Protein kinase D regulates positive selection of CD4+ thymocytes through phosphorylation of SHP-1

Eri Ishikawa, Hidetaka Kosako, Tomoharu Yasuda, Masaki Ohmuraya, Kimi Araki, Tomohiro Kurosaki, Takashi Saito, Sho Yamasaki

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Thymic selection shapes an appropriate T cell antigen receptor (TCR) repertoire during T cell development. Here, we show that a serine/threonine kinase, protein kinase D (PKD), is crucial for thymocyte positive selection. In T cell-specific PKD-deficient (PKD2/PKD3 double-deficient) mice, the generation of CD4 single positive thymocytes is abrogated. This defect is likely caused by attenuated TCR signalling during positive selection and incomplete CD4 lineage specification in PKD-deficient thymocytes; however, TCR-proximal tyrosine phosphorylation is not affected. PKD is activated in CD4+ CD8+ double positive (DP) thymocytes on stimulation with positively selecting peptides. By phosphoproteomic analysis, we identify SH2-containing protein tyrosine phosphatase-1 (SHP-1) as a direct substrate of PKD. Substitution of wild-type SHP-1 by phosphorylation-defective mutant (SHP-1S557A) impairs generation of CD4+ thymocytes. These results suggest that the PKD-SHP-1 axis positively regulates TCR signalling to promote CD4+ T cell development.

Original languageEnglish
Article number12756
JournalNature communications
Volume7
DOIs
Publication statusPublished - Sep 27 2016

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Protein Phosphatase 1
phosphorylation
Phosphorylation
Protein Tyrosine Phosphatases
phosphatases
tyrosine
Thymocytes
T-Cell Antigen Receptor
T-cells
proteins
antigens
T-Lymphocytes
Protein-Serine-Threonine Kinases
Tyrosine
Substitution reactions
protein kinase D
Specifications
stimulation
Defects
Peptides

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Ishikawa, E., Kosako, H., Yasuda, T., Ohmuraya, M., Araki, K., Kurosaki, T., ... Yamasaki, S. (2016). Protein kinase D regulates positive selection of CD4+ thymocytes through phosphorylation of SHP-1. Nature communications, 7, [12756]. https://doi.org/10.1038/ncomms12756

Protein kinase D regulates positive selection of CD4+ thymocytes through phosphorylation of SHP-1. / Ishikawa, Eri; Kosako, Hidetaka; Yasuda, Tomoharu; Ohmuraya, Masaki; Araki, Kimi; Kurosaki, Tomohiro; Saito, Takashi; Yamasaki, Sho.

In: Nature communications, Vol. 7, 12756, 27.09.2016.

Research output: Contribution to journalArticle

Ishikawa, E, Kosako, H, Yasuda, T, Ohmuraya, M, Araki, K, Kurosaki, T, Saito, T & Yamasaki, S 2016, 'Protein kinase D regulates positive selection of CD4+ thymocytes through phosphorylation of SHP-1', Nature communications, vol. 7, 12756. https://doi.org/10.1038/ncomms12756
Ishikawa, Eri ; Kosako, Hidetaka ; Yasuda, Tomoharu ; Ohmuraya, Masaki ; Araki, Kimi ; Kurosaki, Tomohiro ; Saito, Takashi ; Yamasaki, Sho. / Protein kinase D regulates positive selection of CD4+ thymocytes through phosphorylation of SHP-1. In: Nature communications. 2016 ; Vol. 7.
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