Lipid Raft Targeting of Hematopoietic Protein Tyrosine Phosphatase by Protein Kinase C θ-Mediated Phosphorylation

Abstract

Protein kinase C θ (PKC θ) is unique among PKC isozymes in its translocation to the center of the immune synapse in T cells and its unique downstream signaling. Here we show that the hematopoietic protein tyrosine phosphatase (HePTP) also accumulates in the immune synapse in a PKC θ-dependent manner upon antigen recognition by T cells and is phosphorylated by PKC θ at Ser-225, which is required for lipid raft translocation. Immune synapse translocation was completely absent in antigen-specific T cells from PKC θ^−/− mice. In intact T cells, HePTP-S225A enhanced T-cell receptor (TCR)-induced NFAT/AP-1 transactivation, while the acidic substitution mutant was as efficient as wild-type HePTP. We conclude that HePTP is phosphorylated in the immune synapse by PKC θ and thereby targeted to lipid rafts to temper TCR signaling. This represents a novel mechanism for the active immune synapse recruitment and activation of a phosphatase in TCR signaling.

This work was supported by grants AI48032, AI53585, AI55741, AI35603, and CA96949 from the National Institutes of Health.