Janus kinase
Encyclopedia
Janus kinase is a family of intracellular, non-receptor tyrosine kinase
s that transduce cytokine
-mediated signals via the JAK-STAT pathway. They were initially named "just another kinase" 1 & 2 (since they were just two of a large number of discoveries in a PCR-based screen of kinases), but were ultimately published as "Janus kinase". The name is taken from the two-faced Roman
god of doorways, Janus
, because the JAKs possess two near-identical phosphate-transferring domains. One domain exhibits the kinase activity while the other negatively regulates the kinase activity of the first.
There are four JAK family members:
Transgenic mice that do not express JAK1 have defective responses to some cytokines such as interferon-gamma
. JAK1 and JAK2 are involved in type II interferon (interferon-gamma) signalling, whereas JAK1 and TYK2 are involved in type I interferon signalling. Mice that do not express TYK2 have defective natural killer cell
function.
Since members of the type I
and type II cytokine receptor
families possess no catalytic kinase
activity, they rely on the JAK family of tyrosine kinase
s to phosphorylate and activate downstream proteins involved in their signal transduction
pathways. The receptor
s exist as paired polypeptides thus exhibiting two intracellular signal-transducing domains. JAKs associate with a proline
-rich region in each intracellular
domain, which is adjacent to the cell membrane
and called a box1/box2 region. After the receptor associates with its respective cytokine
/ligand
it goes through a conformational change, bringing the two JAKs close enough to phosphorylate each other. The JAK autophosphorylation induces a conformational change within itself enabling it to transduce the intracellular signal by further phosphorylating and activating transcription factor
s called STATs
. The activated STATs dissociate from the receptor and form dimers before translocating to the cell nucleus
where they regulate transcription
of selected gene
s.
Some examples of the molecules that utilize JAK/STAT signaling pathway are colony-stimulating factor
, prolactin
, growth hormone
, and many cytokines.
, rheumatoid arthritis
, polycythemia vera
, essential thrombocythemia, and myeloid metaplasia with myelofibrosis
.
JAKs range from 120-140 kDa in size and have seven defined regions of homology called Janus homology domain 1–7 (JH1-7). JH1 is the kinase
domain important for the enzymatic
activity of the JAK and contains typical features of a tyrosine kinase
such as conserved tyrosine
s necessary for JAK activation (e.g. Y1038/Y1039 in JAK1, Y1007/Y1008 in JAK2, Y980/Y981 in JAK3, and Y1054/Y1055 in Tyk2). Phosphorylation of these dual tyrosines leads to the conformational changes in the JAK protein to facilitate binding of substrate
. JH2 is a pseudokinase domain, a domain structurally similar to a tyrosine kinase and is essential for a normal kinase activity yet lacks enzymatic activity. This domain may be involved in regulating the activity of JH1. The JH3-JH4 domain of JAKs shares homology with Src-homology
-2 (SH2
) domains. The amino terminal (NH2) end (JH4-JH7) of Jaks is called a FERM domain
(short for band 4.1 ezrin, radixin and moesin); this domain is also found in the focal adhesion kinase (FAK) family and is involved in association of JAKs with cytokine
receptors and/or other kinases.
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....
s that transduce cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
-mediated signals via the JAK-STAT pathway. They were initially named "just another kinase" 1 & 2 (since they were just two of a large number of discoveries in a PCR-based screen of kinases), but were ultimately published as "Janus kinase". The name is taken from the two-faced Roman
Roman mythology
Roman mythology is the body of traditional stories pertaining to ancient Rome's legendary origins and religious system, as represented in the literature and visual arts of the Romans...
god of doorways, Janus
Janus (mythology)
In ancient Roman religion and mythology, Janus is the god of beginnings and transitions, thence also of gates, doors, doorways, endings and time. He is usually a two-faced god since he looks to the future and the past...
, because the JAKs possess two near-identical phosphate-transferring domains. One domain exhibits the kinase activity while the other negatively regulates the kinase activity of the first.
The Janus kinase family
- Janus kinase 1Janus kinase 1JAK1 is a human tyrosine kinase protein essential for signaling for certain type I and type II cytokines. It interacts with the common gamma chain of type I cytokine receptors, to elicit signals from the IL-2 receptor family , the IL-4 receptor family , the gp130 receptor family JAK1 is a human...
(JAK1) - Janus kinase 2Janus kinase 2Janus kinase 2 is a human protein that has been implicated in signaling by members of the type II cytokine receptor family , the GM-CSF receptor family , the gp130 receptor family , and the single chain receptors...
(JAK2) - Janus kinase 3Janus kinase 3Tyrosine-protein kinase JAK3 is an enzyme that in humans is encoded by the JAK3 gene.Since JAK3 expression is restricted mostly to hematopoietic cells, its role in cytokine signaling is thought to be more restricted than other JAKs. It is most commonly expressed in T cells and NK cells, but has...
(JAK3) - Tyrosine kinase 2Tyrosine kinase 2Non-receptor tyrosine-protein kinase TYK2 is an enzyme that in humans is encoded by the TYK2 gene.Tyk2 was the first member of the JAK family that was described...
(TYK2)
Transgenic mice that do not express JAK1 have defective responses to some cytokines such as interferon-gamma
Interferon-gamma
Interferon-gamma is a dimerized soluble cytokine that is the only member of the type II class of interferons. This interferon was originally called macrophage-activating factor, a term now used to describe a larger family of proteins to which IFN-γ belongs...
