Janus kinase (JAK) is a family of intracellular, non-receptor tyrosine kinases that transduce

cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...

-mediated signals via the

JAK-STAT pathway The JAK-STAT signaling pathway is a chain of interactions between proteins in a cell, and is involved in processes such as immunity, cell division, cell death, and tumour formation. The pathway communicates information from chemical signals out ...

. They were initially named "just another kinase" 1 and 2 (since they were just two of many 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 or Romans most often refers to: *Rome, the capital city of Italy *Ancient Rome, Roman civilization from 8th century BC to 5th century AD *Roman people, the people of ancient Rome *'' Epistle to the Romans'', shortened to ''Romans'', a lette ...

god of beginnings, endings and duality, 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.

Family

The four JAK family members are: *

Janus kinase 1 JAK1 is a human tyrosine kinase protein essential for signaling for certain type I and type II cytokines. It interacts with the common gamma chain (γc) of type I cytokine receptors, to elicit signals from the IL-2 receptor family (e.g. IL-2R, ...

(JAK1) *

Janus kinase 2 Janus kinase 2 (commonly called JAK2) is a non-receptor tyrosine kinase. It is a member of the Janus kinase family and has been implicated in signaling by members of the type II cytokine receptor family (e.g. interferon receptors), the GM-CSF rece ...

(JAK2) *

Janus kinase 3 Tyrosine-protein kinase JAK3 is a tyrosine kinase enzyme that in humans is encoded by the ''JAK3'' gene. Janus kinases Janus kinase 3 is a tyrosine kinase that belongs to the janus family of kinases. Other members of the Janus family include ...

(JAK3) *

Tyrosine kinase 2 Non-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 (the other members are JAK1, JAK2, and JAK3). It has been implicated in IFN-� ...

(TYK2) Transgenic mice that do not express JAK1 have defective responses to some cytokines, such as

interferon-gamma Interferon gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheeloc ...

. JAK1 and JAK2 are involved in type II interferon (interferon-gamma) signalling, whereas JAK1 and TYK2 are involved in

type I interferon The type-I interferons (IFN) are cytokines which play essential roles in inflammation, immunoregulation, tumor cells recognition, and T cell, T-cell responses. In the human genome, a cluster of thirteen functional IFN genes is located at the 9p2 ...

signalling. Mice that do not express TYK2 have defective natural killer cell function.

Functions

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 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 ...

s to

phosphorylate In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, ...

and activate downstream proteins involved in their signal transduction pathways. The

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 ...

s exist as paired polypeptides, thus exhibiting two intracellular signal-transducing domains. JAKs associate with a proline-rich region in each

intracellular This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...

domain that is adjacent to the

cell membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...

and called a box1/box2 region. After the receptor associates with its respective

ligand In coordination chemistry, a ligand is an ion or molecule ( functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's elec ...

, it goes through a conformational change, bringing the two JAKs close enough to

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 In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The f ...

s called STATs (Signal Transducer and Activator of Transcription, or Signal Transduction And Transcription). The activated STATs dissociate from the receptor and form dimers before translocating to the cell nucleus, where they regulate

transcription Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including: Genetics * Transcription (biology), the copying of DNA into RNA, the fir ...

of selected

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 ...

s. Some examples of the molecules that use the JAK/STAT signaling pathway are

colony-stimulating factor Colony-stimulating factors (CSFs) 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 differentia ...

prolactin Prolactin (PRL), also known as lactotropin, is a protein best known for its role in enabling mammals to produce milk. It is influential in over 300 separate processes in various vertebrates, including humans. Prolactin is secreted from the pit ...

growth hormone Growth hormone (GH) or somatotropin, also known as human growth hormone (hGH or HGH) in its human form, is a peptide hormone that stimulates growth, cell reproduction, and cell regeneration in humans and other animals. It is thus important in h ...

, and many cytokines. Janus Kinases have also been reported to have a role in the maintenance of X chromosome inactivation.

Clinical significance

JAK inhibitor A Janus kinase inhibitor, also known as JAK inhibitor or jakinib, is a type of immune modulating medication, which inhibits the activity of one or more of the Janus kinase family of enzymes ( JAK1, JAK2, JAK3, TYK2), thereby interfering with th ...

s are used for the treatment of atopic dermatitis and

rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are invol ...

. They are also being studied in

psoriasis Psoriasis is a long-lasting, noncontagious autoimmune disease characterized by raised areas of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity from small, localized patches to complete ...

polycythemia vera Polycythemia vera is an uncommon myeloproliferative neoplasm (a type of chronic leukemia) 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 healt ...

alopecia Hair loss, also known as alopecia or baldness, refers to a loss of hair from part of the head or body. Typically at least the head is involved. The severity of hair loss can vary from a small area to the entire body. Inflammation or scar ...

