scholarly journals Integration of Calcium and Cyclic AMP Signaling Pathways by 14-3-3

2000 ◽  
Vol 20 (2) ◽  
pp. 702-712 ◽  
Author(s):  
Chi-Wing Chow ◽  
Roger J. Davis
Keyword(s):  
T Cells ◽  
Cyclic Amp ◽  
Signaling Pathways ◽  
Interleukin 2 ◽  
Camp Signaling ◽  
Phosphorylation Sites ◽  
Nuclear Factor ◽  
Activated T Cells ◽  
Transcription Activity ◽  
Kinase A

ABSTRACT Calcium-stimulated nuclear factor of activated T cells (NFAT) transcription activity at the interleukin-2 promoter is negatively regulated by cyclic AMP (cAMP). This effect of cAMP is mediated, in part, by protein kinase A phosphorylation of NFAT. The mechanism of regulation involves the creation of a phosphorylation-dependent binding site for 14-3-3. Decreased NFAT phosphorylation caused by the calcium-stimulated phosphatase calcineurin, or mutation of the PKA phosphorylation sites, disrupted 14-3-3 binding and increased NFAT transcription activity. In contrast, NFAT phosphorylation caused by cAMP increased 14-3-3 binding and reduced NFAT transcription activity. The regulated interaction between NFAT and 14-3-3 provides a mechanism for the integration of calcium and cAMP signaling pathways.

Costimulatory action of glycoinositolphospholipids from Trypanosoma cruzi: increased interleukin 2 secretion and induction of nuclear translocation of the nuclear factor of activated T cells 1

1999 ◽  
Vol 13 (12) ◽  
pp. 1627-1636 ◽  
Author(s):  
Maria Bellio ◽  
Ana‐Carolina S. C. Oliveira ◽  
Claudia S. Mermelstein ◽  
Marcia A. M. Capella ◽  
João P. B. Viola ◽  
...  
Keyword(s):  
T Cells ◽  
Trypanosoma Cruzi ◽  
Nuclear Translocation ◽  
Interleukin 2 ◽  
Nuclear Factor ◽  
Activated T Cells

Regulation of nuclear factor of activated T cells by phosphotyrosyl-specific phosphatase activity: a positive effect on HIV-1 long terminal repeat–driven transcription and a possible implication of SHP-1

Blood ◽  
2001 ◽  
Vol 97 (8) ◽  
pp. 2390-2400 ◽  
Author(s):  
Jean-François Fortin ◽  
Benoit Barbeau ◽  
Gilles A. Robichaud ◽  
Marie-Ève Paré ◽  
Anne-Marie Lemieux ◽  
...  
Keyword(s):  
T Cells ◽  
Long Terminal Repeat ◽  
Nuclear Translocation ◽  
Interleukin 2 ◽  
Dominant Negative ◽  
Terminal Repeat ◽  
Nuclear Factor ◽  
Activated T Cells ◽  
Nfat Activation ◽  
Hiv 1

Abstract Although protein tyrosine phosphatase (PTP) inhibitors used in combination with other stimuli can induce interleukin 2 (IL-2) production in T cells, a direct implication of nuclear factor of activated T cells (NFAT) has not yet been demonstrated. This study reports that exposure of leukemic T cells and human peripheral blood mononuclear cells to bis-peroxovanadium (bpV) PTP inhibitors markedly induce activation and nuclear translocation of NFAT. NFAT activation by bpV was inhibited by the immunosuppressive drugs FK506 and cyclosporin A, as well as by a specific peptide inhibitor of NFAT activation. Mobility shift assays showed specific induction of the NFAT1 member by bpV molecules. The bpV-mediated NFAT activation was observed to be important for the up-regulation of the human immunodeficiency virus 1 (HIV-1) long terminal repeat (LTR) and the IL-2 promoter; NFAT1 was demonstrated to be particularly important in bpV-dependent positive action on HIV-1 LTR transcription. The active participation of p56lck, ZAP-70, p21ras, and calcium in the bpV-mediated signaling cascade leading to NFAT activation was confirmed, using deficient cell lines and dominant-negative mutants. Finally, overexpression of wild-type SHP-1 resulted in a greatly diminished activation of NFAT by bpV, suggesting an involvement of SHP-1 in the regulation of NFAT activation. These data were confirmed by constitutive NFAT translocation observed in Jurkat cells stably expressing a dominant-negative version of SHP-1. The study proposes that PTP activity attenuates constitutive kinase activities that otherwise would lead to constant NFAT activation and that this activation is participating in HIV-1 LTR stimulation by PTP inhibition.

