scholarly journals Protein Kinase D1 Phosphorylates HDAC7 and Induces Its Nuclear Export after T-cell Receptor Activation

2004 ◽  
Vol 280 (14) ◽  
pp. 13762-13770 ◽  
Author(s):  
Maribel Parra ◽  
Herbert Kasler ◽  
Timothy A. McKinsey ◽  
Eric N. Olson ◽  
Eric Verdin
Keyword(s):  
T Cell ◽  
Protein Kinase ◽  
T Cell Receptor ◽  
Nuclear Export ◽  
Cell Receptor ◽  
Receptor Activation ◽  
Protein Kinase D1

scholarly journals Phosphorylation of histone deacetylase 7 by protein kinase D mediates T cell receptor–induced Nur77 expression and apoptosis

2005 ◽  
Vol 201 (5) ◽  
pp. 793-804 ◽  
Author(s):  
Franck Dequiedt ◽  
Johan Van Lint ◽  
Emily Lecomte ◽  
Viktor Van Duppen ◽  
Thomas Seufferlein ◽  
...  
Keyword(s):  
T Cell ◽  
Protein Kinase ◽  
T Cell Receptor ◽  
Nuclear Export ◽  
Histone Deacetylases ◽  
Negative Selection ◽  
Cell Receptor ◽  
Protein Kinase D ◽  
Orphan Nuclear Receptor ◽  
Nuclear Exclusion

The molecular basis of thymocyte negative selection, a crucial mechanism in establishing central tolerance, is not yet resolved. Histone deacetylases (HDACs) have emerged as key transcriptional regulators in several major developmental programs. Recently, we showed that the class IIa member, HDAC7, regulates negative selection by repressing expression of Nur77, an orphan nuclear receptor involved in antigen-induced apoptosis of thymocytes. Engagement of the T cell receptor (TCR) alleviates this repression through phosphorylation-dependent nuclear exclusion of HDAC7. However, the identity of the TCR-activated kinase that phosphorylates and inactivates HDAC7 was still unknown. Here, we demonstrate that TCR-induced nuclear export of HDAC7 and Nur77 expression is mediated by activation of protein kinase D (PKD). Indeed, active PKD stimulates HDAC7 nuclear export and Nur77 expression. In contrast, inhibition of PKD prevents TCR-mediated nuclear exclusion of HDAC7 and associated Nur77 activation. Furthermore, we show that HDAC7 is an interaction partner and a substrate for PKD. We identify four serine residues in the NH2 terminus of HDAC7 as targets for PKD. More importantly, a mutant of HDAC7 specifically deficient in phosphorylation by PKD, inhibits TCR-mediated apoptosis of T cell hybridomas. These findings indicate that PKD is likely to play a key role in the signaling pathways controlling negative selection.

scholarly journals Large-scale proteomic analysis of tyrosine-phosphorylation induced by T-cell receptor or B-cell receptor activation reveals new signaling pathways

PROTEOMICS ◽  
2009 ◽  
Vol 9 (13) ◽  
pp. 3549-3563 ◽  
Author(s):  
Masaki Matsumoto ◽  
Koji Oyamada ◽  
Hidehisa Takahashi ◽  
Takamichi Sato ◽  
Shigetsugu Hatakeyama ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Signaling Pathways ◽  
Tyrosine Phosphorylation ◽  
T Cell Receptor ◽  
Proteomic Analysis ◽  
Large Scale ◽  
Cell Receptor ◽  
Receptor Activation ◽  
B Cell Receptor

scholarly journals Activation of Hematopoietic Progenitor Kinase 1 Involves Relocation, Autophosphorylation, and Transphosphorylation by Protein Kinase D1

2005 ◽  
Vol 25 (6) ◽  
pp. 2364-2383 ◽  
Author(s):  
Rüdiger Arnold ◽  
Irene M. Patzak ◽  
Brit Neuhaus ◽  
Sadia Vancauwenbergh ◽  
André Veillette ◽  
...  
Keyword(s):  
T Cell ◽  
Protein Kinase ◽  
Adaptor Protein ◽  
Cell Receptor ◽  
Hematopoietic Progenitor ◽  
Kinase Activation ◽  
Protein Kinase D1 ◽  
Enzymatic Activation ◽  
Antigen Presenting

