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BTK
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesBTK, AGMX1, AT, ATK, BPK, IMD1, PSCTK1, XLA, Bruton tyrosine kinase, IGHD3
External IDsOMIM: 300300 MGI: 88216 HomoloGene: 30953 GeneCards: BTK
Orthologs
SpeciesHumanMouse
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 MbChr X: 133.44 – 133.48 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/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[edit]

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[edit]

Involvement of BTK in B cell receptor signaling
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[edit]

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[edit]

Approved drugs that inhibit BTK:

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

Discovery[edit]

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

Interactions[edit]

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

References[edit]

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000010671 – Ensembl, May 2017
  2. ^ a b c 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. ^ a b 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.
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  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.
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  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
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  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
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  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.
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Further reading[edit]

External links[edit]

source: https://en.wikipedia.org/wiki/Bruton%27s_tyrosine_kinase

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