A novel intramolecular negative regulation of mouse Jak3 activity by tyrosine 820

Yuichi Sekine, Kazuna Kikkawa, Bruce A. Witthuhn, Jun Ichi Kashiwakura, Ryuta Muromoto, Yuichi Kitai, Masahiro Fujimuro, Kenji Oritani, Tadashi Matsuda

Research output: Contribution to journalArticlepeer-review

Abstract

Jak3, a member of the Janus kinase family, is essential for the cytokine receptor common gamma chain (γc)-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 Jak3-mediated 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.

Original languageEnglish (US)
Pages (from-to)303-312
Number of pages10
JournalInternational Immunology
Volume34
Issue number6
DOIs
StatePublished - Jun 1 2022

Bibliographical note

Publisher Copyright:
© 2022 The Author(s) 2022. Published by Oxford University Press on behalf of The Japanese Society for Immunology. All rights reserved.

Keywords

  • cytokine
  • signal transducers activators of transcription 5 (STAT5)
  • tyrosine-protein kinase

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