Janus kinase 2 (commonly called JAK2) is a
non-receptor tyrosine kinase. It is a member of the
Janus kinase
Janus kinase (JAK) is a family of intracellular, non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. They were initially named "just another kinase" 1 and 2 (since they were just two of many discoverie ...
family and has been implicated in signaling by members of the
type II cytokine receptor family (e.g.
interferon
Interferons (IFNs, ) are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten ...
receptors), the
GM-CSF receptor family (
IL-3R,
IL-5R and
GM-CSF-R), the
gp130 receptor family (e.g.,
IL-6R), and the single chain receptors (e.g.
Epo-R,
Tpo-R,
GH-R,
PRL-R).
The distinguishing feature between janus kinase 2 and other JAK kinases is the lack of Src homology binding domains (
SH2/
SH3) and the presence of up to seven
JAK homology domains (JH1-JH7). Nonetheless the terminal JH domains retain a high level of homology to tyrosine kinase domains. An interesting note is that only one of these carboxy-terminal JH domains retains full kinase function (JH1) while the other (JH2), previously thought to have no kinase functionality and accordingly termed a
pseudokinase domain, has since been found to be catalytically active, albeit at only 10% that of the JH1 domain.
Loss of JAK2 is lethal by embryonic day 12 in mice.
''JAK2''
orthologs
Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a spec ...
have been identified in all
mammals
A mammal () is a vertebrate animal of the class Mammalia (). Mammals are characterised by the presence of milk-producing mammary glands for feeding their young, a broad neocortex region of the brain, fur or hair, and three middle e ...
for which complete genome data are available.
Clinical significance
''JAK2'' gene fusions with the ''TEL''(''ETV6'') (
TEL-JAK2
TEL- JAK2 is a gene fusion resulting from a chromosomal translocation between chromosomes 9 and 12 observed in human leukemia. The 5' moiety of ''TEL'' is fused to the 3' end of ''JAK2''.
The oligomerisation domain of the TEL protein (also c ...
) and ''PCM1'' genes have been found in patients suffering
leukemia
Leukemia ( also spelled leukaemia; pronounced ) is a group of blood cancers that usually begin in the bone marrow and produce high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or '' ...
, particularly
clonal eosinophilia
Clonal hypereosinophilia, also termed primary hypereosinophilia or clonal eosinophilia, is a grouping of hematological disorders all of which are characterized by the development and growth of a pre-malignant or malignant population of eosinophil ...
forms of the disease.
Mutations in JAK2 have been implicated in
polycythemia vera
In oncology, polycythemia vera (PV) is an uncommon myeloproliferative neoplasm in which the bone marrow makes too many red blood cells. Approximately 98% of PV patients have a JAK2 gene mutation in their blood-forming cells (compared with 0.1-0 ...
,
essential thrombocythemia, and
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 activation and growth of mutated cells in ...
as well as other
myeloproliferative disorders.
This mutation (V617F), a change of
valine
Valine (symbol Val or V) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated −NH3+ form under biological conditions), an α- carboxylic acid group (which is in the deproton ...
to
phenylalanine
Phenylalanine (symbol Phe or F) is an essential α-amino acid with the chemical formula, formula . It can be viewed as a benzyl group substituent, substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of ...
at the 617 position, appears to render
hematopoietic cell
A blood cell (also called a hematopoietic cell, hemocyte, or hematocyte) is a cell produced through hematopoiesis and found mainly in the blood. Major types of blood cells include red blood cells (erythrocytes), white blood cells (leukocytes) ...
s more sensitive to growth factors such as
erythropoietin
Erythropoietin (; EPO), also known as erythropoetin, haematopoietin, or haemopoietin, is a glycoprotein cytokine secreted mainly by the kidneys in response to cellular hypoxia; it stimulates red blood cell production ( erythropoiesis) in th ...
and
thrombopoietin
Thrombopoietin (THPO) also known as megakaryocyte growth and development factor (MGDF) is a protein that in humans is encoded by the ''THPO'' gene.
