Bruton's tyrosine kinase
Encyclopedia
Bruton's tyrosine kinase (or Btk) is a type of kinase
enzyme
implicated in the primary immunodeficiency
disease X-linked agammaglobulinemia
(Bruton's agammaglobulinemia). Its exact mechanism of action
remains unknown, but it plays a crucial role in B cell
maturation as well as mast cell
activation through the high-affinity IgE
receptor. 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 mutation
s of the BTK gene have been identified.
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 messagers, inositol triphosphate
(IP3) and diacylglycerol
(DAG), which then go on to modulate the activity of downstream proteins during B-cell signalling. Patients often have sinopulmonary infections beginning 6 months after birth (maternally derived antibodies offer some protection until that time).
Bruton's tyrosine kinase
was discovered in 1993 and is named for Dr. Ogden Bruton
, who first described XLA in 1952.
with GNAQ
, PLCG2
, Protein kinase D1
, B-cell linker
, SH3BP5
, Caveolin 1, ARID3A
and GTF2I
.
Kinase
In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
implicated in the primary immunodeficiency
Primary immunodeficiency
Primary immunodeficiencies are disorders in which part of the body's immune system is missing or does not function properly. To be considered a primary immunodeficiency, the cause of the immune deficiency must not be secondary in nature...
disease X-linked agammaglobulinemia
X-linked agammaglobulinemia
X-linked agammaglobulinemia is a rare X-linked genetic disorder that was discovered in 1952 which affects the body's ability to fight infection. XLA is an X-linked disorder, and therefore is more common in males...
(Bruton's agammaglobulinemia). Its exact mechanism of action
Mechanism of action
In pharmacology, the term mechanism of action refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect...
remains unknown, but it plays a crucial role in B cell
B cell
B cells are lymphocytes that play a large role in the humoral immune response . The principal functions of B cells are to make antibodies against antigens, perform the role of antigen-presenting cells and eventually develop into memory B cells after activation by antigen interaction...
maturation as well as mast cell
Mast cell
A mast cell is a resident cell of several types of tissues and contains many granules rich in histamine and heparin...
activation through the high-affinity IgE
IGE
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receptor. Patients with XLA have normal pre-B cell populations in their bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
but these cells fail to mature and enter the circulation. The BTK gene is located on the X chromosome
X chromosome
The X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals and is common in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system...
. At least 400 mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s of the BTK gene have been identified.
Btk contains a PH domain that binds Phosphatidylinositol (3,4,5)-trisphosphate
Phosphatidylinositol (3,4,5)-trisphosphate
Phosphatidylinositol -triphosphate , abbreviated PIP3, is the product of the class I phosphoinositide 3-kinases phosphorylation on phosphatidylinositol -bisphosphate .-Discovery:...
(PIP3). PIP3 binding induces Btk to phosphorylate phospholipase C
Phospholipase C
Phosphoinositide phospholipase C is a family of eukaryotic intracellular enzymes that play an important role in signal transduction processes. In general, this enzyme is denoted as Phospholipase C, although three other families of phospholipase C enzymes have been identified in bacteria and in...
, which in turn hydrolyzes PIP2, a phosphatidylinositol
Phosphatidylinositol
Phosphatidylinositol is a negatively charged phospholipid and a minor component in the cytosolic side of eukaryotic cell membranes....
, into two second messagers, inositol triphosphate
Inositol triphosphate
Inositol trisphosphate or inositol 1,4,5-trisphosphate , together with diacylglycerol , is a secondary messenger molecule used in signal transduction and lipid signaling in biological cells. While DAG stays inside the membrane, IP3 is soluble and diffuses through the cell...
(IP3) and diacylglycerol
Diglyceride
A diglyceride, or a diacylglycerol , is a glyceride consisting of two fatty acid chains covalently bonded to a glycerol molecule through ester linkages....
(DAG), which then go on to modulate the activity of downstream proteins during B-cell signalling. Patients often have sinopulmonary infections beginning 6 months after birth (maternally derived antibodies offer some protection until that time).
Bruton's tyrosine kinase
Tyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions....
was discovered in 1993 and is named for Dr. Ogden Bruton
Ogden Bruton
Ogden Carr Bruton was a pediatrician and chief of pediatrics at Walter Reed Army Hospital, where he organized the first pediatric residency at this hospital...
, who first described XLA in 1952.
Interactions
Bruton's tyrosine kinase has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with GNAQ
GNAQ
Guanine nucleotide-binding protein G subunit alpha is a protein that in humans is encoded by the GNAQ gene.-Interactions:GNAQ has been shown to interact with Sodium-hydrogen antiporter 3 regulator 1, RIC8A, RGS16, Beta adrenergic receptor kinase, RGS4 and Bruton's tyrosine kinase.-Further reading:...
, PLCG2
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 and water-soluble phosphorylated derivatives of the lipid...
, Protein kinase D1
Protein kinase D1
Serine/threonine-protein kinase D1 is an enzyme that in humans is encoded by the PRKD1 gene.-Interactions:Protein kinase D1 has been shown to interact with Centaurin, alpha 1, C1QBP, YWHAQ, Metallothionein 2A and Bruton's tyrosine kinase....
, B-cell linker
B-cell linker
The B-cell linker protein is encoded by the BLNK gene and is an adaptor protein also known as SLP-65, BASH, and BCA. BLNK is expressed in B cells and macrophages and plays a large role in B cell receptor signalling, in a fashion analogous to the role its paralogue SLP-76 plays in T cell receptor...
, SH3BP5
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.-Further reading:...
, Caveolin 1, ARID3A
ARID3A
AT-rich interactive domain-containing protein 3A is a protein that in humans is encoded by the ARID3A gene.-Interactions:ARID3A has been shown to interact with E2F1 and Bruton's tyrosine kinase....
and GTF2I
GTF2I
General transcription factor II-I is a protein that in humans is encoded by the GTF2I gene.-Interactions:GTF2I has been shown to interact with USF1 , Histone deacetylase 2, PRKG1, Myc, MAPK3, HDAC3, Serum response factor and Bruton's tyrosine kinase.-Further reading:...
.