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

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

doi:10.1016/j.bpj.2008.12.3680

Cited by 21 publications

(31 citation statements)

References 18 publications

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“…KCa3.1 is expressed at low levels in resting naïve CD4 T cells and is transcriptionally activated following TCR stimulation, leading to increased numbers of KCa3.1 channels in activated cells (10,30,31). We found that KCa3.1 channel activity is also markedly up-regulated following differentiation into Th1 and Th2 cells, and KCa3.1 accounts for the majority of the K + current in these cells.…”

Section: Discussionmentioning

confidence: 68%

Inhibition of the K⁺channel KCa3.1 ameliorates T cell–mediated colitis

Srivastava

Zhdanova

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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138

136

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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. To assess the role of KCa3.1 channels in lymphocyte activation in vivo, we studied T cell function in KCa3.1 −/− mice. CD4 T helper (i.e., Th0) cells isolated from KCa3.1 −/− mice lacked KCa3.1 channel activity, which resulted in decreased T cell receptor–stimulated Ca 2+ influx and IL-2 production. Although loss of KCa3.1 did not interfere with CD4 T cell differentiation, both Ca 2+ influx and cytokine production were impaired in KCa3.1 −/− Th1 and Th2 CD4 T cells, whereas T-regulatory and Th17 function were normal. We found that inhibition of KCa3.1 −/− protected mice from developing severe colitis in two mouse models of inflammatory bowel disease, which were induced by ( i ) the adoptive transfer of mouse naïve CD4 T cells into rag2 −/− recipients and ( ii ) trinitrobenzene sulfonic acid. Pharmacologic inhibitors of KCa3.1 have already been shown to be safe in humans. Thus, if these preclinical studies continue to show efficacy, it may be possible to rapidly test whether KCa3.1 inhibitors are efficacious in patients with inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis.

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Section: Discussionmentioning

confidence: 68%

Inhibition of the K⁺channel KCa3.1 ameliorates T cell–mediated colitis

Srivastava

Zhdanova

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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138

136

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“…Silencing of PI3K-C2␣ and PI3K-C2␤ in the various experiments was confirmed by RT-PCR as previously described (Srivastava et al, 2008). PI3K-C2␤ mutant (PI3K-C2␤ mt) was generated by a point mutation and cloned into the vector pEGFP (Clontech, Palo Alto, CA).…”

Section: Reagentsmentioning

confidence: 99%

“…In addition, we identified two new negative regulators of KCa3.1, the PI(3)P phosphatase myotubularin-related protein 6 (MTMR6) and the histidine phosphatase, phosphohistidine phosphatase-1 (PHPT-1), which inhibit KCa3.1 by dephosphorylating PI(3)P and KCa3.1, respectively (Srivastava et al, 2006a(Srivastava et al, , 2008. These molecules also play a critical role in the reactivation of human CD4 T-cell; NDPK-B is required for T-cell receptor (TCR)-stimulated Ca 2ϩ flux and proliferation, whereas both MTMR6 and PHPT-1 inhibit these responses.…”

Section: Introductionmentioning

confidence: 99%

The Class II Phosphatidylinositol 3 kinase C2β Is Required for the Activation of the K⁺Channel KCa3.1 and CD4 T-Cells

Srivastava

Zhdanova

et al. 2009

MBoC

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The Ca 2؉ -activated K ؉ channel KCa3.1 is required for Ca 2؉ influx and the subsequent activation of T-cells. We previously showed that nucleoside diphosphate kinase beta (NDPK-B), a mammalian histidine kinase, directly phosphorylates and activates KCa3.1 and is required for the activation of human CD4 T lymphocytes. We now show that the class II phosphatidylinositol 3 kinase C2␤ (PI3K-C2␤) is activated by the T-cell receptor (TCR) and functions upstream of NDPK-B to activate KCa3.1 channel activity. Decreased expression of PI3K-C2␤ by siRNA in human CD4 T-cells resulted in inhibition of KCa3.1 channel activity. The inhibition was due to decreased phosphatidylinositol 3-phosphate [PI(3)P] because dialyzing PI3K-C2␤ siRNA-treated T-cells with PI(3)P rescued KCa3.1 channel activity. Moreover, overexpression of PI3K-C2␤ in KCa3.1-transfected Jurkat T-cells led to increased TCR-stimulated activation of KCa3.1 and Ca 2؉ influx, whereas silencing of PI3K-C2␤ inhibited both responses. Using total internal reflection fluorescence microscopy and planar lipid bilayers, we found that PI3K-C2␤ colocalized with Zap70 and the TCR in peripheral microclusters in the immunological synapse. This is the first demonstration that a class II PI3K plays a critical role in T-cell activation.

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“…28 In this particular case, it is not clear which isomer of pHis is formed and on which His residue. Mammalian pHis phosphatases, which have been characterized include: protein pHis phosphatase 1 (PHPT1); 17,[29][30][31][32][33][34][35] Lys/His phosphatase (LHPPase); 36,37 Ser Thr protein phosphatases (PP1/2 A/2C); 38,39 T-cell ubiquitin ligand-2 (TULA-2); 40,41 and the recently reported phosphoglycerate mutase-5 (PGAM5). 42 In addition, pHis phosphatase activity has been reported in rat tissue extracts but these have not been fully characterized.…”

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confidence: 99%

Advances in development of new tools for the study of phosphohistidine

Makwana

Muimo

Jackson

2018

Laboratory Investigation

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Protein phosphorylation is an important post-translational modification that is an integral part of cellular function. The O-phosphorylated amino-acid residues, such as phosphoserine (pSer), phosphothreonine (pThr) and phosphotyrosine (pTyr), have dominated the literature while the acid labile N-linked phosphorylated amino acids, such as phosphohistidine (pHis), have largely been historically overlooked because of the acidic conditions routinely used in amino-acid detection and analysis. This review highlights some misinterpretations that have arisen in the existing literature, pinpoints outstanding questions and potential future directions to clarify the role of pHis in mammalian signalling systems. Particular emphasis is placed on pHis isomerization and the hybrid functionality for both pHis and pTyr of the proposed τ-pHis analogue bearing the triazole residue.

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

Cited by 21 publications

References 18 publications

Inhibition of the K⁺channel KCa3.1 ameliorates T cell–mediated colitis

Inhibition of the K⁺channel KCa3.1 ameliorates T cell–mediated colitis

The Class II Phosphatidylinositol 3 kinase C2β Is Required for the Activation of the K⁺Channel KCa3.1 and CD4 T-Cells

Advances in development of new tools for the study of phosphohistidine

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

Cited by 21 publications

References 18 publications

Inhibition of the K+channel KCa3.1 ameliorates T cell–mediated colitis

Inhibition of the K+channel KCa3.1 ameliorates T cell–mediated colitis

The Class II Phosphatidylinositol 3 kinase C2β Is Required for the Activation of the K+Channel KCa3.1 and CD4 T-Cells

Advances in development of new tools for the study of phosphohistidine

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Inhibition of the K⁺channel KCa3.1 ameliorates T cell–mediated colitis

Inhibition of the K⁺channel KCa3.1 ameliorates T cell–mediated colitis

The Class II Phosphatidylinositol 3 kinase C2β Is Required for the Activation of the K⁺Channel KCa3.1 and CD4 T-Cells