scholarly journals Protein Kinase Cα (PKCα) Acts Upstream of PKCθ To Activate IκB Kinase and NF-κB in T Lymphocytes

2003 ◽  
Vol 23 (19) ◽  
pp. 7068-7081 ◽  
Author(s):  
Sergey A. Trushin ◽  
Kevin N. Pennington ◽  
Eva M. Carmona ◽  
Susana Asin ◽  
Doris N. Savoy ◽  
...  
Keyword(s):  
T Cell ◽  
Protein Kinase ◽  
T Lymphocytes ◽  
T Cell Activation ◽  
Cell Activation ◽  
Phase 1 ◽  
Cross Linking ◽  
Iκb Kinase ◽  
Ikk Complex ◽  
Tcr Activation

ABSTRACT NF-κB is an ubiquitous transcription factor that is a key in the regulation of the immune response and inflammation. T-cell receptor (TCR) cross-linking leads to NF-κB activation, an IκB kinase (IKK)-dependent process. However, the upstream kinases that regulate IKK activity following TCR activation remain to be fully characterized. Herein, we demonstrate using genetic analysis, pharmacological inhibition, and RNA interference (RNAi) that the conventional protein kinase C (PKC) isoform PKCα, but not PKCβ1, is required for the activation of the IKK complex following T-cell activation triggered by CD3/CD28 cross-linking. We find that in the presence of Ca2+ influx, the catalytically active PKCαA25E induces IKK activity and NF-κB-dependent transcription; which is abrogated following the mutations of two aspartates at positions 246 and 248, which are required for Ca2+ binding to PKCα and cell membrane recruitment. Kinetic studies reveal that an early phase (1 to 5 min) of IKK activation following TCR/CD28 cross-linking is PKCα dependent and that a later phase (5 to 25 min) of IKK activation is PKCθ dependent. Activation of IKK- and NF-κB-dependent transcription by PKCαA25E is abrogated by the PKCθ inhibitor rottlerin or the expression of the kinase-inactive form of PKCθ. Taken together, our results suggest that PKCα acts upstream of PKCθ to activate the IKK complex and NF-κB in T lymphocytes following TCR activation.

p38 MAPK Mediates Inhibition of Activation Induced Cell Death in T Lymphocytes Via Upregulation of Bcl-xL and FLIPshort upon Ligation of CD137/4-1BB or CD28.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3320-3320
Author(s):  
Christian Scholz ◽  
Lilian Stärck ◽  
Mario Lehmann ◽  
Bernd Dörken ◽  
Peter T. Daniel
Keyword(s):  
Cell Death ◽  
T Cell ◽  
Protein Kinase ◽  
T Lymphocytes ◽  
Family Member ◽  
P38 Mapk ◽  
T Cell Activation ◽  
Cell Activation ◽  
Activation Induced Cell Death ◽  
Costimulatory Signals

Abstract Costimulation is essential for the induction of proliferation in naive T cells and for the inhibition of activation induced cell death (AICD) in activated T lymphocytes. While costimulatory signals mediated through the immunglobulin family member CD28 play a prominent role during primary T cell activation, ligation of the tumor necrosis factor receptor family member CD137/4-1BB is more important during late primary and secondary T cell activation. Signals mediated through either costimulatory protein block AICD. Inhibition of AICD through ligation of CD137/4-1BB or CD28 involves upregulation of Bcl-xL and FLIPshort (Eur J Immunol 2005, 35: 1257–66). We further demonstrated that costimulatory signals mediated through CD137/4-1BB or CD28 depend on the activity of phosphatidylinositol 3-kinase and AKT/protein kinase B, two kinases that had formerly been implied in CD28-induced signaling, indicating that CD28- and CD137/4-1BB-mediated signals share downstream signaling pathways. Here, we demonstrate that p38 mitogen-activated protein kinase (MAPK) mediates CD137/4-1BB-induced as well as CD28-mediated costimulation of cell proliferation and inhibition of AICD. This coincides with upregulation of Bcl-xL and FLIPshort. Inhibition of p38 MAPK abrogates T cell receptor induced proliferation and antagonizes costimulation mediated survival. Thus, p38 MAPK, which was previously thought to be primarily involved in CD137/4-1BB-mediated signaling, is similarly important for CD28-induced costimulation and survival. This indicates that, while involving different protein families, signal transduction by CD28 and CD137/4-1BB depends on a common upstream and downstream network of survival kinases.

