Protein Kinase D Regulates Positive Selection of CD4 Thymocytes Through Phosphorylation of SHP-1

Overview

Journal Nat Commun

Specialty Biology

Date 2016 Sep 28

PMID 27670070

Citations 19

Authors

Eri Ishikawa

Hidetaka Kosako

Tomoharu Yasuda

Masaki Ohmuraya

Kimi Araki

Tomohiro Kurosaki

Takashi Saito

Sho Yamasaki

Affiliations

Soon will be listed here.

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 CD4CD8 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-1) impairs generation of CD4 thymocytes. These results suggest that the PKD-SHP-1 axis positively regulates TCR signalling to promote CD4 T cell development.

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