JAK2 (Janus kinase 2)

Gene

• Entrez ID: 3717
• Gene name: Janus kinase 2
• Gene symbol: JAK2
• Synonyms: JTK10
• Chromosome: 9
• Chromosome location: 9p24.1
• Summary: 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. [provided by RefSeq, Jul 2020]

miRNA

miRTarBase ID	miRNA	Experiments	Reference
MIRT000707	hsa-miR-135a-5p	Luciferase reporter assay, Western blot	19666866
MIRT000707	hsa-miR-135a-5p	qRT-PCR, Western blot	22310976
MIRT001749	hsa-miR-375	Luciferase reporter assay, Western blot, Reporter assay;Western blot	20548334
MIRT001749	hsa-miR-375	Reporter assay	15806104
MIRT001749	hsa-miR-375	Immunohistochemistry, Luciferase reporter assay, qRT-PCR, Western blot	24718681
MIRT001749	hsa-miR-375	Luciferase reporter assay, qRT-PCR	25055044
MIRT001749	hsa-miR-375	Western blot	28186962
MIRT001749	hsa-miR-375	Luciferase reporter assay	28006751
MIRT017973	hsa-miR-335-5p	Microarray	18185580
MIRT044858	hsa-miR-195-5p	CLASH	23622248
MIRT051067	hsa-miR-16-5p	CLASH	23622248
MIRT379479	hsa-miR-101-3p	Luciferase reporter assay, qRT-PCR, Western blot	26498873
MIRT379479	hsa-miR-101-3p	Flow, qRT-PCR	27517565
MIRT623561	hsa-miR-8485	HITS-CLIP	23824327
MIRT623561	hsa-miR-8485	HITS-CLIP	23313552
MIRT623561	hsa-miR-8485	HITS-CLIP	22927820
MIRT623561	hsa-miR-8485	HITS-CLIP	27418678
MIRT628089	hsa-miR-548as-3p	HITS-CLIP	23824327
MIRT628089	hsa-miR-548as-3p	HITS-CLIP	23313552
MIRT628089	hsa-miR-548as-3p	HITS-CLIP	22927820
MIRT678308	hsa-miR-568	HITS-CLIP	23824327
MIRT678309	hsa-miR-5692a	HITS-CLIP	23824327
MIRT678309	hsa-miR-5692a	HITS-CLIP	23313552
MIRT678309	hsa-miR-5692a	HITS-CLIP	22927820
MIRT678309	hsa-miR-5692a	HITS-CLIP	27418678
MIRT734987	hsa-miR-125b-5p	qRT-PCR, Western blot	26011312
MIRT734988	hsa-miR-125a-5p	qRT-PCR, Western blot	26011312
MIRT735041	hsa-miR-216a-5p	Luciferase reporter assay, qRT-PCR, Western blot	26149212
MIRT735423	hsa-miR-204-5p	Luciferase reporter assay, qRT-PCR, Western blot	27323056

Transcription factors

Transcription factor	Regulation	Reference
BRCA1	Unknown	11163768
ESR1	Unknown	19876927
STAT1	Activation	21239533
STAT3	Activation	17151100
STAT3	Unknown	19783654

