Bruton's tyrosine kinase

Last updated

BTK
1bwn opm.png
Available structures
PDB Ortholog search: PDBe RCSB
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
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 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]

Structure of BTK.svg

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 Involvement of Bruton's tyrosine kinase in B cell receptor signaling.svg
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:

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

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:

Related Research Articles

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<span class="mw-page-title-main">Bcl-2</span> Protein found in humans

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<span class="mw-page-title-main">X-linked agammaglobulinemia</span> Medical condition

X-linked agammaglobulinemia (XLA) is a rare genetic disorder discovered in 1952 that affects the body's ability to fight infection. As the form of agammaglobulinemia that is X-linked, it is much more common in males. In people with XLA, the white blood cell formation process does not generate mature B cells, which manifests as a complete or near-complete lack of proteins called gamma globulins, including antibodies, in their bloodstream. B cells are part of the immune system and normally manufacture antibodies, which defend the body from infections by sustaining a humoral immunity response. Patients with untreated XLA are prone to develop serious and even fatal infections. A mutation occurs at the Bruton's tyrosine kinase (Btk) gene that leads to a severe block in B cell development and a reduced immunoglobulin production in the serum. Btk is particularly responsible for mediating B cell development and maturation through a signaling effect on the B cell receptor BCR. Patients typically present in early childhood with recurrent infections, in particular with extracellular, encapsulated bacteria. XLA is deemed to have a relatively low incidence of disease, with an occurrence rate of approximately 1 in 200,000 live births and a frequency of about 1 in 100,000 male newborns. It has no ethnic predisposition. XLA is treated by infusion of human antibody. Treatment with pooled gamma globulin cannot restore a functional population of B cells, but it is sufficient to reduce the severity and number of infections due to the passive immunity granted by the exogenous antibodies.

<span class="mw-page-title-main">P110δ</span> Protein-coding gene in the species Homo sapiens

Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta isoform also known as phosphoinositide 3-kinase (PI3K) delta isoform or p110δ is an enzyme that in humans is encoded by the PIK3CD gene.

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<span class="mw-page-title-main">Tyrosine-protein kinase SYK</span>

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B-lymphocyte antigen CD19, also known as CD19 molecule, B-Lymphocyte Surface Antigen B4, T-Cell Surface Antigen Leu-12 and CVID3 is a transmembrane protein that in humans is encoded by the gene CD19. In humans, CD19 is expressed in all B lineage cells. Contrary to some early doubts, human plasma cells do express CD19. CD19 plays two major roles in human B cells: on the one hand, it acts as an adaptor protein to recruit cytoplasmic signaling proteins to the membrane; on the other, it works within the CD19/CD21 complex to decrease the threshold for B cell receptor signaling pathways. Due to its presence on all B cells, it is a biomarker for B lymphocyte development, lymphoma diagnosis and can be utilized as a target for leukemia immunotherapies.

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<span class="mw-page-title-main">Ibrutinib</span> Medication used in cancer treatment

Ibrutinib, sold under the brand name Imbruvica among others, is a small molecule drug that inhibits B-cell proliferation and survival by irreversibly binding the protein Bruton's tyrosine kinase (BTK). Blocking BTK inhibits the B-cell receptor pathway, which is often aberrantly active in B cell cancers. Ibrutinib is therefore used to treat such cancers, including mantle cell lymphoma, chronic lymphocytic leukemia, and Waldenström's macroglobulinemia. Ibrutinib also binds to C-terminal Src Kinases. These are off-target receptors for the BTK inhibitor. Ibrutinib binds to these receptors and inhibits the kinase from promoting cell differentiation and growth. This leads to many different side effects like left atrial enlargement and atrial fibrillation during the treatment of Chronic Lymphocytic Leukemia.

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<span class="mw-page-title-main">Zanubrutinib</span> Chemical compound

Zanubrutinib, sold under the brand name Brukinsa, is an anticancer medication used for the treatment of mantle cell lymphoma (MCL), Waldenström's macroglobulinemia (WM), marginal zone lymphoma (MZL), and chronic lymphocytic leukemia (CLL). Zanubrutinib is classified as a Bruton's tyrosine kinase (BTK) inhibitor. It is given by mouth.

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<span class="mw-page-title-main">Pirtobrutinib</span> Chemical compound

Pirtobrutinib, sold under the brand name Jaypirca, is an anticancer medication that is used to treat mantle cell lymphoma. It inhibits B cell lymphocyte proliferation and survival by binding and inhibiting Bruton's tyrosine kinase (BTK). It is taken by mouth.

<span class="mw-page-title-main">Nemtabrutinib</span> Chemical compound

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References

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  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000031264 – Ensembl, May 2017
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  18. ↑ BeiGene Announces Initiation of a Combination Trial of the BTK Inhibitor BGB-3111 with the PD-1 Antibody BGB-A317. June 2016
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  26. ↑ Clinical trial number NCT02975349 for "A Study of Efficacy and Safety of M2951 in Subjects With Relapsing Multiple Sclerosis" at ClinicalTrials.gov
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  32. ↑ 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
  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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  45. 1 2 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.
  47. ↑ 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.
  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.
  49. ↑ 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.
  50. ↑ 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.
  51. ↑ 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.
  52. ↑ 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.
  53. ↑ 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. Bibcode:1999FEBSL.461...68J. doi:10.1016/S0014-5793(99)01424-6. PMID   10561498. S2CID   86153017.
  54. ↑ 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.
  55. ↑ 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.

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