Bruton's tyrosine kinase

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.

Function

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. It also has a role in mast cell activation through the high-affinity IgE receptor.

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.

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. 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).X-Linked Agammaglobulinemia
Patient and Family Handbook for The Primary Immune Diseases. Third Edition. 2001. Published by the Immune Deficiency Foundation. At least 400 mutations of the BTK gene have been identified. Of these, at least 212 are considered to be disease-causing mutations.

BTK inhibitors

Approved drugs that inhibit BTK:
* Ibrutinib (PCI-32765), a selective Bruton's tyrosine kinase inhibitor.
* Acalabrutinib, approved in October 2017 for relapsed mantle cell lymphoma
* Zanubrutinib for mantle cell lymphoma. It can be taken orally.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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* Tirabrutinib, approved in March 2020 in Japan for the treatment of recurrent or refractory primary central nervous system lymphoma.

Various drugs that inhibit BTK are in clinical trials:
* Phase 3:
** Acalabrutinib, for relapsed chronic lymphocytic leukemia (CLL), 95% overall remission reported.
** Evobrutinib for multiple sclerosis.
** Tolebrutinib, for multiple sclerosis.
** Remibrutinib, for multiple sclerosis.
* Phase 2:
** ABBV-105 for systemic lupus erythematosus (SLE)
** Fenebrutinib (GDC-0853, RG7845) for rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis and chronic spontaneous urticaria.
** Pirtobrutinib (LOXO-305) for relapsed B-cell lymphoma or B-cell leukemia.
* Phase 1:
** ONO-4059 for non-Hodgkin lymphoma and/or CLL. Renamed GS-4059 and now in trial NCT02457598.
** Spebrutinib (AVL-292, CC-292)
**HM71224 for autoimmune diseases, under development by Hanmi Pharmaceutical and Lilly as of 2015

Discovery

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

Interactions

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

* ARID3A
* BLNK (SLP-65),
* CAV1,
* GNAQ,
* GTF2I,
* PLCG2,
* PRKD1, and
* SH3BP5.

See also

* Ibrutinib (PCI-32765)
* Acalabrutinib

References

Further reading

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External links

GeneReviews/NCBI/NIH/UW entry on X-Linked or Brunton's Agammaglobulinemia
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{{DEFAULTSORT:Bruton's Tyrosine Kinase
Peripheral membrane proteins
Tyrosine kinases