ABSTRACT Adaptive immune signaling can be coupled to stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK) and NF-κB activation by the hematopoietic progenitor kinase 1 (HPK1), a mammalian hematopoiesis-specific Ste20 kinase. To gain insight into the regulation of leukocyte signal transduction, we investigated the molecular details of HPK1 activation. Here we demonstrate the capacity of the Src family kinase Lck and the SLP-76 family adaptor protein Clnk (cytokine-dependent hematopoietic cell linker) to induce HPK1 tyrosine phosphorylation and relocation to the plasma membrane, which in lymphocytes results in recruitment of HPK1 to the contact site of antigen-presenting cell (APC)-T-cell conjugates. Relocation and clustering of HPK1 cause its enzymatic activation, which is accompanied by phosphorylation of regulatory sites in the HPK1 kinase activation loop. We show that full activation of HPK1 is dependent on autophosphorylation of threonine 165 and phosphorylation of serine 171, which is a target site for protein kinase D (PKD) in vitro. Upon T-cell receptor stimulation, PKD robustly augments HPK1 kinase activity in Jurkat T cells and enhances HPK1-driven SAPK/JNK and NF-κB activation; conversely, antisense down-regulation of PKD results in reduced HPK1 activity. Thus, activation of major lymphocyte signaling pathways via HPK1 involves (i) relocation, (ii) autophosphorylation, and (iii) transphosphorylation of HPK1 by PKD.

scholarly journals ASK1 Mediates Nur77 Expression in T-Cell Receptor Mediated Thymocyte Apoptosis

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 585
Author(s):  
Jianxin Huo ◽  
Shengli Xu ◽  
Kong-Peng Lam
Keyword(s):  
T Cell ◽  
Protein Kinase ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Mitogen Activated Protein Kinase ◽  
Signaling Cascades ◽  
Signaling Mechanism ◽  
Apoptotic Protein ◽  
Mitogen Activated Protein ◽  
Thymocyte Apoptosis

Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase (MAPKKK) that activates downstream JNK and p38 mitogen-activated protein kinase (MAPK) to relay death signals into cells in response to various environmental stress. However, whether ASK1 plays a role in T cell receptor (TCR)-mediated apoptosis of thymocytes is unclear. Here, we show that ASK1 is activated upon TCR stimulation and plays an important role in TCR-mediated apoptosis of thymocytes by triggering downstream JNK and p38 signaling cascades. Mechanistically, ASK1-JNK/p38 signaling leads to the upregulation of neuron-derived clone 77 (Nur77), a critical pro-apoptotic protein involved in TCR-mediated apoptosis of thymocytes. Furthermore, we demonstrate that the activation of ASK1 is negatively modulated by Akt upon TCR stimulation. Thus, our results identify a previously unappreciated signaling mechanism involving ASK1 in TCR-mediated apoptosis of thymocytes.

scholarly journals 9-cis retinoic acid inhibition of activation-induced apoptosis is mediated via regulation of fas ligand and requires retinoic acid receptor and retinoid X receptor activation.

1995 ◽  
Vol 15 (10) ◽  
pp. 5576-5585 ◽  
Author(s):  
R P Bissonnette ◽  
T Brunner ◽  
S B Lazarchik ◽  
N J Yoo ◽  
M F Boehm ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
T Cell ◽  
T Cell Receptor ◽  
Target Genes ◽  
Fas Ligand ◽  
Apoptotic Cell ◽  
Cell Receptor ◽  
Receptor Activation ◽  
Retinoid Receptor ◽  
Induced Apoptosis

T-cell hybridomas, thymocytes, and T cells can be induced to undergo apoptotic cell death by activation through the T-cell receptor. This process requires macromolecular synthesis and thus gene expression, and it has been shown to be influenced by factors regulating transcription. Recently, activation, T-cell hybridomas rapidly express the Fas/CD95 receptor and its ligand, Fas ligand (FasL), which interact to transduce the death signal in the activated cell. Retinoids, the active metabolites of vitamin A, modulate expression of specific target genes by binding to two classes of intracellular receptors, retinoic acid receptors (RARs) and retinoid X receptors (RXRs). They are potent modulators of apoptosis in a number of experimental models, and they have been shown to inhibit activation-induced apoptosis in T-cell hybridomas and thymocytes. Particularly effective is the prototypic pan-agonist 9-cis retinoic acid (9-cis RA), which has high affinity for both RARs and RXRs. We report here that 9-cis RA inhibits T-cell receptor-mediated apoptosis in T-cell hybridomas by blocking the expression of Fas ligand following activation. This inhibition appears to be at the level of FasL mRNA, with the subsequent failure to express cell surface FasL. RAR-selective (TTNPB) or RXR-selective (LG100268) ligands alone were considerably less potent than RAR-RXR pan-agonists. However, the addition of both RAR- and RXR-selective ligands was as effective as the addition of 9-cis RA alone. The demonstrates that the inhibitory effect requires the ligand-mediated activation of both retinoid receptor signaling pathways.

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