Thrombopoietin is a glycoprotein hormone produced by the liver and kidney which regulates the pro ...
, because the receptors for these growth factors require JAK2 for signal transduction.
JAK2 mutation, when demonstrable, is one of the methods of diagnosing
polycythemia vera
In oncology, polycythemia vera (PV) is an uncommon myeloproliferative neoplasm in which the bone marrow makes too many red blood cells. Approximately 98% of PV patients have a JAK2 gene mutation in their blood-forming cells (compared with 0.1-0 ...
.
Interactions
Janus kinase 2 has been shown to
interact with:
*
DNAJA3
*
EGFR
*
EPOR
*
FYN
*
Grb2
Growth factor receptor-bound protein 2, also known as Grb2, is an adaptor protein involved in signal transduction/ cell communication. In humans, the GRB2 protein is encoded by the ''GRB2'' gene.
The protein encoded by this gene binds recepto ...
*
GHR
*
IRS1
Insulin receptor substrate 1 (IRS-1) is a signaling adapter protein that in humans is encoded by the ''IRS1'' gene. It is a 180 kDa protein with amino acid sequence of 1242 residues. It contains a single pleckstrin homology (PH) domain at the N-t ...
*
IL12RB2
*
IL5RA
*
PIK3R1
Phosphatidylinositol 3-kinase regulatory subunit alpha is an enzyme that in humans is encoded by the ''PIK3R1'' gene.
Function
Phosphatidylinositol 3-kinase phosphorylates the inositol ring of phosphatidylinositol at the 3-prime position. ...
*
PPP2R4[
* ]PTK2
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 ...
PTPN11
Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) also known as protein-tyrosine phosphatase 1D (PTP-1D), Src homology region 2 domain-containing phosphatase-2 (SHP-2), or protein-tyrosine phosphatase 2C (PTP-2C) is an enzyme that in hu ...
PTPN6
Tyrosine-protein phosphatase non-receptor type 6, also known as Src homology region 2 domain-containing phosphatase-1 (SHP-1), is an enzyme that in humans is encoded by the ''PTPN6'' gene.
Function
The protein encoded by this gene is a member ...
SH2B1
SH2B adapter protein 1 is a protein that in humans is encoded by the ''SH2B1'' gene.
Interactions
SH2B1 has been shown to interact with:
* Grb2,
* Insulin receptor,
* Janus kinase 2, and
* TrkA.
Clinical significance
Variations close ...
SHC1
SHC-transforming protein 1 is a protein that in humans is encoded by the ''SHC1'' gene. SHC has been found to be important in the regulation of apoptosis and drug resistance in mammalian cells.
SCOP
A ( or ) was a poet as represented in Old ...
STAT5A
Signal transducer and activator of transcription 5A is a protein that in humans is encoded by the ''STAT5A'' gene. ''STAT5A'' orthologs have been identified in several placentals for which complete genome data are available.
Structure
STAT5a s ...
[
* STAM]VAV1
Proto-oncogene vav is a protein that in humans is encoded by the ''VAV1'' gene.
Function
The protein encoded by this proto-oncogene is a member of the Dbl family of guanine nucleotide exchange factors (GEF) for the Rho family of GTP binding ...
YES1
Tyrosine-protein kinase Yes is a Enzyme, non-receptor tyrosine kinase that in humans is encoded by the ''YES1'' gene.
This gene is the cellular homolog of the Yamaguchi sarcoma virus oncogene. The encoded protein has tyrosine kinase activity and ...
[
]Prolactin
Prolactin (PRL), also known as lactotropin and mammotropin, 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 secr ...
signals through JAK2 are dependent on STAT5, and on the RUSH transcription factors.
See also
*Janus kinase 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 ...
, medical drugs under development
*Ruxolitinib
Ruxolitinib (sold under the brand names Jakafi and Jakavi among others, and as Opzelura in cream form) is a medication used for the treatment of intermediate or high-risk myelofibrosis, a type of myeloproliferative neoplasm that affects the b ...
References
Further reading
*
*
*
*
External links
*
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Tyrosine kinases