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Molecular and Cellular Biology, March 2006, p. 1806-1816, Vol. 26, No. 5
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.5.1806-1816.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

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

Konstantina Nika,¹ Céline Charvet,² Scott Williams,¹ Lutz Tautz,¹ Shane Bruckner,¹ Souad Rahmouni,^1, Nunzio Bottini,^1, Stephen P. Schoenberger,² Gottfried Baier,³ Amnon Altman,² and Tomas Mustelin^1*

Program of Inflammation, Infectious and Inflammatory Disease Center, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, California,¹ La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, California,² Institute for Medical Biology and Human Genetics, University of Innsbruck, Innsbruck, Austria³

Received 12 September 2005/ Returned for modification 23 October 2005/ Accepted 14 December 2005

Protein kinase C (PKC ) 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 -dependent manner upon antigen recognition by T cells and is phosphorylated by PKC at Ser-225, which is required for lipid raft translocation. Immune synapse translocation was completely absent in antigen-specific T cells from PKC ^–/– 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 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.

Present address: University of Liège, B35, Avenue de l’Hôpital, 3, 4000 Liège 1, Belgium.

Present address: Institute for Genetic Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA 90033.

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