Protein histidine phosphatase 1 negatively regulates CD4 T cells by inhibiting the K+ channel KCa3.1.
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.
Srivastava
Shekhar
S
Department of Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
Zhdanova
Olga
O
Di
Lie
L
Li
Zhai
Z
Albaqumi
Mamdouh
M
Wulff
Heike
H
Skolnik
Edward Y
EY
D000328:Adult; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology; D049109:Cell Proliferation; D006224:Cricetinae; D003412:Cricetulus; D015870:Gene Expression; D020868:Gene Silencing; D006639:Histidine / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism
D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496923:KCNN4 protein, human; D034741:RNA, Small Interfering; D006639:Histidine; C504019:PHPT1 protein, human; D010744:Phosphoric Monoester Hydrolases; D002118:Calcium
Biochem J. 2007 Feb 15;402(1):1-15
17238862
Curr Opin Drug Discov Devel. 2003 Sep;6(5):640-7
14579513
Mol Cell Biol. 2006 Aug;26(15):5595-602
16847315
Nat Immunol. 2001 Apr;2(4):316-24
11276202
Biochim Biophys Acta. 2005 Dec 30;1754(1-2):281-90
16188507
Cancer Lett. 2003 Feb 10;190(1):1-12
12536071
Proc Natl Acad Sci U S A. 2000 Jul 5;97(14):8151-6
10884437
J Clin Immunol. 2001 Jul;21(4):235-52
11506193
Eur J Biochem. 2002 Oct;269(20):5016-23
12383260
Biochim Biophys Acta. 2005 Dec 30;1754(1-2):291-5
16194631
Curr Biol. 2003 Oct 28;13(21):1858-66
14588241
Biochem Biophys Res Commun. 2005 Nov 25;337(3):887-91
16219293
J Biol Chem. 2006 Nov 10;281(45):33830-4
16990267
Biochemistry. 2002 Mar 26;41(12):3843-51
11900524
J Cereb Blood Flow Metab. 2002 Dec;22(12):1420-4
12468887
J Biochem. 2003 May;133(5):607-14
12801912
Curr Opin Pharmacol. 2004 Aug;4(4):415-22
15251138
J Virol. 2003 Jul;77(14):8153-8
12829854
Mol Cell. 2006 Dec 8;24(5):665-675
17157250