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0000165	Process	MAPK cascade	TAS
GO:0000186	Process	Activation of MAPKK activity	IEA
GO:0000791	Component	Euchromatin	IEA
GO:0001774	Process	Microglial cell activation	ISS
GO:0002250	Process	Adaptive immune response	IEA
GO:0004672	Function	Protein kinase activity	TAS
GO:0004713	Function	Protein tyrosine kinase activity	EXP	9111318, 15143187, 19665053, 20304997
GO:0004713	Function	Protein tyrosine kinase activity	IDA	23061660
GO:0004713	Function	Protein tyrosine kinase activity	ISS
GO:0004713	Function	Protein tyrosine kinase activity	TAS
GO:0004715	Function	Non-membrane spanning protein tyrosine kinase activity	TAS
GO:0005102	Function	Signaling receptor binding	IPI	11201744
GO:0005131	Function	Growth hormone receptor binding	IBA	21873635
GO:0005131	Function	Growth hormone receptor binding	ISS
GO:0005143	Function	Interleukin-12 receptor binding	ISS
GO:0005515	Function	Protein binding	IPI	9516124, 11679576, 11694501, 11970898, 15821101, 16437163, 17474147, 18692472, 19234114, 20353823, 21806020, 24931576, 25092874, 26175413, 30413785
GO:0005524	Function	ATP binding	IEA
GO:0005634	Component	Nucleus	IDA	10502458, 19783980
GO:0005654	Component	Nucleoplasm	IDA
GO:0005654	Component	Nucleoplasm	TAS
GO:0005730	Component	Nucleolus	IEA
GO:0005737	Component	Cytoplasm	IDA	10502458
GO:0005829	Component	Cytosol	TAS
GO:0005856	Component	Cytoskeleton	IEA
GO:0005886	Component	Plasma membrane	IDA
GO:0005901	Component	Caveola	ISS
GO:0005925	Component	Focal adhesion	IDA
GO:0006468	Process	Protein phosphorylation	TAS	9670957
GO:0006915	Process	Apoptotic process	ISS
GO:0006919	Process	Activation of cysteine-type endopeptidase activity involved in apoptotic process	ISS
GO:0007165	Process	Signal transduction	ISS
GO:0007167	Process	Enzyme linked receptor protein signaling pathway	ISS
GO:0007186	Process	G protein-coupled receptor signaling pathway	IEA
GO:0007204	Process	Positive regulation of cytosolic calcium ion concentration	IEA
GO:0007259	Process	Receptor signaling pathway via JAK-STAT	ISS
GO:0007260	Process	Tyrosine phosphorylation of STAT protein	IBA	21873635
GO:0007260	Process	Tyrosine phosphorylation of STAT protein	ISS
GO:0007498	Process	Mesoderm development	TAS	9590174
GO:0007596	Process	Blood coagulation	TAS
GO:0008022	Function	Protein C-terminus binding	IEA
GO:0008285	Process	Negative regulation of cell population proliferation	ISS
GO:0008631	Process	Intrinsic apoptotic signaling pathway in response to oxidative stress	IEA
GO:0010667	Process	Negative regulation of cardiac muscle cell apoptotic process	IEA
GO:0010811	Process	Positive regulation of cell-substrate adhesion	IDA	10925297
GO:0014068	Process	Positive regulation of phosphatidylinositol 3-kinase signaling	ISS
GO:0014068	Process	Positive regulation of phosphatidylinositol 3-kinase signaling	TAS
GO:0018108	Process	Peptidyl-tyrosine phosphorylation	ISS
GO:0019221	Process	Cytokine-mediated signaling pathway	IBA	21873635
GO:0019221	Process	Cytokine-mediated signaling pathway	IDA	8609418
GO:0019221	Process	Cytokine-mediated signaling pathway	ISS
GO:0019221	Process	Cytokine-mediated signaling pathway	TAS
GO:0019901	Function	Protein kinase binding	IDA	10925297
GO:0020037	Function	Heme binding	IDA	21036157
GO:0022408	Process	Negative regulation of cell-cell adhesion	IEA
GO:0030041	Process	Actin filament polymerization	NAS	10925297
GO:0030154	Process	Cell differentiation	ISS
GO:0030218	Process	Erythrocyte differentiation	IBA	21873635
GO:0030218	Process	Erythrocyte differentiation	ISS
GO:0030335	Process	Positive regulation of cell migration	IEA
GO:0031103	Process	Axon regeneration	IEA
GO:0031702	Function	Type 1 angiotensin receptor binding	IEA
GO:0031904	Component	Endosome lumen	TAS
GO:0031959	Process	Mineralocorticoid receptor signaling pathway	IEA
GO:0032024	Process	Positive regulation of insulin secretion	IEA
GO:0032496	Process	Response to lipopolysaccharide	ISS
GO:0032516	Process	Positive regulation of phosphoprotein phosphatase activity	IEA
GO:0032731	Process	Positive regulation of interleukin-1 beta production	ISS
GO:0032760	Process	Positive regulation of tumor necrosis factor production	ISS
GO:0033130	Function	Acetylcholine receptor binding	IEA
GO:0033194	Process	Response to hydroperoxide	IEA
GO:0033209	Process	Tumor necrosis factor-mediated signaling pathway	IDA	8609418
