Bruton's tyrosine kinase


Bruton's tyrosine kinase, 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 domain, a proline-rich TEC homology domain, SRC homology domains SH2 and SH3, as well as a protein kinase domain with tyrosine phosphorylation activity.
Part of the TH domain is folded against the PH domain while the rest is intrinsically disordered.

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 binding induces BTK to phosphorylate phospholipase C, which in turn hydrolyzes PIP2, a phosphatidylinositol, into two second messengers, inositol triphosphate and diacylglycerol, 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 ; 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. At least 400 mutations of the BTK gene have been identified. Of these, at least 212 are considered to be disease-causing mutations.
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). As BTK is also linked to autoimmune disorders, 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).

BTK inhibitors

Approved drugs that inhibit BTK:
Various drugs that inhibit BTK are in clinical trials:

Discovery

Bruton's tyrosine kinase is named for Ogden Bruton, who first described XLA in 1952. Later studies in 1993 and 1994 reported the discovery of BTK and found that BTK levels are reduced in B cells from XLA patients.

Interactions

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