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 (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
in humans. BTK plays a crucial role in
B cell
B cells, also known as B lymphocytes, are a type of white blood cell 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 ...
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 phospha ...
(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
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 par ...
activation through the high-affinity
IgE
Immunoglobulin E (IgE) is a type of antibody (or immunoglobulin (Ig) " isotype") that has been found only in mammals. IgE is synthesised by plasma cells. Monomers of IgE consist of two heavy chains (ε chain) and two light chains, with the ε c ...
receptor
Receptor may refer to:
* Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...
.
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 ...
, which in turn hydrolyzes PIP
2, a
phosphatidylinositol
Phosphatidylinositol (or Inositol Phospholipid) consists of a family of lipids as illustrated on the right, where red is x, blue is y, and black is z, in the context of independent variation, a class of the phosphatidylglycerides. In such molecul ...
, into two second messengers,
inositol triphosphate
Inositol trisphosphate or inositol 1,4,5-trisphosphate abbreviated InsP3 or Ins3P or IP3 is an inositol phosphate signaling molecule. It is made by hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2), a phospholipid that is located in the p ...
(IP3) and
diacylglycerol
A diglyceride, or diacylglycerol (DAG), is a glyceride consisting of two fatty acid chains covalently bonded to a glycerol molecule through ester linkages. Two possible forms exist, 1,2-diacylglycerols and 1,3-diacylglycerols. DAGs can act as s ...
(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
Primary immunodeficiencies are disorders in which part of the body's immune system is missing or does not function normally. To be considered a ''primary'' immunodeficiency (PID), the cause of the immune deficiency must not be secondary in nature ...
disease
X-linked agammaglobulinemia
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 whit ...
(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 tissue found within the 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 is composed of hematopoietic ce ...
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-determining chromosomes (allosomes) in many organisms, including mammals (the other is the Y chromosome), and is found in both males and females. It is a part of the XY sex-determination system and XO sex-d ...
(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, mi ...
s 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
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 ...
(PCI-32765), a selective Bruton's tyrosine kinase inhibitor.
*
Acalabrutinib
Acalabrutinib, sold under the brand name Calquence, is a medication used to treat various types of non-Hodgkin lymphoma, including mantle cell lymphoma (MCL) and chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL). It may be used ...
, approved in October 2017 for relapsed
mantle cell lymphoma
Mantle cell lymphoma (MCL) is a type of non-Hodgkin's lymphoma (NHL), comprising about 6% of NHL cases. There are only about 15,000 patients presently in the United States with mantle cell lymphoma. It is named for the mantle zone of the lymph n ...
*
Zanubrutinib
Zanubrutinib, sold under the brand name Brukinsa, is a medication used for the treatment of mantle cell lymphoma (MCL), Waldenström's macroglobulinemia (WM), marginal zone lymphoma (MZL), and chronic lymphocytic leukemia (CLL). 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]
/ref>
* Tirabrutinib
Tirabrutinib (brand name Velexbru) is a drug used for the treatment of autoimmune disorders and hematological malignancies.
Tirabrutinib was approved in March 2020 in Japan for the treatment of recurrent or refractory primary central nervous syst ...
, 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
Acalabrutinib, sold under the brand name Calquence, is a medication used to treat various types of non-Hodgkin lymphoma, including mantle cell lymphoma (MCL) and chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL). It may be used ...
, for relapsed chronic lymphocytic leukemia (CLL), 95% overall remission reported.
** Evobrutinib for multiple sclerosis
Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This d ...
.
** 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
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 ...
(LOXO-305) for relapsed B-cell lymphoma
The B-cell lymphomas are types of lymphoma affecting B cells. Lymphomas are "blood cancers" in the lymph nodes. They develop more frequently in older adults and in immunocompromised individuals.
B-cell lymphomas include both Hodgkin's lympho ...
or B-cell leukemia
A B-cell leukemia is any of several types of lymphoid leukemia which affect B cells.
Types include (with ICD-O code):
* 9823/3 - B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma
* 9826/3 - Acute lymphoblastic leukemia, mature B-ce ...
.
* Phase 1:
** ONO-4059 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 tiredness. ...
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 arising from an abnormal immune response to a functioning body part. At least 80 types of autoimmune diseases have been identified, with some evidence suggesting that there may be more than 100 types. Nearly a ...
, under development by Hanmi Pharmaceutical
Hanmi Pharmaceutical () is a South Korean pharmaceutical industry, pharmaceutical company that is headquartered in Seoul.
History 1973 to 2009
Hanmi was founded in 1973 by Lim Sung-ki, who was a pharmacist. It was originally named Lim, Sung-k ...
and Lilly as of 2015
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 ...
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
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with:
* ARID3A
AT-rich interactive domain-containing protein 3A is a protein that in humans is encoded by the ''ARID3A'' gene.
Function
This gene encodes a member of the ARID (AT-rich interaction domain) family of DNA binding proteins. It was found by homolo ...
* BLNK (SLP-65),
* CAV1,
* GNAQ
Guanine nucleotide-binding protein G(q) subunit alpha is a protein that in humans is encoded by the ''GNAQ'' gene. Together with GNA11 (its paralogue), it functions as a Gq alpha subunit.
Function
Guanine nucleotide-binding proteins are a fam ...
,
* GTF2I
General transcription factor II-I is a protein that in humans is encoded by the ''GTF2I'' gene.
Function
This gene encodes a multifunctional phosphoprotein, TFII-I, with roles in transcription and signal transduction. Haploinsuffiency (deletio ...
,
* PLCG2
1-Phosphatidylinositol-4,5-bisphosphate phosphodiesterase gamma-2 is an enzyme that in humans is encoded by the ''PLCG2'' gene.
Function
Enzymes of the phospholipase C family catalyze the hydrolysis of phospholipids to yield diacylglycerols an ...
,
* PRKD1, and
* SH3BP5
SH3 domain-binding protein 5 is a protein that in humans is encoded by the ''SH3BP5'' gene.
Interactions
SH3BP5 has been shown to interact with Bruton's tyrosine kinase and MAPK8
Mitogen-activated protein kinase 8 (also known as JNK1) is a ubi ...
.
See also
* Ibrutinib
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 ...
(PCI-32765)
*Acalabrutinib
Acalabrutinib, sold under the brand name Calquence, is a medication used to treat various types of non-Hodgkin lymphoma, including mantle cell lymphoma (MCL) and chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL). It may be used ...
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