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; OMA:BTK - orthologs
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 granulocyte spleen bone marrow cells lymph node blood appendix epithelium of nasopharynx right lung upper lobe of left lung Top expressed in granulocyte spleen fetal liver hematopoietic progenitor cell mesenteric lymph nodes tibiofemoral joint blood bone marrow secondary oocyte zygote stroma of bone marrow 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 protein kinase domain with tyrosine phosphorylation activity.^[5]

Part of the TH domain is folded against the PH domain while the rest is intrinsically disordered.

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 (PLC), 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 is important for the survival and proliferation of leukemic B cells, which motivated efforts to develop BTK inhibitors as treatments for B cell malignancies such as mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL).^[12] As BTK is also linked to autoimmune disorders,^[13][14] recent efforts have sought to evaluate BTK inhibition as a therapeutic strategy for treatment of diseases such as multiple sclerosis (MS) and rheumatoid arthritis (RA).^[15]

BTK inhibitors

Approved drugs that inhibit BTK:

• Ibrutinib (Imbruvica), a selective Bruton's tyrosine kinase inhibitor.
• Acalabrutinib (Calquence), approved in October 2017^[16] for relapsed mantle cell lymphoma and in October 2019 for Chronic lymphocytic leukemia (CLL) and Small lymphocytic lymphoma (SLL)
• Zanubrutinib (Brukinsa) for mantle cell lymphoma, chronic lymphocytic leukemia (CLL), or small lymphocytic lymphoma (SLL).^[17] It can be taken by mouth.^[18][19]
• Tirabrutinib (Velexbru), approved in March 2020, in Japan, for the treatment of recurrent or refractory primary central nervous system lymphoma.^[20]
• Pirtobrutinib (Jaypirca), a reversible (non-covalent) inhibitor of BTK, for mantle cell lymphoma.^[21][22]
• 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.^[23]

Various drugs that inhibit BTK are in clinical trials:^[24]

• Phase 3:
  • Evobrutinib for multiple sclerosis.^[25][26][27]
  • Tolebrutinib, for multiple sclerosis.^[28][29]
  • Remibrutinib, for multiple sclerosis.^[30]
  • Fenebrutinib (RG7845) for multiple sclerosis.^[31][32]
• Phase 2:
  • ABBV-105 for systemic lupus erythematosus (SLE)^[33]
  • Fenebrutinib (GDC-0853) for rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis and chronic spontaneous urticaria.^[34]
• Phase 1:
  • Tirabrutinib, for non-Hodgkin lymphoma and/or CLL.^[35] Renamed GS-4059 and now in trial NCT02457598.^[36]
  • Spebrutinib (AVL-292, CC-292) ^[37]
  • HM71224, for autoimmune diseases, under development by Hanmi Pharmaceutical and Lilly as of 2015^[38]
  • 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.^[39]

Discovery

Bruton's tyrosine kinase is named for Ogden Bruton, who first described XLA in 1952.^[10][40] Later studies in 1993 and 1994 reported the discovery of BTK (initially termed B cell progenitor kinase or BPK) and found that BTK levels are reduced in B cells from XLA patients.^[41][42][43]

Interactions

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

• ARID3A^[44]
• BLNK (SLP-65),^[45][46]
• CAV1,^[47]
• GNAQ,^[48]
• GTF2I,^[49][50][51]
• PLCG2,^[45][52]
• PRKD1,^[53] and
• SH3BP5.^[54][55]

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.
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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.
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10. X-Linked Agammaglobulinemia Patient and Family Handbook for The Primary Immune Diseases. Third Edition. 2001. Published by the Immune Deficiency Foundation.
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33. 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
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35. 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
36. "Novel BTK, PI3K Inhibitors on Horizon for Relapsed CLL. March 2016". Archived from the original on 5 April 2016. Retrieved 22 March 2016.
37. 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
38. Garde D (19 March 2015). "Lilly inks a $690M deal to get its hands on an autoimmune drug". FierceBiotech.
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41. Vetrie D, Vořechovský I, Sideras P, Holland J, Davies A, Flinter F, et al. (21 January 1993). "The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases". Nature. 361 (6409): 226–233. Bibcode:1993Natur.361..226V. doi:10.1038/361226a0. ISSN 0028-0836. PMID 8380905.
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45. 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.
46. 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.
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48. 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.
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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.