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 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 b ...
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 o ...
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
The immunoglobulin heavy chain (IgH) is the large polypeptide subunit of an antibody (immunoglobulin). In human genome, the IgH gene loci are on chromosome 14.
A typical antibody is composed of two immunoglobulin (Ig) heavy chains and two Ig li ...
rearrangement. It also has a role in
mast cell activation through the high-affinity
IgE 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 n ...
.
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 (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
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 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-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 ...
(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, m ...
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 (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]
/ref>
* 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
Chronic lymphocytic leukemia (CLL) is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell). Early on, there are typically no symptoms. Later, non-painful lymph node swelling, feeling tired, fever ...
(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 ...
.
** 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
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-cell ...
.
* 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 tiredne ...
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 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-ki Pharmaceutical Co., but ...
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
Advocates for Informed Choice, doing business as, 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 trai ...
with:
* ARID3A
* BLNK (SLP-65),
* CAV1,
* GNAQ,
* 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,
* PRKD1, and
* SH3BP5.
See also
* Ibrutinib (PCI-32765)
* Acalabrutinib
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