Protein kinase D regulates positive selection of CD4+thymocytes through phosphorylation of SHP-1.
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.
Division of Molecular Immunology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi Higashiku, Fukuoka 812-8582, Japan.
Eri
E
Ishikawa
Division of Cell Signaling, Fujii Memorial Institute of Medical Sciences, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
Hidetaka
H
Kosako
Laboratory for Lymphocyte Differentiation, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.
Tomoharu
T
Yasuda
Institute of Resource Development and Analysis, Kumamoto University, 2-2-1, Honjo, Chuo-ku, Kumamoto 860-0811, Japan.
Masaki
M
Ohmuraya
Institute of Resource Development and Analysis, Kumamoto University, 2-2-1, Honjo, Chuo-ku, Kumamoto 860-0811, Japan.
Kimi
K
Araki
Laboratory for Lymphocyte Differentiation, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.|Laboratory for Lymphocyte Differentiation, WPI Immunology Frontier Research Center (iFReC), Osaka University, 3-1 Yamadaoka, Suita 565-0871, Japan.
Tomohiro
T
Kurosaki
Laboratory for Cell Signaling, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.|Laboratory for Cell Signaling, WPI Immunology Frontier Research Center (iFReC), Osaka University, 3-1 Yamadaoka, Suita 565-0871, Japan.
Takashi
T
Saito
Division of Molecular Immunology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi Higashiku, Fukuoka 812-8582, Japan.
Sho
S
Yamasaki
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