Protein Histidine Phosphatase 1 Negatively Regulates CD4 T Cells by Inhibiting the K+ Channel KCa3.1

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2008 Sep 18

PMID 18796614

Citations 68

Authors

Shekhar Srivastava

Olga Zhdanova

Lie Di

Zhai Li

Mamdouh Albaqumi

Heike Wulff

Edward Y Skolnik

Affiliations

Soon will be listed here.

Abstract

The calcium activated K(+) channel KCa3.1 plays an important role in T lymphocyte Ca(2+) signaling by helping to maintain a negative membrane potential, which provides an electrochemical gradient to drive Ca(2+) influx. We previously showed that nucleoside diphosphate kinase beta (NDPK-B), a mammalian histidine kinase, is required for KCa3.1 channel activation in human CD4 T lymphocytes. We now show that the mammalian protein histidine phosphatase (PHPT-1) directly binds and inhibits KCa3.1 by dephosphorylating histidine 358 on KCa3.1. Overexpression of wild-type, but not a phosphatase dead, PHPT-1 inhibited KCa3.1 channel activity. Decreased expression of PHPT-1 by siRNA in human CD4 T cells resulted in an increase in KCa3.1 channel activity and increased Ca(2+) influx and proliferation after T cell receptor (TCR) activation, indicating that endogenous PHPT-1 functions to negatively regulate CD4 T cells. Our findings provide a previously unrecognized example of a mammalian histidine phosphatase negatively regulating TCR signaling and are one of the few examples of histidine phosphorylation/dephosphorylation influencing a biological process in mammals.

Citing Articles

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A salt bridge of the C-terminal carboxyl group regulates PHPT1 substrate affinity and catalytic activity.

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Reduction of Ca Entry by a Specific Block of KCa3.1 Channels Optimizes Cytotoxic Activity of NK Cells against T-ALL Jurkat Cells.

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