999). "Bruton's tyrosine kinase activity is negatively regulated by Sab, the Btk-SH3 domain-binding protein". Proceedings of the National Academy of Sciences of the United States of America. 96 (11): 6341–6346. Bibcode:1999PNAS...96.6341Y. doi: 10.1073/pnas.96.11.6341 . PMC   26883 . PMID   10339589.

Further reading

• Ochs HD, Aruffo A (December 1993). "Advances in X-linked immunodeficiency diseases". Current Opinion in Pediatrics. 5 (6): 684–691. doi:10.1097/00008480-199312000-00008. PMID   7907259.
• Uckun FM (September 1998). "Bruton's tyrosine kinase (BTK) as a dual-function regulator of apoptosis". Biochemical Pharmacology. 56 (6): 683–691. doi:10.1016/S0006-2952(98)00122-1. PMID   9751072.
• Tsubata T, Wienands J (2001). "B cell signaling. Introduction". International Reviews of Immunology. 20 (6): 675–678. doi:10.3109/08830180109045584. PMID   11913944. S2CID   218878743.
• Etzioni A (April 2002). "Novel aspects of hypogammaglobulinemic states". The Israel Medical Association Journal. 4 (4): 294–297. PMID   12001708.
• Niiro H, Clark EA (November 2003). "Branches of the B cell antigen receptor pathway are directed by protein conduits Bam32 and Carma1". Immunity. 19 (5): 637–640. doi: 10.1016/S1074-7613(03)00303-0 . PMID   14614850.
• Carpenter CL (April 2004). "Btk-dependent regulation of phosphoinositide synthesis". Biochemical Society Transactions. 32 (Pt 2): 326–329. doi:10.1042/BST0320326. PMID   15046600. S2CID   41318916.
• Hendriks RW, Kersseboom R (February 2006). "Involvement of SLP-65 and Btk in tumor suppression and malignant transformation of pre-B cells". Seminars in Immunology. 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 U.S. 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 .