GO:0034612	Process	Response to tumor necrosis factor	IDA	8609418
GO:0035401	Function	Histone kinase activity (H3-Y41 specific)	IBA	21873635
GO:0035401	Function	Histone kinase activity (H3-Y41 specific)	IDA	19783980
GO:0035409	Process	Histone H3-Y41 phosphorylation	IBA	21873635
GO:0035409	Process	Histone H3-Y41 phosphorylation	IDA	19783980
GO:0035556	Process	Intracellular signal transduction	ISS
GO:0035722	Process	Interleukin-12-mediated signaling pathway	IDA	7528775
GO:0035722	Process	Interleukin-12-mediated signaling pathway	TAS
GO:0038155	Process	Interleukin-23-mediated signaling pathway	TAS
GO:0042169	Function	SH2 domain binding	IPI	9727029
GO:0042307	Process	Positive regulation of protein import into nucleus	IEA
GO:0042393	Function	Histone binding	IDA	19783980
GO:0042531	Process	Positive regulation of tyrosine phosphorylation of STAT protein	ISS
GO:0042802	Function	Identical protein binding	IPI	21841788, 22820988
GO:0042976	Process	Activation of Janus kinase activity	ISS
GO:0042981	Process	Regulation of apoptotic process	IBA	21873635
GO:0043388	Process	Positive regulation of DNA binding	IEA
GO:0043392	Process	Negative regulation of DNA binding	ISS
GO:0043524	Process	Negative regulation of neuron apoptotic process	IEA
GO:0043548	Function	Phosphatidylinositol 3-kinase binding	IEA
GO:0043560	Function	Insulin receptor substrate binding	IEA
GO:0045121	Component	Membrane raft	ISS
GO:0045348	Process	Positive regulation of MHC class II biosynthetic process	ISS
GO:0045428	Process	Regulation of nitric oxide biosynthetic process	ISS
GO:0045429	Process	Positive regulation of nitric oxide biosynthetic process	IEA
GO:0045597	Process	Positive regulation of cell differentiation	IEA
GO:0045822	Process	Negative regulation of heart contraction	IEA
GO:0046425	Process	Regulation of receptor signaling pathway via JAK-STAT	ISS
GO:0046579	Process	Positive regulation of Ras protein signal transduction	TAS
GO:0046677	Process	Response to antibiotic	IDA	16280321
GO:0046777	Process	Protein autophosphorylation	ISS
GO:0046872	Function	Metal ion binding	IEA
GO:0048008	Process	Platelet-derived growth factor receptor signaling pathway	IEA
GO:0050727	Process	Regulation of inflammatory response	IDA	10925297
GO:0050729	Process	Positive regulation of inflammatory response	IEA
GO:0050731	Process	Positive regulation of peptidyl-tyrosine phosphorylation	ISS
GO:0050804	Process	Modulation of chemical synaptic transmission	IEA
GO:0050867	Process	Positive regulation of cell activation	IEA
GO:0051091	Process	Positive regulation of DNA-binding transcription factor activity	IEA
GO:0051428	Function	Peptide hormone receptor binding	IEA
GO:0051770	Process	Positive regulation of nitric-oxide synthase biosynthetic process	ISS
GO:0060333	Process	Interferon-gamma-mediated signaling pathway	TAS
GO:0060334	Process	Regulation of interferon-gamma-mediated signaling pathway	TAS
GO:0060391	Process	Positive regulation of SMAD protein signal transduction	IGI	28334068
GO:0060396	Process	Growth hormone receptor signaling pathway	IDA	10925297
GO:0060397	Process	Growth hormone receptor signaling pathway via JAK-STAT	ISS
GO:0060397	Process	Growth hormone receptor signaling pathway via JAK-STAT	TAS
GO:0060399	Process	Positive regulation of growth hormone receptor signaling pathway	ISS
GO:0061180	Process	Mammary gland epithelium development	ISS
GO:0070102	Process	Interleukin-6-mediated signaling pathway	TAS
GO:0070106	Process	Interleukin-27-mediated signaling pathway	TAS
GO:0070671	Process	Response to interleukin-12	IDA	7528775
GO:0070757	Process	Interleukin-35-mediated signaling pathway	TAS
GO:0097191	Process	Extrinsic apoptotic signaling pathway	ISS
GO:0097296	Process	Activation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway	ISS
GO:0098794	Component	Postsynapse	IEA
GO:0098978	Component	Glutamatergic synapse	IEA
GO:0099527	Process	Postsynapse to nucleus signaling pathway	IEA
GO:0120162	Process	Positive regulation of cold-induced thermogenesis	ISS	26515423
GO:1902728	Process	Positive regulation of growth factor dependent skeletal muscle satellite cell proliferation	IEA
GO:1904037	Process	Positive regulation of epithelial cell apoptotic process	IEA
GO:1904707	Process	Positive regulation of vascular associated smooth muscle cell proliferation	IEA
GO:2000273	Process	Positive regulation of signaling receptor activity	ISS

