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Bruton's tyrosine kinase (abbreviated Btk or BTK), also known as tyrosine-protein kinase BTK, is a
tyrosine kinase A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions. Tyrosine kinases belong to a larger cla ...
that is encoded by the ''BTK''
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
in humans. BTK plays a crucial role in
B cell B cells, also known as B lymphocytes, are a type of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or inserted into the plasm ...
development.


Structure

BTK contains five different protein interaction domains. These domains include an amino terminal
pleckstrin homology Pleckstrin homology domain (PH domain) or (PHIP) is a protein domain of approximately 120 amino acids that occurs in a wide range of proteins involved in intracellular signaling or as constituents of the cytoskeleton. This domain can bind phosph ...
(PH) domain, a proline-rich TEC homology (TH) domain, SRC homology (SH) domains SH2 and SH3, as well as a
protein kinase domain The protein kinase domain is a structurally conserved sequence, conserved protein domain containing the catalytic function of protein kinases. Protein kinases are a group of enzymes that move a phosphate group onto proteins, in a process called ph ...
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 A mast cell (also known as a mastocyte or a labrocyte) is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from the myeloid stem cell that is a p ...
activation through the high-affinity IgE
receptor Receptor may refer to: * Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and respond ...
. BTK contains a PH domain that binds phosphatidylinositol (3,4,5)-trisphosphate (PIP3). PIP3 binding induces BTK to phosphorylate
phospholipase C Phospholipase C (PLC) is a class of membrane-associated enzymes that cleave phospholipids just before the phosphate group (see figure). It is most commonly taken to be synonymous with the human forms of this enzyme, which play an important role i ...
(PLC), which in turn hydrolyzes PIP2, a
phosphatidylinositol Phosphatidylinositol or inositol phospholipid is a biomolecule. It was initially called "inosite" when it was discovered by Léon Maquenne and Johann Joseph von Scherer in the late 19th century. It was discovered in bacteria but later also found ...
, 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 Bone marrow is a semi-solid biological tissue, tissue found within the Spongy bone, spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It i ...
but these cells fail to mature and enter the circulation. The BTK gene is located on the
X chromosome The X chromosome is one of the two sex chromosomes in many organisms, including mammals, and is found in both males and females. It is a part of the XY sex-determination system and XO sex-determination system. The X chromosome was named for its u ...
(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
mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...
s 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: * Ibrutinib (Imbruvica), a selective Bruton's tyrosine kinase inhibitor. *
Acalabrutinib Acalabrutinib, sold under the brand name Calquence, is a anti-cancer medication used to treat various types of non-Hodgkin lymphoma, including mantle cell lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma. It may be used bo ...
(Calquence), approved in October 2017 for relapsed
mantle cell lymphoma Mantle cell lymphoma (MCL) is a type of Non-Hodgkin lymphoma, non-Hodgkin's lymphoma, comprising about 6% of cases. It is named for the mantle zone of the lymph nodes where it develops. The term 'mantle cell lymphoma' was first adopted by Raffe ...
and in October 2019 for
Chronic lymphocytic leukemia Chronic lymphocytic leukemia (CLL) is a type of cancer that affects the blood and bone marrow. In CLL, the bone marrow makes too many lymphocytes, which are a type of white blood cell. In patients with CLL, B cell lymphocytes can begin to colle ...
(CLL) and Small lymphocytic lymphoma (SLL) * Zanubrutinib (Brukinsa) for mantle cell lymphoma, chronic lymphocytic leukemia (CLL), or small lymphocytic lymphoma (SLL). It can be taken
by mouth Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...
.BeiGene Announces Initiation of a Combination Trial of the BTK Inhibitor BGB-3111 with the PD-1 Antibody BGB-A317. June 2016
/ref> * Tirabrutinib (Velexbru), approved in March 2020, in Japan, for the treatment of recurrent or refractory primary central nervous system lymphoma. * Pirtobrutinib (Jaypirca), a reversible (non-covalent) inhibitor of BTK, for mantle cell lymphoma. * Orelabrutinib, approved in China for patients with
mantle cell lymphoma Mantle cell lymphoma (MCL) is a type of Non-Hodgkin lymphoma, non-Hodgkin's lymphoma, comprising about 6% of cases. It is named for the mantle zone of the lymph nodes where it develops. The term 'mantle cell lymphoma' was first adopted by Raffe ...
(MCL) and
chronic lymphocytic leukemia Chronic lymphocytic leukemia (CLL) is a type of cancer that affects the blood and bone marrow. In CLL, the bone marrow makes too many lymphocytes, which are a type of white blood cell. In patients with CLL, B cell lymphocytes can begin to colle ...
/ small lymphocytic lymphoma (CLL/SLL), who have received at least one treatment in the past. Various drugs that inhibit BTK are in clinical trials: * Phase 3: ** Evobrutinib for
multiple sclerosis Multiple sclerosis (MS) is an autoimmune disease resulting in damage to myelinthe insulating covers of nerve cellsin the brain and spinal cord. As a demyelinating disease, MS disrupts the nervous system's ability to Action potential, transmit ...
. ** Tolebrutinib, for multiple sclerosis. ** Remibrutinib, for multiple sclerosis. ** Fenebrutinib (RG7845) for multiple sclerosis. * Rilzabrutinib * Phase 2: ** ABBV-105 for systemic lupus erythematosus (SLE) **Fenebrutinib (GDC-0853) for rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis and chronic spontaneous urticaria. * Phase 1: ** Tirabrutinib, for
non-Hodgkin lymphoma Non-Hodgkin lymphoma (NHL), also known as non-Hodgkin's lymphoma, is a group of blood cancers that includes all types of lymphomas except Hodgkin lymphomas. Symptoms include enlarged lymph nodes, fever, night sweats, weight loss, and tiredn ...
and/or CLL. Renamed GS-4059 and now in trial NCT02457598. ** Spebrutinib (AVL-292, CC-292) ** HM71224, for
autoimmune diseases An autoimmune disease is a condition that results from an anomalous response of the adaptive immune system, wherein it mistakenly targets and attacks healthy, functioning parts of the body as if they were foreign organisms. It is estimated that ...
, under development by Hanmi Pharmaceutical and Lilly as of 2015 ** Luxeptinib (CG-806), for CLL, SLL, non-Hodgkin lymphoma,
acute myeloid leukaemia Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with normal blood cell production. Symptoms may inclu ...
, and
myelodysplastic syndrome A myelodysplastic syndrome (MDS) is one of a group of cancers in which blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may includ ...
s
Phase I TrialPhase I Trial
. The inhibitor targets multiple kinase pathways, including BTK and FLT3. * Elsubrutinib * Vecabrutinib * Nemtabrutinib


Discovery

Bruton's
tyrosine kinase A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions. Tyrosine kinases belong to a larger cla ...
is named for Ogden Bruton, who first described XLA in 1952. 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.


Interactions

Bruton's tyrosine kinase has been shown to interact with: * ARID3A * BLNK (SLP-65), * CAV1, * GNAQ, * GTF2I, * PLCG2, * PRKD1, and * SH3BP5.


References


Further reading

* * * * * * *


External links


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