Protein histidine phosphatase 1 negatively regulates CD4 T cells by inhibiting the K+ channel KCa3.1

Shekhar Srivastava, Olga Zhdanova, Lie Di, Zhai Li, Mamdouh Albaqumi, Heike Wulff, Edward Y. Skolnik

Research output: Contribution to journalArticle

74 Citations (Scopus)

Abstract

The calcium activated K+ channel KCa3.1 plays an important role in T lymphocyte Ca2+ 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 Ca2+ 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.

Original languageEnglish (US)
Pages (from-to)14442-14446
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number38
DOIs
StatePublished - Sep 23 2008

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Protein Phosphatase 1
Histidine
T-Lymphocytes
T-Cell Antigen Receptor
Phosphoric Monoester Hydrolases
Nucleoside-Diphosphate Kinase
Biological Phenomena
Calcium-Activated Potassium Channels
Phosphoprotein Phosphatases
Membrane Potentials
Small Interfering RNA
Mammals
Phosphorylation

Keywords

  • CRAC channel
  • Histidine kinase
  • NM23-H2
  • Nucleoside diphosphate kinase
  • PHPT-1

ASJC Scopus subject areas

  • General

Cite this

Protein histidine phosphatase 1 negatively regulates CD4 T cells by inhibiting the K+ channel KCa3.1. / Srivastava, Shekhar; Zhdanova, Olga; Di, Lie; Li, Zhai; Albaqumi, Mamdouh; Wulff, Heike; Skolnik, Edward Y.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 38, 23.09.2008, p. 14442-14446.

Research output: Contribution to journalArticle

Srivastava, Shekhar ; Zhdanova, Olga ; Di, Lie ; Li, Zhai ; Albaqumi, Mamdouh ; Wulff, Heike ; Skolnik, Edward Y. / Protein histidine phosphatase 1 negatively regulates CD4 T cells by inhibiting the K+ channel KCa3.1. In: Proceedings of the National Academy of Sciences of the United States of America. 2008 ; Vol. 105, No. 38. pp. 14442-14446.
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