JAK2

This gene encodes a non-receptor tyrosine kinase that plays a central role in cytokine and growth factor signalling. The primary isoform of this protein has an N-terminal FERM domain that is required for erythropoietin receptor association, an SH2 domain that binds STAT transcription factors, a pseudokinase domain and a C-terminal tyrosine kinase domain. Cytokine binding induces autophosphorylation and activation of this kinase. This kinase then recruits and phosphorylates signal transducer and activator of transcription (STAT) proteins. Growth factors like TGF-beta 1 also induce phosphorylation and activation of this kinase and translocation of downstream STAT proteins to the nucleus where they influence gene transcription. Mutations in this gene are associated with numerous inflammatory diseases and malignancies. This gene is a downstream target of the pleiotropic cytokine IL6 that is produced by B cells, T cells, dendritic cells and macrophages to produce an immune response or inflammation. Disregulation of the IL6/JAK2/STAT3 signalling pathways produces increased cellular proliferation and myeloproliferative neoplasms of hematopoietic stem cells. A nonsynonymous mutation in the pseudokinase domain of this gene disrupts the domains inhibitory effect and results in constitutive tyrosine phosphorylation activity and hypersensitivity to cytokine signalling. This gene and the IL6/JAK2/STAT3 signalling pathway is a therapeutic target for the treatment of excessive inflammatory responses to viral infections. Alternative splicing results in multiple transcript variants encoding distinct isoforms.

Janus kinase 2

Non-receptor tyrosine kinase involved in various processes such as cell growth, development, differentiation or histone modifications. Mediates essential signaling events in both innate and adaptive immunity. In the cytoplasm, plays a pivotal role in signal transduction via its association with type I receptors such as growth hormone (GHR), prolactin (PRLR), leptin (LEPR), erythropoietin (EPOR), thrombopoietin (THPO); or type II receptors including IFN-alpha, IFN-beta, IFN-gamma and multiple interleukins (PubMed:7615558).
Following ligand-binding to cell surface receptors, phosphorylates specific tyrosine residues on the cytoplasmic tails of the receptor, creating docking sites for STATs proteins (PubMed:9618263).
Subsequently, phosphorylates the STATs proteins once they are recruited to the receptor. Phosphorylated STATs then form homodimer or heterodimers and translocate to the nucleus to activate gene transcription. For example, cell stimulation with erythropoietin (EPO) during erythropoiesis leads to JAK2 autophosphorylation, activation, and its association with erythropoietin receptor (EPOR) that becomes phosphorylated in its cytoplasmic domain. Then, STAT5 (STAT5A or STAT5B) is recruited, phosphorylated and activated by JAK2. Once activated, dimerized STAT5 translocates into the nucleus and promotes the transcription of several essential genes involved in the modulation of erythropoiesis. Part of a signaling cascade that is activated by increased cellular retinol and that leads to the activation of STAT5 (STAT5A or STAT5B) (PubMed:21368206).
In addition, JAK2 mediates angiotensin-2-induced ARHGEF1 phosphorylation (PubMed:20098430).
Plays a role in cell cycle by phosphorylating CDKN1B (PubMed:21423214).
Cooperates with TEC through reciprocal phosphorylation to mediate cytokine-driven activation of FOS transcription. In the nucleus, plays a key role in chromatin by specifically mediating phosphorylation of 'Tyr-41' of histone H3 (H3Y41ph), a specific tag that promotes exclusion of CBX5 (HP1 alpha) from chromatin (PubMed:19783980).