scholarly journals A Transcription Function for the T Cell–Specific Adapter (Tsad) Protein in T Cells

2001 ◽  
Vol 193 (12) ◽  
pp. 1425-1430 ◽  
Author(s):  
Francesc Marti ◽  
Nicholas H. Post ◽  
Elena Chan ◽  
Philip D. King
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nuclear Import ◽  
Regulatory Protein ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Sh2 Domain ◽  
Nuclear Factor ◽  
Transcription Activator ◽  
Activated T Cells

T cell–specific adapter (TSAd) protein is an Src homology 2 (SH2) domain–containing adapter molecule implicated in T cell receptor for antigen (TCR)-mediated interleukin 2 (IL-2) secretion in T cells. Here, we demonstrate that a substantial fraction of TSAd is found in the T cell nucleus. Nuclear import of TSAd is an active process that depends on TSAd SH2 domain recognition of a phosphotyrosine-containing ligand. Importantly, we show that TSAd can act as a potent transcriptional activator in T cells. Furthermore, the TSAd SH2 domain appears to be essential for this transcription-activating function independent of its role in nuclear import. Biochemical analyses suggest that a single TSAd SH2 domain ligand of 95–100 kD may be involved in these processes. Consistent with a role as a transcription activator, cotransfection of TSAd with an IL-2 promoter–reporter gene construct results in a considerable upregulation of IL-2 promoter activity. Further, we show that this augmentation requires a functional TSAd SH2 domain. However, TSAd does not appear to modulate the activity of the major recognized IL-2 gene transcription factors, nuclear factor κB (NF-κB), nuclear factor of activated T cells (NFAT), or activator protein 1 (AP-1). These findings point to the function of TSAd as a novel transcription-regulatory protein in T cells and illustrate the importance of the TSAd SH2 domain in this role.

scholarly journals p21ras and calcineurin synergize to regulate the nuclear factor of activated T cells.

1993 ◽  
Vol 178 (5) ◽  
pp. 1517-1522 ◽  
Author(s):  
M Woodrow ◽  
N A Clipstone ◽  
D Cantrell
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Protein Tyrosine Kinase ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Cytosolic Calcium ◽  
Nuclear Factor ◽  
Activated T Cells ◽  
Guanine Nucleotide Binding Protein

In T lymphocytes, triggering of the T cell receptor (TCR) induces several signaling cascades which ultimately synergize to induce the activity of the nuclear factor of activated T cells (NFAT), a DNA binding complex critical to the inducibility and T cell specificity of the T cell growth factor interleukin 2. One immediate consequence of T cell activation via the TCR is an increase in cytosolic calcium. Calcium signals are important for NFAT induction, and recent studies have identified calcineurin, a calcium-calmodulin dependent serine-threonine phosphatase, as a prominent component of the calcium signaling pathway in T cells. A second important molecule in TCR signal transduction is the guanine nucleotide binding protein, p21ras, which is coupled to the TCR by a protein tyrosine kinase dependent mechanism. The experiments presented here show that expression by transfection of mutationally activated calcineurin or activated p21ras alone is insufficient for NFAT transactivation. However, coexpression of the activated calcineurin with activated p21ras could mimic TCR signals in NFAT induction. These data identify calcineurin and p21ras as cooperative partners in T cell activation.

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