Janus kinase 2 (commonly called JAK2) is a
non-receptor tyrosine kinase
A non-receptor tyrosine kinase (nRTK) is a cytosolic enzyme that is responsible for catalysing the transfer of a phosphate group from a nucleoside triphosphate donor, such as ATP, to tyrosine residues in proteins. Non-receptor tyrosine kinases a ...
. 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 discoveries ...
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 the ...
receptors), the
GM-CSF
Granulocyte-macrophage colony-stimulating factor (GM-CSF), also known as colony-stimulating factor 2 (CSF2), is a monomeric glycoprotein secreted by macrophages, T cells, mast cells, natural killer cells, endothelial cells and fibroblasts that ...
receptor family (
IL-3R
The interleukin-3 receptor ( CD123) is a molecule found on cells which helps transmit the signal of interleukin-3, a soluble cytokine important in the immune system.
The gene coding for the receptor is located in the pseudoautosomal region of t ...
,
IL-5R and
GM-CSF-R
The granulocyte-macrophage colony-stimulating factor receptor also known as CD116 (Cluster of Differentiation 116), is a receptor for granulocyte-macrophage colony-stimulating factor, which stimulates the production of white blood cells. In contr ...
), the
gp130
Glycoprotein 130 (also known as gp130, IL6ST, IL6R-beta or CD130) is a transmembrane protein which is the founding member of the class of all cytokine receptors. It forms one subunit of the type I cytokine receptor within the IL-6 receptor famil ...
receptor family (e.g.,
IL-6R), and the single chain receptors (e.g.
Epo-R
The erythropoietin receptor (EpoR) is a protein that in humans is encoded by the ''EPOR'' gene. EpoR is a 52kDa peptide with a single carbohydrate chain resulting in an approximately 56-57 kDa protein found on the surface of EPO responding cells. ...
,
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
Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur or ...
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 ...
) and PCM1 genes have been found in patients suffering
leukemia
Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in 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 eosinophils ...
forms of the disease.
Mutations in JAK2 have been implicated in
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 health ...
,
essential thrombocythemia
Essential thrombocythemia (ET) is a rare chronic blood cancer (myeloproliferative neoplasm) characterised by the overproduction of platelets (thrombocytes) by megakaryocytes in the bone marrow. It may, albeit rarely, develop into acute myeloid leuk ...
, 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 growth of abnormal cells in the bone marrow. ...
as well as other
myeloproliferative disorders
Myeloproliferative neoplasms (MPNs) are a group of rare blood cancers in which excess red blood cells, white blood cells or platelets are produced in the bone marrow. ''Myelo'' refers to the bone marrow, ''proliferative'' describes the rapid growt ...
.
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 deprotonat ...
to
phenylalanine
Phenylalanine (symbol Phe or F) is an essential α-amino acid with the formula . It can be viewed as a benzyl group substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of alanine. This essential amino a ...
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), a ...
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 the bo ...
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. An inhibitor of JAK2-STAT5, AZD1480, was pointed as having activity in primary and CRPC.
Jak2 mutation, when demonstrable, is one of the methods of diagnosing
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 health ...
.
Interactions
Janus kinase 2 has been shown to
interact
Advocates for Informed Choice, 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 traits. The organizati ...
with:
*
DNAJA3
*
EGFR
*
EPOR
*
FYN
Funen ( da, Fyn, ), with an area of , is the third-largest island of Denmark, after Zealand and Vendsyssel-Thy. It is the 165th-largest island in the world. It is located in the central part of the country and has a population of 469,947 as ...
*
Grb2
*
GHR
*
IRS1
Insulin receptor substrate 1 (IRS-1) is a signaling adapter protein that in humans is encoded by the ''IRS-1'' gene. It is a 131 kDa protein with amino acid sequence of 1242 residues. It contains a single pleckstrin homology (PH) domain at the N-te ...
*
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. The e ...
*
PPP2R4
Serine/threonine-protein phosphatase 2A regulatory subunit B is an enzyme that in humans is encoded by the ''PPP2R4'' gene.
Protein phosphatase 2A is one of the four major Ser/Thr phosphatases and is implicated in the negative control of cell gro ...
[
* ]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 huma ...
* 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 ...
* PRMT5
* 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 to ...
* 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
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of pro ...
* SOCS3
Suppressor of cytokine signaling 3 (SOCS3 or SOCS-3) is a protein that in humans is encoded by the ''SOCS3'' gene.
This gene encodes a member of the STAT-induced STAT inhibitor (SSI), also known as suppressor of cytokine signaling (SOCS), family. ...
* 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 ...
* STAT5B[
* STAM]
* SOCS1
Suppressor of cytokine signaling 1 is a protein that in humans is encoded by the ''SOCS1'' gene. ''SOCS1'' orthologs have been identified in several mammals for which complete genome data are available.
Function
This gene encodes a member of ...
* TEC
* TNFRSF1A
Tumor necrosis factor receptor 1 (TNFR1), also known as tumor necrosis factor receptor superfamily member 1A (TNFRSF1A) and CD120a, is a ubiquitous membrane receptor that binds tumor necrosis factor-alpha (TNFα).
Function
The protein encoded b ...
* 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
Proto-oncogene tyrosine-protein kinase Yes is a 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 acti ...
[
]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 ...
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 the ...
, medical drugs under development
*Ruxolitinib
Ruxolitinib, sold under the brand names Jakafi and Jakavi, is a medication used for the treatment of intermediate or high-risk myelofibrosis, a type of myeloproliferative disorder that affects the bone marrow; polycythemia vera (PCV), when ther ...
References
Further reading
*
*
*
*
External links
*
{{Portal bar, Biology, border=no
Tyrosine kinases