Actin filament polymerization1 PublicationNAS:BHF-UCL
Activation of cysteine-type endopeptidase activity involved in apoptotic processISS:BHF-UCL
Activation of cysteine-type endopeptidase activity involved in apoptotic signaling pathwayISS:BHF-UCL
Activation of Janus kinase activityISS:UniProtKB
Adaptive immune responseIEA:UniProtKB-KW
Apoptotic processISS:BHF-UCL
Axon regenerationIEA:Ensembl
Cell differentiationISS:BHF-UCL
Cellular response to dexamethasone stimulusIEA:Ensembl
Cellular response to interleukin-3IEA:Ensembl
Cellular response to lipopolysaccharideIEA:Ensembl
Chromatin organizationIEA:UniProtKB-KW
Collagen-activated signaling pathwayManual Assertion Based On ExperimentIMP:ARUK-UCL
Cytokine-mediated signaling pathwayManual Assertion Based On ExperimentIDA:BHF-UCL
Enzyme linked receptor protein signaling pathwayISS:BHF-UCL
Erythrocyte differentiationISS:UniProtKB
Extrinsic apoptotic signaling pathwayISS:BHF-UCL
G protein-coupled receptor signaling pathwayIEA:Ensembl
Granulocyte-macrophage colony-stimulating factor signaling pathwayManual Assertion Based On ExperimentIDA:ComplexPortal
Growth hormone receptor signaling pathwayManual Assertion Based On ExperimentIDA:BHF-UCL
Growth hormone receptor signaling pathway via JAK-STATISS:UniProtKB
Histone H3-Y41 phosphorylationManual Assertion Based On ExperimentIDA:UniProtKB
Interferon-gamma-mediated signaling pathwayTAS:Reactome
Interleukin-12-mediated signaling pathwayManual Assertion Based On ExperimentIDA:BHF-UCL
Interleukin-35-mediated signaling pathwayTAS:Reactome
Interleukin-6-mediated signaling pathwayTAS:Reactome
Intracellular signal transductionISS:BHF-UCL
Intrinsic apoptotic signaling pathway in response to oxidative stressIEA:Ensembl
Mammary gland epithelium developmentISS:BHF-UCL
Mesoderm developmentManual Assertion Based On ExperimentTAS:ProtInc
Microglial cell activationISS:ARUK-UCL
Mineralocorticoid receptor signaling pathwayIEA:Ensembl
Modulation of chemical synaptic transmissionIEA:Ensembl
Negative regulation of cardiac muscle cell apoptotic processIEA:Ensembl
Negative regulation of cell population proliferationISS:BHF-UCL
Negative regulation of cell-cell adhesionIEA:Ensembl
Negative regulation of DNA bindingISS:BHF-UCL
Negative regulation of heart contractionIEA:Ensembl
Negative regulation of neuron apoptotic processIEA:Ensembl
Peptidyl-tyrosine phosphorylationISS:BHF-UCL
Platelet-derived growth factor receptor signaling pathwayIEA:Ensembl
Positive regulation of apoptotic signaling pathwayIEA:Ensembl
Positive regulation of cell differentiationIEA:Ensembl
Positive regulation of cell migrationIEA:Ensembl
Positive regulation of cell-substrate adhesionManual Assertion Based On ExperimentIDA:BHF-UCL
Positive regulation of cold-induced thermogenesisBy SimilarityISS:YuBioLab
Positive regulation of cytosolic calcium ion concentrationIEA:Ensembl
Positive regulation of DNA bindingIEA:Ensembl
Positive regulation of DNA-binding transcription factor activityIEA:Ensembl
Positive regulation of epithelial cell apoptotic processIEA:Ensembl
Positive regulation of growth factor dependent skeletal muscle satellite cell proliferationIEA:Ensembl
Positive regulation of growth hormone receptor signaling pathwayISS:BHF-UCL
Positive regulation of inflammatory responseIEA:Ensembl
Positive regulation of insulin secretionIEA:Ensembl
Positive regulation of interferon-gamma productionManual Assertion Based On ExperimentIDA:ComplexPortal
Positive regulation of interleukin-1 beta productionISS:ARUK-UCL
Positive regulation of leukocyte proliferationManual Assertion Based On ExperimentIDA:ComplexPortal
Positive regulation of MAPK cascadeIEA:Ensembl
Positive regulation of MHC class II biosynthetic processISS:ARUK-UCL
Positive regulation of natural killer cell proliferationManual Assertion Based On ExperimentIDA:ComplexPortal
Positive regulation of nitric oxide biosynthetic processIEA:Ensembl
Positive regulation of nitric-oxide synthase biosynthetic processISS:ARUK-UCL
Positive regulation of NK T cell proliferationManual Assertion Based On ExperimentIDA:ComplexPortal
Positive regulation of peptidyl-tyrosine phosphorylationISS:BHF-UCL
Positive regulation of phosphatidylinositol 3-kinase signalingISS:BHF-UCL
Positive regulation of phosphoprotein phosphatase activityIEA:Ensembl
Positive regulation of platelet activationManual Assertion Based On ExperimentIDA:ARUK-UCL
Positive regulation of platelet aggregationManual Assertion Based On ExperimentIDA:ARUK-UCL
Positive regulation of protein import into nucleusIEA:Ensembl
Positive regulation of receptor signaling pathway via JAK-STATManual Assertion Based On ExperimentIDA:ComplexPortal
Positive regulation of signaling receptor activityISS:ARUK-UCL
Positive regulation of SMAD protein signal transductionManual Assertion Based On ExperimentIGI:MGI
Positive regulation of T cell proliferationManual Assertion Based On ExperimentIDA:ComplexPortal
Positive regulation of transcription by RNA polymerase IIIEA:Ensembl
Positive regulation of tumor necrosis factor productionISS:ARUK-UCL
Positive regulation of tyrosine phosphorylation of STAT proteinISS:UniProtKB
Positive regulation of vascular associated smooth muscle cell proliferationIEA:Ensembl
Post-embryonic hemopoiesisIEA:Ensembl
Postsynapse to nucleus signaling pathwayIEA:Ensembl
Programmed cell death induced by symbiontIEA:Ensembl
Protein autophosphorylationISS:UniProtKB
Protein phosphorylationManual Assertion Based On ExperimentIDA:ComplexPortal
Receptor signaling pathway via JAK-STATManual Assertion Based On ExperimentIDA:ARUK-UCL
Regulation of apoptotic processManual Assertion Based On ExperimentIBA:GO_Central
Regulation of inflammatory responseManual Assertion Based On ExperimentIDA:BHF-UCL
Regulation of nitric oxide biosynthetic processISS:ARUK-UCL
Regulation of receptor signaling pathway via JAK-STATISS:BHF-UCL
Response to amineIEA:Ensembl
Response to antibioticManual Assertion Based On ExperimentIDA:MGI
Response to hydroperoxideIEA:Ensembl
Response to interleukin-12Manual Assertion Based On ExperimentIDA:BHF-UCL
Response to lipopolysaccharideISS:BHF-UCL
Response to tumor necrosis factorManual Assertion Based On ExperimentIDA:BHF-UCL
Signal transductionISS:UniProtKB
Tumor necrosis factor-mediated signaling pathwayManual Assertion Based On ExperimentIDA:BHF-UCL
Tyrosine phosphorylation of STAT proteinISS:BHF-UCL

