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Inhibition of JAK3 leads to STAT5 inhibition
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Inhibition of JAK3 leading to impairment of T-Cell Dependent Antibody Response||adjacent||High||High||Yasuhiro Yoshida (send email)||Under development: Not open for comment. Do not cite||Under Development|
Life Stage Applicability
|All life stages||High|
Key Event Relationship Description
Signal transducer and activator of transcription (STAT) activation is regulated by JAK through phosphorylation. Thus, JAK inhibitors commonly interfere with STAT activation.
Evidence Supporting this KER
STAT5 plays a major role in regulating vital cellular functions such as proliferation, differentiation, and apoptosis of hematopoietic and immune cells (20-Wakao-1992). STAT5 is activated by phosphorylation of a single tyrosine residue (Y694 in STAT5). Janus kinase (JAK)3 phosphorylates tyrosine Y694 of STAT5.
Uncertainties and Inconsistencies
Dose-response analysis of the effects of JAK3 highly selective inhibitor RB1 on JAK3 kinase activity showed that RB1 inhibits JAK3 kinase activity in a dose-dependent manner with an IC50 value of 40nM without inhibiting JAK1, JAK2 or Tyrosine kinase 2 (TYK2) (77-Pei-2018).
Normal rats were administered with peficitinib at 10 and 20 mg/kg, bled the animals after 13 h of dosing, and then assessed STAT5 phosphorylation. IL-2-induced STAT5 phosphorylation of CD3-positive lymphocytes in peripheral blood from peficitinib-treated rats was suppressed by 37% at a dose of 10 mg/kg and 78% at 20 mg/kg (42-Gianti-2015).
The enzymatic activities against JAK1, JAK2, JAK3, and TYK2 were immediately tested by a Caliper Mobility Shift Assay with an ATP concentration at Km (77-Pei-2018).
CTLL-2 cells were treated with 10 µM adenosine (plus coformycin) for 15 min at 37°C and then stimulated with IL-2 (10 U/ml) for different lengths of time (5 min-12 h). Adenosine dramatically decreased dose-dependent STAT5a/b tyrosine phosphorylation in response to IL-2 over the entire 12-h time course (78-Zhang-2004).
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
20. Wakao, H., Schmitt-Ney, M., and Groner, B. (1992) Mammary gland-specific nuclear factor is present in lactating rodent and bovine mammary tissue and composed of a single polypeptide of 89 kDa. J Biol Chem 267, 16365-16370
42. Gianti, E., and Zauhar, R. J. (2015) An SH2 domain model of STAT5 in complex with phospho-peptides define "STAT5 Binding Signatures". J Comput Aided Mol Des 29, 451-470
76. Al-Shami, A., Mahanna, W., and Naccache, P. H. (1998) Granulocyte-macrophage colony-stimulating factor-activated signaling pathways in human neutrophils. Selective activation of Jak2, Stat3, and Stat5b. J Biol Chem 273, 1058-1063
77. Pei, H., He, L., Shao, M., Yang, Z., Ran, Y., Li, D., Zhou, Y., Tang, M., Wang, T., Gong, Y., Chen, X., Yang, S., Xiang, M., and Chen, L. (2018) Discovery of a highly selective JAK3 inhibitor for the treatment of rheumatoid arthritis. Scientific reports 8, 5273
78. Zhang, H., Conrad, D. M., Butler, J. J., Zhao, C., Blay, J., and Hoskin, D. W. (2004) Adenosine acts through A2 receptors to inhibit IL-2-induced tyrosine phosphorylation of STAT5 in T lymphocytes: role of cyclic adenosine 3',5'-monophosphate and phosphatases. J Immunol 173, 932-944