Tyrosine-protein kinase JAK1

UniProt P23458 Organism Homo sapiens Gene JAK1, JAK1A, JAK1B EC 2.7.10.2

Also known as: JAK1, JAK1A, JAK1B

Function

Non-membrane spanning protein tyrosine kinase that phosphorylates signal-transducing subunits of cytokine receptor complexes like IL2RB, IL10RA, IFNAR2, IL6ST, LIFR, OSMR and IL31RA. Functionnally, is involved in the IFN-alpha/beta/gamma signal pathway. Mechanistically, in response to interferon-binding to IFNAR1-IFNAR2 heterodimer, phosphorylates and activates its binding partner IFNAR2, creating docking sites for STAT proteins. Directly phosphorylates STAT proteins but also activates STAT signaling through the transactivation of other JAK kinases associated with signaling receptors. Involved in the MT-RNR2/humanin-mediated signaling pathway leading to STAT3 phosphorylation. 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). 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). Involved in the Interleukin-31-mediated signaling pathway through the IL31 receptor complex (heterodimers composed of OSMR and IL31RA).

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, Kinase-like_dom_sf, Prot_kinase_dom, Protein_kinase_ATP_BS, 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_Jak1
Functional cluster: Serine/Threonine Protein Kinases

Experimental structures · PDB · 51

3EYG X-ray 1.90A
3EYH X-ray 2.00A
4E4L X-ray 2.00A
4E4N X-ray 1.90A
4E5W X-ray 1.86A
4EHZ X-ray 2.17A
4EI4 X-ray 2.22A
4FK6 X-ray 2.20A
4GS0 X-ray 1.80A
4I5C X-ray 2.10A
4IVB X-ray 1.90A
4IVC X-ray 2.35A
… and 39 more

A predicted model is available from AlphaFold.

Gene Ontology · 40

Disease associations

autoinflammation, immune dysregulation, and eosinophilia MONDO:0033558

Drugs targeting this protein · 21

MOMELOTINIB inhibitor
RUXOLITINIB PHOSPHATE inhibitor
TOFACITINIB CITRATE inhibitor
BARICITINIB inhibitor
TRICETAMIDE inhibitor
PEFICITINIB inhibitor
SOLCITINIB inhibitor
FILGOTINIB inhibitor
ITACITINIB inhibitor
ABROCITINIB inhibitor
CERDULATINIB inhibitor
BREPOCITINIB inhibitor
DELGOCITINIB inhibitor
FILGOTINIB MALEATE inhibitor
GOLIDOCITINIB inhibitor
GUSACITINIB inhibitor
DEURUXOLITINIB PHOSPHATE inhibitor
IZENCITINIB inhibitor
NEZULCITINIB inhibitor
UPADACITINIB HEMIHYDRATE inhibitor
MOMELOTINIB DIHYDROCHLORIDE MONOHYDRATE inhibitor

Related proteins · sequence + function similarity

Tyrosine-protein kinase JAK1 1.00
Tyrosine-protein kinase JAK1 0.96
Tyrosine-protein kinase JAK2 0.92
Tyrosine-protein kinase JAK2 0.92
Tyrosine-protein kinase JAK2 0.92
Tyrosine-protein kinase JAK1 0.91
Tyrosine-protein kinase JAK2 0.91
Tyrosine-protein kinase JAK2 0.91
Tyrosine-protein kinase JAK2 0.90
Dual specificity protein kinase shkC 0.77
Tyrosine-protein kinase SPK-1 0.76
Tyrosine-protein kinase hopscotch 0.76

Co-cited proteins · studied together in the literature

Non-receptor tyrosine-protein kinase TYK2 4 shared papers
E3 ubiquitin-protein ligase RNF125 1 shared papers
Interleukin-10 receptor subunit alpha 1 shared papers
Interferon alpha/beta receptor 2 1 shared papers
Tyrosine-protein kinase JAK3 2 shared papers
Interferon gamma receptor 2 1 shared papers
Janus kinase and microtubule-interacting protein 1 1 shared papers
Janus kinase and microtubule-interacting protein 2 1 shared papers
Interleukin-31 receptor subunit alpha 1 shared papers
Interleukin-6 receptor subunit beta 3 shared papers
Tyrosine-protein kinase receptor UFO 2 shared papers
Interferon gamma receptor 1 1 shared papers

Literature · 26 cited papers

Complex Autoinflammatory Syndrome Unveils Fundamental Principles of JAK1 Kinase Transcriptional and Biochemical Function. Immunity · 2020
JAK1 gain-of-function causes an autosomal dominant immune dysregulatory and hypereosinophilic syndrome. J. Allergy Clin. Immunol. · 2017
The mitochondrial-derived peptide humanin activates the ERK1/2, AKT, and STAT3 signaling pathways and has age-dependent signaling differences in the hippocampus. Oncotarget · 2016
Downregulation of the ubiquitin ligase RNF125 underlies resistance of melanoma cells to BRAF inhibitors via JAK1 deregulation. Cell Rep. · 2015
An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome. J. Proteomics · 2014
Initial characterization of the human central proteome. BMC Syst. Biol. · 2011
Large-scale proteomics analysis of the human kinome. Mol. Cell. Proteomics · 2009
Dissecting specificity in the Janus kinases: the structures of JAK-specific inhibitors complexed to the JAK1 and JAK2 protein tyrosine kinase domains. J. Mol. Biol. · 2009
Patterns of somatic mutation in human cancer genomes. Nature · 2007
The DNA sequence and biological annotation of human chromosome 1. Nature · 2006
JAK1 and Tyk2 activation by the homologous polycythemia vera JAK2 V617F mutation: cross-talk with IGF1 receptor. J. Biol. Chem. · 2005
The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. · 2004
… and 14 more in the literature graph

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