Endomembrane system; Cytoplasm; Nucleus

Budd-Chiari syndrome (BDCHS):
A syndrome caused by obstruction of hepatic venous outflow involving either the hepatic veins or the terminal segment of the inferior vena cava. Obstructions are generally caused by thrombosis and lead to hepatic congestion and ischemic necrosis. Clinical manifestations observed in the majority of patients include hepatomegaly, right upper quadrant pain and abdominal ascites. Budd-Chiari syndrome is associated with a combination of disease states including primary myeloproliferative syndromes and thrombophilia due to factor V Leiden, protein C deficiency and antithrombin III deficiency. Budd-Chiari syndrome is a rare but typical complication in patients with polycythemia vera.
Polycythemia vera (PV):
A myeloproliferative disorder characterized by abnormal proliferation of all hematopoietic bone marrow elements, erythroid hyperplasia, an absolute increase in total blood volume, but also by myeloid leukocytosis, thrombocytosis and splenomegaly.
Thrombocythemia 3 (THCYT3):
A myeloproliferative disorder characterized by excessive platelet production, resulting in increased numbers of circulating platelets. It can be associated with spontaneous hemorrhages and thrombotic episodes.
Myelofibrosis (MYELOF):
A disorder characterized by replacement of the bone marrow by fibrous tissue, occurring in association with a myeloproliferative disorder. Clinical manifestations may include anemia, pallor, splenomegaly, hypermetabolic state, petechiae, ecchymosis, bleeding, lymphadenopathy, hepatomegaly, portal hypertension.
Leukemia, acute myelogenous (AML):
A subtype of acute leukemia, a cancer of the white blood cells. AML is a malignant disease of bone marrow characterized by maturational arrest of hematopoietic precursors at an early stage of development. Clonal expansion of myeloid blasts occurs in bone marrow, blood, and other tissue. Myelogenous leukemias develop from changes in cells that normally produce neutrophils, basophils, eosinophils and monocytes.

Autophosphorylated, leading to regulate its activity. Leptin promotes phosphorylation on tyrosine residues, including phosphorylation on Tyr-813 (By similarity).
Autophosphorylation on Tyr-119 in response to EPO down-regulates its kinase activity (By similarity).
Autophosphorylation on Tyr-868, Tyr-966 and Tyr-972 in response to growth hormone (GH) are required for maximal kinase activity (By similarity).
Also phosphorylated by TEC (By similarity).
Phosphorylated on tyrosine residues in response to interferon gamma signaling (PubMed:7615558, PubMed:7673114).
Phosphorylated on tyrosine residues in response to a signaling cascade that is activated by increased cellular retinol (PubMed:21368206).
Undergoes Notch-induced ubiquitination and subsequent proteasomal degradation which is mediated by ASB1 or ASB2, the substrate-recognition components of probable ECS E3 ubiquitin-protein ligase complexes.