Other IDs

• MIM: 147796
• HGNC: 6192
• e!Ensembl: ENSG00000096968

Protein

• UniProt ID: O60674
• Protein name: Tyrosine-protein kinase JAK2 (EC 2.7.10.2) (Janus kinase 2) (JAK-2)
• Protein 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 (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).
• PDB: 2B7A, 2W1I, 2XA4, 3E62, 3E63, 3E64, 3FUP, 3IO7, 3IOK, 3JY9, 3KCK, 3KRR, 3LPB, 3Q32, 3RVG, 3TJC, 3TJD, 3UGC, 3ZMM, 4AQC, 4BBE, 4BBF, 4C61, 4C62, 4D0W, 4D0X, 4D1S, 4E4M, 4E6D, 4E6Q, 4F08, 4F09, 4FVP, 4FVQ, 4FVR, 4GFM, 4GMY, 4HGE, 4IVA, 4JI9, 4JIA, 4P7E, 4YTC, 4YTF, 4YTH, 4YTI, 4Z32, 4ZIM, 5AEP, 5CF4, 5CF5
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF18379	FERM_F1	39 → 134	FERM F1 ubiquitin-like domain	Domain
  PF18377	FERM_F2	142 → 261	FERM F2 acyl-CoA binding protein-like domain	Domain
  PF17887	Jak1_Phl	299 → 381	Jak1 pleckstrin homology-like domain	Domain
  PF00017	SH2	400 → 481	SH2 domain	Domain
  PF07714	PK_Tyr_Ser-Thr	545 → 805	Protein tyrosine and serine/threonine kinase	Domain
  PF07714	PK_Tyr_Ser-Thr	849 → 1123	Protein tyrosine and serine/threonine kinase	Domain

• Sequence:

  MGMACLTMTEMEGTSTSSIYQNGDISGNANSMKQIDPVLQVYLYHSLGKSEADYLTFPSG
  EYVAEEICIAASKACGITPVYHNMFALMSETERIWYPPNHVFHIDESTRHNVLYRIRFYF
  PRWYCSGSNRAYRHGISRGAEAPLLDDFVMSYLFAQWRHDFVHGWIKVPVTHETQEECLG
  MAVLDMMRIAKENDQTPLAIYNSISYKTFLPKCIRAKIQDYHILTRKRIRYRFRRFIQQF
  SQCKATARNLKLKYLINLETLQSAFYTEKFEVKEPGSGPSGEEIFATIIITGNGGIQWSR
  GKHKESETLTEQDLQLYCDFPNIIDVSIKQANQEGSNESRVVTIHKQDGKNLEIELSSLR
  EALSFVSLIDGYYRLTADAHHYLCKEVAPPAVLENIQSNCHGPISMDFAISKLKKAGNQT
  GLYVLRCSPKDFNKYFLTFAVERENVIEYKHCLITKNENEEYNLSGTKKNFSSLKDLLNC
  YQMETVRSDNIIFQFTKCCPPKPKDKSNLLVFRTNGVSDVPTSPTLQRPTHMNQMVFHKI
  RNEDLIFNESLGQGTFTKIFKGVRREVGDYGQLHETEVLLKVLDKAHRNYSESFFEAASM
  MSKLSHKHLVLNYGVCVCGDENILVQEFVKFGSLDTYLKKNKNCINILWKLEVAKQLAWA
  MHFLEENTLIHGNVCAKNILLIREEDRKTGNPPFIKLSDPGISITVLPKDILQERIPWVP
  PECIENPKNLNLATDKWSFGTTLWEICSGGDKPLSALDSQRKLQFYEDRHQLPAPKWAEL
  ANLINNCMDYEPDFRPSFRAIIRDLNSLFTPDYELLTENDMLPNMRIGALGFSGAFEDRD
  PTQFEERHLKFLQQLGKGNFGSVEMCRYDPLQDNTGEVVAVKKLQHSTEEHLRDFEREIE
  ILKSLQHDNIVKYKGVCYSAGRRNLKLIMEYLPYGSLRDYLQKHKERIDHIKLLQYTSQI
  CKGMEYLGTKRYIHRDLATRNILVENENRVKIGDFGLTKVLPQDKEYYKVKEPGESPIFW
  YAPESLTESKFSVASDVWSFGVVLYELFTYIEKSKSPPAEFMRMIGNDKQGQMIVFHLIE
  LLKNNGRLPRPDGCPDEIYMIMTECWNNNVNQRPSFRDLALRVDQIRDNMAG

• Sequence length: 1132