InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: JAK2

Summary

InnateDB Protein

IDBP-47041.6

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

JAK2

Protein Name

Janus kinase 2

Synonyms

JTK10; THCYT3;

Species

Homo sapiens

Ensembl Protein

ENSP00000371067

InnateDB Gene

IDBG-47039 (JAK2)

Protein Structure

UniProt Annotation

Function

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. Following ligand-binding to cell surface receptors, phosphorylates specific tyrosine residues on the cytoplasmic tails of the receptor, creating docking sites for STATs proteins. 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. In addition, JAK2 mediates angiotensin-2-induced ARHGEF1 phosphorylation. Plays a role in cell cycle by phosphorylating CDKN1B. 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. {ECO:0000269PubMed:12023369, ECO:0000269PubMed:19783980, ECO:0000269PubMed:20098430, ECO:0000269PubMed:21423214}.

Subcellular Localization

Endomembrane system {ECO:0000250}; Peripheral membrane protein {ECO:0000250}. Cytoplasm {ECO:0000269PubMed:19783980}. Nucleus {ECO:0000269PubMed:19783980}.

Disease Associations

Note=Chromosomal aberrations involving JAK2 are found in both chronic and acute forms of eosinophilic, lymphoblastic and myeloid leukemia. Translocation t(8;9)(p22;p24) with PCM1 links the protein kinase domain of JAK2 to the major portion of PCM1. Translocation t(9;12)(p24;p13) with ETV6.Budd-Chiari syndrome (BDCHS) [MIM:600880]: 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. {ECO:0000269PubMed:16707754}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.Polycythemia vera (PV) [MIM:263300]: 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. {ECO:0000269PubMed:15781101, ECO:0000269PubMed:15793561, ECO:0000269PubMed:15858187, ECO:0000269PubMed:16603627}. Note=The disease is caused by mutations affecting the gene represented in this entry.Thrombocythemia 3 (THCYT3) [MIM:614521]: 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. {ECO:0000269PubMed:16325696, ECO:0000269PubMed:22397670}. Note=The disease may be caused by mutations affecting the gene represented in this entry.Myelofibrosis (MYELOF) [MIM:254450]: 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. Note=The disease is caused by mutations affecting the gene represented in this entry.Leukemia, acute myelogenous (AML) [MIM:601626]: 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. {ECO:0000269PubMed:16247455}. Note=The disease is caused by mutations affecting the gene represented in this entry.

Tissue Specificity

Ubiquitously expressed throughout most tissues. {ECO:0000269PubMed:16424865}.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 141 experimentally validated interaction(s) in this database.
They are also associated with 44 interaction(s) predicted by orthology.

Experimentally validated
Total	141 [view]
Protein-Protein	140 [view]
Protein-DNA	1 [view]
Protein-RNA	0
DNA-DNA	0
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	44 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0004672	protein kinase activity
GO:0004713	protein tyrosine kinase activity
GO:0004715	non-membrane spanning protein tyrosine kinase activity
GO:0005102	receptor binding
GO:0005131	growth hormone receptor binding
GO:0005143	interleukin-12 receptor binding
GO:0005515	protein binding
GO:0005524	ATP binding
GO:0008022	protein C-terminus binding
GO:0016772	transferase activity, transferring phosphorus-containing groups
GO:0019901	protein kinase binding
GO:0020037	heme binding
GO:0031702	type 1 angiotensin receptor binding
GO:0033130	acetylcholine receptor binding
GO:0035401	histone kinase activity (H3-Y41 specific)
GO:0042169	SH2 domain binding
GO:0042393	histone binding
GO:0043548	phosphatidylinositol 3-kinase binding
GO:0043560	insulin receptor substrate binding
GO:0051428	peptide hormone receptor binding