Targeting of T lymphocytes against egf-receptor+ tumor cells by bispecific monoclonal antibodies: Requirement of CD3 molecule cross-linking for t-cell activation

1993 ◽  
Vol 55 (6) ◽  
pp. 931-937 ◽  
Author(s):  
Silvano Ferrini ◽  
Anna Cambiaggi ◽  
Sabrina Sforzini ◽  
Sabrina Marciano ◽  
Silvana Canevari ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
T Cell ◽  
T Lymphocytes ◽  
Tumor Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Egf Receptor ◽  
Cross Linking

scholarly journals Evidence for differential intracellular signaling via CD4 and CD8 molecules.

1994 ◽  
Vol 179 (2) ◽  
pp. 727-732 ◽  
Author(s):  
K S Ravichandran ◽  
S J Burakoff
Keyword(s):  
Protein Kinase C ◽  
T Cell ◽  
Protein Kinase ◽  
T Cell Activation ◽  
Intracellular Signaling ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Kinase Assay ◽  
Cross Linking ◽  
Kinase C

Although both the CD4 and CD8 molecules enhance antigen responsiveness mediated by the T cell receptor (TCR), it is not known whether CD4 and CD8 initiate similar or different intracellular signals when they act as coreceptors. To characterize the early signals transmitted by CD4 and CD8, both CD4 and CD8 alpha were expressed in the same murine T cell hybridoma. In the double positive transfectants, CD4 and CD8 associated with equal amounts of p56lck (Lck), and both molecules enhanced interleukin 2 (IL-2) production equivalently when cross-linked with suboptimal levels of anti-TCR antibody. However, in an in vitro kinase assay, cross-linking CD4 initiated fourfold greater kinase activity compared with CD8 cross-linking. In the same assay, when CD4 or CD8 was cross-linked to the TCR, novel phosphorylated proteins were found associated with the TCR/CD4 complex but not with the TCR/CD8 complex. Consistent with this data, antiphosphotyrosine immunoblotting revealed greater tyrosine phosphorylation of intracellular substrates after TCR/CD4 cross-linking compared with TCR/CD8 cross-linking. Additionally, a specific protein kinase C inhibitor (RO318220) inhibited CD8-mediated enhancement of IL-2 production far more effectively than CD4-mediated enhancement. Thus, it appears that CD8 alpha may depend more on a protein kinase C-mediated signaling pathway, whereas CD4 may rely on greater tyrosine kinase activation. Such differential signaling via CD4 and CD8 has implications for thymic ontogeny and T cell activation.

scholarly journals Protein Kinase C-Mediated Phosphorylation of BCL11B at Serine 2 Negatively Regulates Its Interaction with NuRD Complexes during CD4+T-Cell Activation

2016 ◽  
Vol 36 (13) ◽  
pp. 1881-1898 ◽  
Author(s):  
Marion Dubuissez ◽  
Ingrid Loison ◽  
Sonia Paget ◽  
Han Vorng ◽  
Saliha Ait-Yahia ◽  
...  
Keyword(s):  
T Cells ◽  
Protein Kinase C ◽  
T Cell ◽  
Protein Kinase ◽  
T Cell Activation ◽  
Cell Activation ◽  
Regulatory Protein ◽  
Mitogen Activated Protein Kinase ◽  
Kinase C ◽  
Tcr Activation

The transcription factor BCL11B/CTIP2 is a major regulatory protein implicated in various aspects of development, function and survival of T cells. Mitogen-activated protein kinase (MAPK)-mediated phosphorylation and SUMOylation modulate BCL11B transcriptional activity, switching it from a repressor in naive murine thymocytes to a transcriptional activator in activated thymocytes. Here, we show that BCL11B interacts via its conserved N-terminal MSRRKQ motif with endogenous MTA1 and MTA3 proteins to recruit various NuRD complexes. Furthermore, we demonstrate that protein kinase C (PKC)-mediated phosphorylation of BCL11B Ser2 does not significantly impact BCL11B SUMOylation but negatively regulates NuRD recruitment by dampening the interaction with MTA1 or MTA3 (MTA1/3) and RbAp46 proteins. We detected increased phosphorylation of BCL11B Ser2 uponin vivoactivation of transformed and primary human CD4+T cells. We show that following activation of CD4+T cells, BCL11B still binds toIL-2andId2promoters but activates their transcription by recruiting P300 instead of MTA1. Prolonged stimulation results in the direct transcriptional repression ofBCL11Bby KLF4. Our results unveil Ser2 phosphorylation as a new BCL11B posttranslational modification linking PKC signaling pathway to T-cell receptor (TCR) activation and define a simple model for the functional switch of BCL11B from a transcriptional repressor to an activator during TCR activation of human CD4+T cells.

scholarly journals Non–T Cell Activation Linker (NTAL)