. JAK1 and JAK2 are involved in type II interferon (interferon-gamma) signalling, whereas JAK1 and TYK2 are involved in type I interferon signalling. Mice that do not express TYK2 have defective natural killer cell
Natural killer cell
Natural killer cells are a type of cytotoxic lymphocyte that constitute a major component of the innate immune system. NK cells play a major role in the rejection of tumors and cells infected by viruses...
function.
General functions of the JAK family
Type I cytokine receptor
Type I cytokine receptors are transmembrane receptors expressed on the surface of cells that recognize and respond to cytokines with four α-helical strands. These receptors are also known under the name hemopoietin receptors, and share a common amino acid motif in the extracellular portion...
and type II cytokine receptor
Type II cytokine receptor
Type II cytokine receptors are transmembrane proteins that are expressed on the surface of certain cells, which bind and respond to a select group of cytokines...
families possess no catalytic kinase
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...
activity, they rely on the JAK family of 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....
s to phosphorylate and activate downstream proteins involved in their signal transduction
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
pathways. The receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
s exist as paired polypeptides thus exhibiting two intracellular signal-transducing domains. JAKs associate with a proline
Proline
Proline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...
-rich region in each intracellular
Intracellular
Not to be confused with intercellular, meaning "between cells".In cell biology, molecular biology and related fields, the word intracellular means "inside the cell".It is used in contrast to extracellular...
domain, which is adjacent to the cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
and called a box1/box2 region. After the receptor associates with its respective cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
/ligand
Ligand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
it goes through a conformational change, bringing the two JAKs close enough to phosphorylate each other. The JAK autophosphorylation induces a conformational change within itself enabling it to transduce the intracellular signal by further phosphorylating and activating transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
s called STATs
STAT protein
The STAT protein regulates many aspects of growth, survival and differentiation in cells...
. The activated STATs dissociate from the receptor and form dimers before translocating to the cell nucleus
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
where they regulate transcription
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
of selected gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s.
Some examples of the molecules that utilize JAK/STAT signaling pathway are colony-stimulating factor
Colony-stimulating factor
Colony-stimulating factors are secreted glycoproteins that bind to receptor proteins on the surfaces of hemopoietic stem cells, thereby activating intracellular signaling pathways that can cause the cells to proliferate and differentiate into a specific kind of blood cell Colony-stimulating...
, prolactin
Prolactin
Prolactin also known as luteotropic hormone is a protein that in humans is encoded by the PRL gene.Prolactin is a peptide hormone discovered by Henry Friesen...
, growth hormone
Growth hormone
Growth hormone is a peptide hormone that stimulates growth, cell reproduction and regeneration in humans and other animals. Growth hormone is a 191-amino acid, single-chain polypeptide that is synthesized, stored, and secreted by the somatotroph cells within the lateral wings of the anterior...
, and many cytokines.
Clinical significance
JAK inhibitors are under development for the treatment of psoriasisPsoriasis
Psoriasis is an autoimmune disease that appears on the skin. It occurs when the immune system mistakes the skin cells as a pathogen, and sends out faulty signals that speed up the growth cycle of skin cells. Psoriasis is not contagious. However, psoriasis has been linked to an increased risk of...
, rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
, polycythemia vera
Polycythemia vera
Polycythemia vera is a blood disorder in which the bone marrow makes too many red blood cells. It may also result in the overproduction of white blood cells and platelets. Most of the health concerns associated with polycythemia vera are caused by the blood being thicker as a result of the...
, essential thrombocythemia, and myeloid metaplasia with myelofibrosis
Myelofibrosis
Myelofibrosis, also known as myeloid metaplasia, chronic idiopathic myelofibrosis, osteomyelofibrosis and primary myelofibrosis is a disorder of the bone marrow...
.
The structure of JAKs
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...
domain important for the enzymatic
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...
activity of the JAK and contains typical features of a 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....
such as conserved tyrosine
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
s necessary for JAK activation (e.g. Y1038/Y1039 in JAK1, Y1007/Y1008 in JAK2, Y980/Y981 in JAK3, and Y1054/Y1055 in Tyk2). Phosphorylation of these dual tyrosines leads to the conformational changes in the JAK protein to facilitate binding of substrate
Substrate (biochemistry)
In biochemistry, a substrate is a molecule upon which an enzyme acts. Enzymes catalyze chemical reactions involving the substrate. In the case of a single substrate, the substrate binds with the enzyme active site, and an enzyme-substrate complex is formed. The substrate is transformed into one or...
. JH2 is a pseudokinase domain, a domain structurally similar to a tyrosine kinase and is essential for a normal kinase activity yet lacks enzymatic activity. This domain may be involved in regulating the activity of JH1. The JH3-JH4 domain of JAKs shares homology with Src-homology
Src (gene)
Proto-oncogene tyrosine-protein kinase Src is an enzyme that in humans is encoded by the SRC gene.Src is a proto-oncogene encoding a tyrosine kinase originally discovered by J. Michael Bishop and Harold E. Varmus, for which they won the 1989 Nobel Prize in Physiology or Medicine. It belongs to a...
-2 (SH2
SH2 domain
The SH2 domain is a structurally conserved protein domain contained within the Src oncoprotein and in many other intracellular signal-transducing proteins...
) domains. The amino terminal (NH2) end (JH4-JH7) of Jaks is called a FERM domain
FERM domain
In molecular biology, the FERM domain is a widespread protein module involved in localising proteins to the plasma membrane. FERM domains are found in a number of cytoskeletal-associated proteins that associate with various proteins at the interface between the plasma membrane and the cytoskeleton...
(short for band 4.1 ezrin, radixin and moesin); this domain is also found in the focal adhesion kinase (FAK) family and is involved in association of JAKs with cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
receptors and/or other kinases.