Biological Process

GO:0000186	activation of MAPKK activity
GO:0006468	protein phosphorylation
GO:0006915	apoptotic process
GO:0006919	activation of cysteine-type endopeptidase activity involved in apoptotic process
GO:0006928	cellular component movement
GO:0006979	response to oxidative stress
GO:0007165	signal transduction
GO:0007167	enzyme linked receptor protein signaling pathway
GO:0007186	G-protein coupled receptor signaling pathway
GO:0007204	positive regulation of cytosolic calcium ion concentration
GO:0007259	JAK-STAT cascade
GO:0007260	tyrosine phosphorylation of STAT protein
GO:0007262	STAT protein import into nucleus
GO:0007498	mesoderm development
GO:0007596	blood coagulation
GO:0008284	positive regulation of cell proliferation
GO:0008285	negative regulation of cell proliferation
GO:0008631	intrinsic apoptotic signaling pathway in response to oxidative stress
GO:0009755	hormone-mediated signaling pathway
GO:0010811	positive regulation of cell-substrate adhesion
GO:0014068	positive regulation of phosphatidylinositol 3-kinase signaling
GO:0018108	peptidyl-tyrosine phosphorylation
GO:0019221	cytokine-mediated signaling pathway
GO:0022408	negative regulation of cell-cell adhesion
GO:0030041	actin filament polymerization
GO:0030099	myeloid cell differentiation
GO:0030154	cell differentiation
GO:0030218	erythrocyte differentiation
GO:0030335	positive regulation of cell migration
GO:0031103	axon regeneration
GO:0031959	mineralocorticoid receptor signaling pathway
GO:0032024	positive regulation of insulin secretion
GO:0032496	response to lipopolysaccharide
GO:0032516	positive regulation of phosphoprotein phosphatase activity
GO:0032731	positive regulation of interleukin-1 beta production
GO:0032760	positive regulation of tumor necrosis factor production
GO:0033160	positive regulation of protein import into nucleus, translocation
GO:0033194	response to hydroperoxide
GO:0033209	tumor necrosis factor-mediated signaling pathway
GO:0034050	host programmed cell death induced by symbiont
GO:0034612	response to tumor necrosis factor
GO:0035409	histone H3-Y41 phosphorylation
GO:0035556	intracellular signal transduction
GO:0035722	interleukin-12-mediated signaling pathway
GO:0042503	tyrosine phosphorylation of Stat3 protein
GO:0042506	tyrosine phosphorylation of Stat5 protein
GO:0042508	tyrosine phosphorylation of Stat1 protein
GO:0042517	positive regulation of tyrosine phosphorylation of Stat3 protein
GO:0042523	positive regulation of tyrosine phosphorylation of Stat5 protein
GO:0042977	activation of JAK2 kinase activity
GO:0043065	positive regulation of apoptotic process
GO:0043066	negative regulation of apoptotic process
GO:0043388	positive regulation of DNA binding
GO:0043392	negative regulation of DNA binding
GO:0043524	negative regulation of neuron apoptotic process
GO:0045087	innate immune response (InnateDB)
GO:0045429	positive regulation of nitric oxide biosynthetic process
GO:0045597	positive regulation of cell differentiation
GO:0045822	negative regulation of heart contraction
GO:0046677	response to antibiotic
GO:0046777	protein autophosphorylation
GO:0048008	platelet-derived growth factor receptor signaling pathway
GO:0050727	regulation of inflammatory response
GO:0050729	positive regulation of inflammatory response
GO:0050731	positive regulation of peptidyl-tyrosine phosphorylation
GO:0050867	positive regulation of cell activation
GO:0051091	positive regulation of sequence-specific DNA binding transcription factor activity
GO:0051770	positive regulation of nitric-oxide synthase biosynthetic process
GO:0060333	interferon-gamma-mediated signaling pathway
GO:0060334	regulation of interferon-gamma-mediated signaling pathway
GO:0060396	growth hormone receptor signaling pathway
GO:0060397	JAK-STAT cascade involved in growth hormone signaling pathway
GO:0060399	positive regulation of growth hormone receptor signaling pathway
GO:0061180	mammary gland epithelium development
GO:0070671	response to interleukin-12
GO:0097191	extrinsic apoptotic signaling pathway
GO:0097296	activation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway
GO:2001235	positive regulation of apoptotic signaling pathway

Cellular Component

GO:0005634	nucleus
GO:0005737	cytoplasm
GO:0005829	cytosol
GO:0005856	cytoskeleton
GO:0005901	caveola
GO:0016020	membrane
GO:0016363	nuclear matrix
GO:0031904	endosome lumen
GO:0045121	membrane raft

Protein Structure and Domains

PDB ID

InterPro

IPR000299 FERM domain
IPR000719 Protein kinase domain
IPR000980 SH2 domain
IPR001245 Serine-threonine/tyrosine-protein kinase catalytic domain
IPR002290 Serine/threonine/dual specificity protein kinase, catalytic domain
IPR011009 Protein kinase-like domain
IPR016251 Tyrosine-protein kinase, non-receptor Jak/Tyk2
IPR019748 FERM central domain
IPR019749 Band 4.1 domain
IPR020635 Tyrosine-protein kinase, catalytic domain
IPR020693 Tyrosine-protein kinase, non-receptor Jak2

PFAM

PF00069
PF00017
PF14633
PF07714
PF00373

PRINTS

PR00401
PR00109
PR01823
PR01825

PIRSF

PIRSF000636

SMART

SM00252
SM00220
SM00295
SM00219

TIGRFAMs

Post-translational Modifications

Modification

Cross-References