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A novel intramolecular negative regulation of mouse Jak3 activity by tyrosine 820
| Title: | A novel intramolecular negative regulation of mouse Jak3 activity by tyrosine 820 |
| Authors: | Sekine, Yuichi Browse this author →KAKEN DB | | Kikkawa, Kazuna Browse this author | | Witthuhn, Bruce A. Browse this author | | Kashiwakura, Jun-Ichi Browse this author →KAKEN DB | | Muromoto, Ryuta Browse this author →KAKEN DB | | Kitai, Yuichi Browse this author →KAKEN DB | | Fujimuro, Masahiro Browse this author | | Oritani, Kenji Browse this author →KAKEN DB | | Matsuda, Tadashi Browse this author →KAKEN DB |
| Keywords: | cytokine | | signal transducers activators of transcription 5 (STAT5) | | tyrosine-protein kinase |
| Issue Date: | 22-Feb-2022 |
| Publisher: | Oxford University Press |
| Journal Title: | International immunology |
| Volume: | 34 |
| Issue: | 6 |
| Start Page: | 303 |
| End Page: | 312 |
| Publisher DOI: | 10.1093/intimm/dxac005 |
| Abstract: | Jak3, a member of the Janus kinase family, is essential for the cytokine receptor common gamma chain (gamma c)-mediated signaling. During activation of Jak3, tyrosine residues are phosphorylated and potentially regulate its kinase activity. We identified a novel tyrosine phosphorylation site within mouse Jak3, Y820, which is conserved in human Jak3, Y824. IL-2-induced tyrosine phosphorylation of Jak3 Y824 in human T cell line HuT78 cells was detected by using a phosphospecific, pY824, antibody. Mutation of mouse Jak3 Y820 to alanine (Y820A) showed increased autophosphorylation of Jak3 and enhanced signal transducer and activator of transcription 5 (STAT5) tyrosine phosphorylation and transcriptional activation. Stably expressed Jak3 Y820A in F7 cells, an IL-2 responsive mouse pro-B cell line Ba/F3, exhibited enhanced IL-2-dependent cell growth. Mechanistic studies demonstrated that interaction between Jak3 and STAT5 increased in Jak3 Y820A compared to wild-type Jak3.These data suggest that Jak3 Y820 plays a role in negative regulation of Jak3mediated STAT5 signaling cascade upon IL-2-stimulation. We speculate that this occurs through an interaction promoted by the tyrosine phosphorylated Y820 or a conformational change by Y820 mutation with either the STAT directly or with the recruitment of molecules such as phosphatases via a SH2 interaction. Additional studies will focus on these interactions as Jak3 plays a crucial role in disease and health. |
| Rights: | This is a pre-copyedited, author-produced version of an article accepted for publication in International Immunology following peer review. The version of record "International Immunology Volume 34, Issue 6, June 2022, Pages 303–312" is available online at: https://doi.org/10.1093/intimm/dxac005. |
| Type: | article (author version) |
| URI: | http://hdl.handle.net/2115/88131 |
| Appears in Collections: | 薬学研究院 (Faculty of Pharmaceutical Sciences) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)
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Submitter: 松田 正
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