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 language | English (US) |
|---|---|
| Pages (from-to) | 14442-14446 |
| Number of pages | 5 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 105 |
| Issue number | 38 |
| DOIs | |
| State | Published - Sep 23 2008 |
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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 journal › Article
}
TY - JOUR
T1 - Protein histidine phosphatase 1 negatively regulates CD4 T cells by inhibiting the K+ channel KCa3.1
AU - Srivastava, Shekhar
AU - Zhdanova, Olga
AU - Di, Lie
AU - Li, Zhai
AU - Albaqumi, Mamdouh
AU - Wulff, Heike
AU - Skolnik, Edward Y.
PY - 2008/9/23
Y1 - 2008/9/23
N2 - 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.
AB - 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.
KW - CRAC channel
KW - Histidine kinase
KW - NM23-H2
KW - Nucleoside diphosphate kinase
KW - PHPT-1
UR - http://www.scopus.com/inward/record.url?scp=55749083563&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=55749083563&partnerID=8YFLogxK
U2 - 10.1073/pnas.0803678105
DO - 10.1073/pnas.0803678105
M3 - Article
C2 - 18796614
AN - SCOPUS:55749083563
VL - 105
SP - 14442
EP - 14446
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 38
ER -