lmmol · Proteins

Tyrosine-protein kinase JAK2

UniProt O60674 Organism Homo sapiens Gene JAK2 EC 2.7.10.2

Also known as: JAK2

Function

Non-membrane spanning protein tyrosine kinase that phosphorylates type I receptors such as growth hormone (GHR), prolactin (PRLR), leptin (LEPR), erythropoietin (EPOR), thrombopoietin receptor (MPL/TPOR); or type II receptors including IFN-alpha, IFN-beta, IFN-gamma and multiple interleukins. Functionnally, plays a pivotal role in signal transduction and is involved in various processes such as cell growth, development, differentiation or histone modifications. Mediates essential signaling events in both innate and adaptive immunity. Mechanistically, 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. Part of a signaling cascade that is activated by increased cellular retinol and that leads to the activation of STAT5 (STAT5A or STAT5B). 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. Up-regulates the potassium voltage-gated channel activity of KCNA3. Binding of CNTF or the CLCF1/CLF heterodimer to CNTFR leads to IL6ST/gp130-LIFR dimerization followed by activation of JAK1 and JAK2 which in turns phosphorylate IL6ST/gp130 and LIFR. The tyrosine phosphorylated signaling receptors serve in turn as docking proteins for STAT3. Involved in the oncostatin-M-mediated signaling pathway through both type I OSM receptor complex (heterodimers composed of LIFR and IL6ST) and type II OSM receptor complex (heterodimers composed of OSMR and IL6ST).

Classification

Family (Pfam)
PF18379 FERM_F1, PF18377 FERM_F2, PF17887 Jak1_Phl, PF07714 PK_Tyr_Ser-Thr, PF21990 SH2_1
InterPro
Band_41_domain, FERM_2, FERM_central, FERM_domain, FERM_F1, FERM_F2, JAK, JAK1-3/TYK2_PHL_dom, JAK2_FERM_C-lobe, JAK2_SH2, Kinase-like_dom_sf, PH-like_dom_sf, Prot_kinase_dom, Protein_kinase_ATP_BS, PTK_Jak2_rpt1, PTKc_Jak2_rpt2, Ser-Thr/Tyr_kinase_cat_dom, SH2, SH2_dom_sf, Tyr_kinase_AS, Tyr_kinase_cat_dom, Tyr_kinase_non-rcpt_Jak/Tyk2, Tyr_kinase_non-rcpt_Jak2
Functional cluster
Serine/Threonine Protein Kinases

Experimental structures · PDB · 164

A predicted model is available from AlphaFold.

Gene Ontology · 114

Disease associations

Drugs targeting this protein · 29

Related proteins · sequence + function similarity

Co-cited proteins · studied together in the literature

Literature · 42 cited papers

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