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 and Sho Yamasaki ()
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Eri Ishikawa: Medical Institute of Bioregulation, Kyushu University
Hidetaka Kosako: Fujii Memorial Institute of Medical Sciences, Tokushima University
Tomoharu Yasuda: Laboratory for Lymphocyte Differentiation, RIKEN Center for Integrative Medical Sciences
Masaki Ohmuraya: Institute of Resource Development and Analysis, Kumamoto University
Kimi Araki: Institute of Resource Development and Analysis, Kumamoto University
Tomohiro Kurosaki: Laboratory for Lymphocyte Differentiation, RIKEN Center for Integrative Medical Sciences
Takashi Saito: Laboratory for Cell Signaling, RIKEN Center for Integrative Medical Sciences
Sho Yamasaki: Medical Institute of Bioregulation, Kyushu University

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12756

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