Bruton´s-Tyrosinkinase

Last updated on: 17.04.2022

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Definition
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Bruton tyrosine kinase (BTK) is a non-receptor kinase essential for both B cell development and mature B cell function. The encoding BTK gene is located on the X chromosome at gene locus Xq22.1. A Bruton tyrosine kinase mutant plays a critical role in oncogenic signaling, which is crucial for proliferation and survival of leukemic cells in many B-cell malignancies. Originally, BTK was shown to be mutated in the primary antibody deficiency (D80.9) in which all Ig isotypes are reduced with decreased or absent B cells(Bruton`s agammaglobulinemia, also referred to as XLA =X-linked agammaglobulinemia).

General information
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The BTK signaling pathway is fundamental for B cell functionality and survival. Binding of antigen to the B cell antigen receptor (BCR) triggers signal transduction that ultimately leads to B cell activation. BTK acts as a platform for the assembly of a variety of signaling proteins and is involved in cytokine receptor signaling pathways. Furthermore, the kinase plays an important role in the function of immune cells of innate and adaptive immunity as a component of the Toll-like receptor (TLR) signaling pathway. The TLR pathway functions as a primary surveillance system for pathogen recognition and is critical for the activation of host defense. BTK is involved in the signaling pathway that links TLR8 and TLR9 to NF-kappa-B.

BTK is also expressed at high levels in certain myeloid cells, such as macrophages and granulocytes. Bruton tyrosine kinase (BTK) comprises 659 amino acids and belongs to a subfamily of SRC-related cytoplasmic tyrosine kinases. The enzyme is expressed throughout B-cell and myeloid development, but not in non-hematopoietic cells. Like SRC, BTK has a carboxy-terminal catalytic domain adjacent to the SH2 and SH3 domains (src homology 2 and 3). However, unlike SRC, Btk has an amino-terminal PH domain (pleckstrin homology) followed by a proline-rich region.

When PIP3 attaches to the domain, BTK phyophorylates phospholipase C, which in turn cleaves phosphatidylinositol-4,5-bisphosphate (PIP2) into inositol triphosphate (IP3) and diacetylglycerol (DAG). Both messengers control immunological activities of B cells (see figure).

Clinical picture
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Diseases associated with BTK include:

Agammaglobulinemia, X-linked and isolated growth hormone deficiency type IGHD3 (short stature due to isolated growth hormone deficiency with X-linked hypogammaglobulinemia), X-linked recessive).

Furthermore, the role of the BTK pathway in the production of autoantibodies and proinflammatory cytokines is associated with a number of autoimmune diseases, including rheumatoid arthritis and systemic lupus erythematosus.

Activation of the Bruton tyrosine kinase (BTK) pathway plays an important role in the pathophysiology of a number of B-cell lymphoproliferative disorders. A number of pre- and clinical studies support the inhibition of BTK as a mechanism for the treatment of B-cell lymphoproliferative disorders (Castillo JJ et al. (2016). See also under Bruton tyrosine kinase inhibitors.

Note(s)
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Recently, small molecule inhibitors of this kinase have shown excellent anti-tumor activity in clinical trials. In particular, the orally administered irreversible BTK inhibitor ibrutinib shows high response rates in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). Because ibrutinibis generally well tolerated and shows durable efficacy as a single agent, it was rapidly approved in 2016 for first-line treatment of patients with CLL (Pal Singh S et al. 2018). Approved 2nd generation BTK inhibitors are: acalabrutinib and zanubrutinib.

Literature
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  1. Burger JA (2019) Bruton tyrosine kinase inhibitors: present and future. Cancer J 25:386-393.
  2. Brullo C et al (2021) Btk Inhibitors: A Medicinal Chemistry and Drug Delivery Perspective. Int J Mol Sci 22:7641.
  3. Castillo JJ et al (2016) Inhibition of the Bruton Tyrosine Kinase Pathway in B-Cell Lymphoproliferative Disorders. Cancer J 22:34-39.
  4. Fancher KMet al.(2020) Drug interactions with Bruton's tyrosine kinase inhibitors: clinical implications and management. Cancer Chemother Pharmacol 86: 507-515.
  5. Pablo Engel JA et al (2011) Therapeutic targeting of B cells for rheumatic autoimmune diseases. Pharmacol Rev 63: 127-156.
  6. Pal Singh S et al (2018) Role of Bruton's tyrosine kinase in B cells and malignancies. Mol Cancer 19: 57

Last updated on: 17.04.2022