, essential

thrombocythemia Thrombocythemia is a condition of high platelet (thrombocyte) count in the blood. Normal count is in the range of 150x109 to 450x109 platelets per liter of blood, but investigation is typically only considered if the upper limit exceeds 750x109/L. ...

ulcerative colitis Ulcerative colitis (UC) is a long-term condition that results in inflammation and ulcers of the colon and rectum. The primary symptoms of active disease are abdominal pain and diarrhea mixed with blood (hematochezia). Weight loss, fever, and ...

, myeloid metaplasia with

myelofibrosis Primary myelofibrosis (PMF) is a rare bone marrow blood cancer. It is classified by the World Health Organization (WHO) as a type of myeloproliferative neoplasm, a group of cancers in which there is growth of abnormal cells in the bone marrow. ...

and

vitiligo Vitiligo is a disorder that causes the skin to lose its color. Specific causes are unknown but studies suggest a link to immune system changes. Signs and symptoms The only sign of vitiligo is the presence of pale patchy areas of depigmen ...

. Examples are

tofacitinib Tofacitinib, sold under the brand Xeljanz among others, is a medication used to treat rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis. Common side effects include diarrhea, headache, and high blood pressure. Serious side eff ...

baricitinib Baricitinib, sold under the brand name Olumiant among others, is a medication used for the treatment of rheumatoid arthritis, alopecia areata, and COVID-19. It acts as an inhibitor of janus kinase (JAK), blocking the subtypes JAK1 and JAK2. ...

upadacitinib Upadacitinib, sold under the brand name Rinvoq, is a Janus kinase (JAK) inhibitor medication for the treatment of moderately to severely active rheumatoid arthritis and psoriatic arthritis in adults where methotrexate (a drug used to treat act ...

and filgotinib (GLPG0634). In 2014 researchers discovered that oral JAK inhibitors, when administered orally, could restore hair growth in some subjects and that applied to the skin, effectively promoted hair growth.

Structure

JAKs range from 120-140

kDa The dalton or unified atomic mass unit (symbols: Da or u) is a non-SI unit of mass widely used in physics and chemistry. It is defined as of the mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state and at re ...

in size and have seven defined regions of homology called Janus homology domains 1 to 7 (JH1-7). JH1 is the kinase domain important for the

enzymatic Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. ...

activity of the JAK and contains typical features of a

such as conserved

tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the G ...

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 essential for a normal kinase activity, yet lacks enzymatic activity. This domain may be involved in regulating the activity of JH1, and was likely a duplication of the JH1 domain which has undergone mutation post-duplication. The JH3-JH4 domains of JAKs share homology with Src-homology-2 ( SH2) domains. The

amino terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...

(NH₂) end (JH4-JH7) of Jaks is called a

FERM domain In molecular biology, the FERM domain (F for 4.1 protein, E for ezrin, R for radixin and M for moesin) is a widespread protein module involved in localising proteins to the plasma membrane. FERM domains are found in a number of cytoskeletal-ass ...

(short for

band 4.1 Protein 4.1, also known as Beatty's Protein, is a protein associated with the cytoskeleton that in humans is encoded by the ''EPB41'' gene. Protein 4.1 is a major structural element of the erythrocyte membrane skeleton. It plays a key role in reg ...

ezrin Ezrin also known as cytovillin or villin-2 is a protein that in humans is encoded by the ''EZR'' gene. Structure The N-terminus of ezrin contains a FERM domain which is further subdivided into three subdomains. The C-terminus contain an ERM d ...

radixin Radixin is a protein that in humans is encoded by the ''RDX'' gene. Radixin is a cytoskeletal protein that may be important in linking actin to the plasma membrane. It is highly similar in sequence to both ezrin and moesin. The radixin gene has ...

and

moesin Moesin is a protein that in humans is encoded by the ''MSN'' gene. Moesin (for membrane-organizing extension spike protein) is a member of the ERM protein family which includes ezrin and radixin. ERM proteins appear to function as cross-linkers ...

); this domain is also found in the

focal adhesion kinase PTK2 protein tyrosine kinase 2 (PTK2), also known as focal adhesion kinase (FAK), is a protein that, in humans, is encoded by the ''PTK2'' gene. PTK2 is a focal adhesion-associated protein kinase involved in cellular adhesion (how cells stick to ...

(FAK) family and is involved in association of JAKs with

receptors and/or other kinases.

References

{{DEFAULTSORT:Janus Kinase Signal transduction Tyrosine kinases