Non-receptor tyrosine-protein kinase TYK2

Function

Non-membrane spanning protein tyrosine kinase involved in numerous cytokines and interferons signaling, which regulates cell growth, development, cell migration, innate and adaptive immunity. Plays both structural and catalytic roles in numerous interleukins and interferons (IFN-alpha/beta) signaling. Associates with heterodimeric cytokine receptor complexes and activates STAT family members including STAT1, STAT3, STAT4 or STAT6. The heterodimeric cytokine receptor complexes are composed of (1) a TYK2-associated receptor chain (IFNAR1, IL12RB1, IL10RB or IL13RA1), and (2) a second receptor chain associated either with JAK1 or JAK2. In response to cytokine-binding to receptors, phosphorylates and activates receptors (IFNAR1, IL12RB1, IL10RB or IL13RA1), creating docking sites for STAT members. In turn, recruited STATs are phosphorylated by TYK2 (or JAK1/JAK2 on the second receptor chain), form homo- and heterodimers, translocate to the nucleus, and regulate cytokine/growth factor responsive genes. Negatively regulates STAT3 activity by promototing phosphorylation at a specific tyrosine that differs from the site used for signaling. 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_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_TYK2_N

Functional cluster

Eukaryotic Transcription Factors & related

Experimental structures · PDB · 52

• 3LXN X-ray 2.50A
• 3LXP X-ray 1.65A
• 3NYX X-ray 2.50A
• 3NZ0 X-ray 2.00A
• 3ZON X-ray 2.15A
• 4GFO X-ray 2.30A
• 4GIH X-ray 2.00A
• 4GII X-ray 2.31A
• 4GJ2 X-ray 2.40A
• 4GJ3 X-ray 2.50A
• 4GVJ X-ray 2.03A
• 4OLI X-ray 2.80A
• … and 40 more

A predicted model is available from AlphaFold.

Gene Ontology · 29

• GO:0005737 cytoplasm
• GO:0009898 cytoplasmic side of plasma membrane
• GO:0005829 cytosol
• GO:0070062 extracellular exosome
• GO:0031234 extrinsic component of cytoplasmic side of plasma membrane
• GO:0019897 extrinsic component of plasma membrane
• GO:0005634 nucleus
• GO:0005886 plasma membrane
• GO:0005524 ATP binding
• GO:0005131 growth hormone receptor binding
• GO:0004715 non-membrane spanning protein tyrosine kinase activity
• GO:0004713 protein tyrosine kinase activity
• GO:0030154 cell differentiation
• GO:0008283 cell population proliferation
• GO:0007259 cell surface receptor signaling pathway via JAK-STAT
• GO:0019221 cytokine-mediated signaling pathway
• GO:0060397 growth hormone receptor signaling pathway via JAK-STAT
• GO:0140105 interleukin-10-mediated signaling pathway
• GO:0035722 interleukin-12-mediated signaling pathway
• GO:0038155 interleukin-23-mediated signaling pathway
• GO:0038043 interleukin-5-mediated signaling pathway
• GO:0035556 intracellular signal transduction
• GO:1900182 positive regulation of protein localization to nucleus
• GO:0042102 positive regulation of T cell proliferation
• GO:0006468 protein phosphorylation
• GO:0046634 regulation of alpha-beta T cell activation
• GO:0046425 regulation of receptor signaling pathway via JAK-STAT
• GO:0060337 type I interferon-mediated signaling pathway
• GO:0060333 type II interferon-mediated signaling pathway

Disease associations

• immunodeficiency 35 MONDO:0012682

Drugs targeting this protein · 14

• TOFACITINIB CITRATE inhibitor
• PEFICITINIB inhibitor
• FILGOTINIB inhibitor
• CERDULATINIB inhibitor
• BREPOCITINIB inhibitor
• DELGOCITINIB inhibitor
• FILGOTINIB MALEATE inhibitor
• DEUCRAVACITINIB negative allosteric modulator
• ROPSACITINIB inhibitor
• GUSACITINIB inhibitor
• DEURUXOLITINIB PHOSPHATE inhibitor
• IZENCITINIB inhibitor
• NEZULCITINIB inhibitor
• UPADACITINIB HEMIHYDRATE inhibitor

Related proteins · sequence + function similarity

• Non-receptor tyrosine-protein kinase TYK2 0.97
• Tyrosine-protein kinase JAK3 0.93
• Tyrosine-protein kinase JAK3 0.92
• Tyrosine-protein kinase JAK3 0.92
• Tyrosine-protein kinase JAK1 0.78
• Non-receptor tyrosine-protein kinase TNK1 0.77
• Non-receptor tyrosine-protein kinase TNK1 0.75
• Megakaryocyte-associated tyrosine-protein kinase 0.74
• Rap guanine nucleotide exchange factor 3 0.74
• Megakaryocyte-associated tyrosine-protein kinase 0.74
• Rap guanine nucleotide exchange factor 3 0.74
• Ephrin type-B receptor 6 0.74

Co-cited proteins · studied together in the literature

• Tyrosine-protein kinase JAK1 4 shared papers
• Interferon alpha/beta receptor 1 2 shared papers
• Latent membrane protein 1 1 shared papers
• Protein E6 1 shared papers
• Thrombopoietin receptor 1 shared papers
• Leukocyte tyrosine kinase receptor 1 shared papers
• Signal transducer and activator of transcription 4 1 shared papers
• Cytoplasmic envelopment protein 2 1 shared papers
• Janus kinase and microtubule-interacting protein 1 1 shared papers
• Janus kinase and microtubule-interacting protein 2 1 shared papers
• Interferon beta 1 shared papers
• Interleukin-12 subunit alpha 1 shared papers

Literature · 28 cited papers

• Epstein-Barr Virus (EBV) Tegument Protein BGLF2 Suppresses Type I Interferon Signaling To Promote EBV Reactivation. J. Virol. · 2020
• TYK2-induced phosphorylation of Y640 suppresses STAT3 transcriptional activity. Sci. Rep. · 2017
• Tyrosine Kinase 2-mediated Signal Transduction in T Lymphocytes Is Blocked by Pharmacological Stabilization of Its Pseudokinase Domain. J. Biol. Chem. · 2015
• Structure of the pseudokinase-kinase domains from protein kinase TYK2 reveals a mechanism for Janus kinase (JAK) autoinhibition. Proc. Natl. Acad. Sci. U.S.A. · 2014
• Toward a comprehensive characterization of a human cancer cell phosphoproteome. J. Proteome Res. · 2013
• Structural and thermodynamic characterization of the TYK2 and JAK3 kinase domains in complex with CP-690550 and CMP-6. J. Mol. Biol. · 2010
• Large-scale proteomics analysis of the human kinome. Mol. Cell. Proteomics · 2009
• Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle. Mol. Cell · 2008
• Patterns of somatic mutation in human cancer genomes. Nature · 2007
• Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. Immunity · 2006
• The Epstein-Barr virus-encoded LMP-1 oncoprotein negatively affects Tyk2 phosphorylation and interferon signaling in human B cells. J. Virol. · 2006
• Janus kinases affect thrombopoietin receptor cell surface localization and stability. J. Biol. Chem. · 2005
• … and 16 more in the literature graph