2002 ◽  
Vol 196 (12) ◽  
pp. 1617-1626 ◽  
Author(s):  
Tomáš Brdička ◽  
Martin Imrich ◽  
Pavla Angelisová ◽  
Naděžda Brdičková ◽  
Ondrej Horváth ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
T Cell Activation ◽  
Cell Activation ◽  
Adaptor Protein ◽  
Cell Receptor ◽  
Cross Linking ◽  
Multicomponent Complex ◽  
Transient Elevation

A key molecule necessary for activation of T lymphocytes through their antigen-specific T cell receptor (TCR) is the transmembrane adaptor protein LAT (linker for activation of T cells). Upon TCR engagement, LAT becomes rapidly tyrosine phosphorylated and then serves as a scaffold organizing a multicomponent complex that is indispensable for induction of further downstream steps of the signaling cascade. Here we describe the identification and preliminary characterization of a novel transmembrane adaptor protein that is structurally and evolutionarily related to LAT and is expressed in B lymphocytes, natural killer (NK) cells, monocytes, and mast cells but not in resting T lymphocytes. This novel transmembrane adaptor protein, termed NTAL (non–T cell activation linker) is the product of a previously identified WBSCR5 gene of so far unknown function. NTAL becomes rapidly tyrosine-phosphorylated upon cross-linking of the B cell receptor (BCR) or of high-affinity Fcγ- and Fcε-receptors of myeloid cells and then associates with the cytoplasmic signaling molecules Grb2, Sos1, Gab1, and c-Cbl. NTAL expressed in the LAT-deficient T cell line J.CaM2.5 becomes tyrosine phosphorylated and rescues activation of Erk1/2 and minimal transient elevation of cytoplasmic calcium level upon TCR/CD3 cross-linking. Thus, NTAL appears to be a structural and possibly also functional homologue of LAT in non–T cells.

scholarly journals The Protein Kinase C-Responsive Inhibitory Domain of CARD11 Functions in NF-κB Activation To Regulate the Association of Multiple Signaling Cofactors That Differentially Depend on Bcl10 and MALT1 for Association

2008 ◽  
Vol 28 (18) ◽  
pp. 5668-5686 ◽  
Author(s):  
Ryan R. McCully ◽  
Joel L. Pomerantz
Keyword(s):  
T Cell ◽  
Protein Kinase ◽  
T Cell Activation ◽  
Cell Activation ◽  
Coiled Coil ◽  
Caspase 8 ◽  
Tcr Signaling ◽  
Iκb Kinase ◽  
Inhibitory Domain ◽  
Multiple Signaling

ABSTRACT The activation of NF-κB by T-cell receptor (TCR) signaling is critical for T-cell activation during the adaptive immune response. CARD11 is a multidomain adapter that is required for TCR signaling to the IκB kinase (IKK) complex. During TCR signaling, the region in CARD11 between the coiled-coil and PDZ domains is phosphorylated by protein kinase Cθ (PKCθ) in a required step in NF-κB activation. In this report, we demonstrate that this region functions as an inhibitory domain (ID) that controls the association of CARD11 with multiple signaling cofactors, including Bcl10, TRAF6, TAK1, IKKγ, and caspase-8, through an interaction that requires both the caspase recruitment domain (CARD) and the coiled-coil domain. Consistent with the ID-mediated control of their association, we demonstrate that TRAF6 and caspase-8 associate with CARD11 in T cells in a signal-inducible manner. Using an RNA interference rescue assay, we demonstrate that the CARD, linker 1, coiled-coil, linker 3, SH3, linker 4, and GUK domains are each required for TCR signaling to NF-κB downstream of ID neutralization. Requirements for the CARD, linker 1, and coiled-coil domains in signaling are consistent with their roles in the association of CARD11 with Bcl10, TRAF6, TAK1, caspase-8, and IKKγ. Using Bcl10- and MALT1-deficient cells, we show that CARD11 can recruit signaling cofactors independently of one another in a signal-inducible manner.

scholarly journals Association of tyrosine protein kinase Zap-70 with the protooncogene product p120c-cbl in T lymphocytes.

1996 ◽  
Vol 183 (1) ◽  
pp. 301-306 ◽  
Author(s):  
M Fournel ◽  
D Davidson ◽  
R Weil ◽  
A Veillette
Keyword(s):  
T Cell ◽  
Protein Kinase ◽  
T Lymphocytes ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Receptor ◽  
Activated T Cells ◽  
Activated T Lymphocytes ◽  
Tyrosine Protein Kinase

Accumulating data show that the tyrosine protein kinase Zap-70 plays an essential role in T cell receptor-mediated signal transduction. However, the model of action, as well as the physiologically relevant substrates of Zap-70, have not been determined. We have attempted to identify a 120-kD tyrosine-phosphorylated protein (p120) that associates with Zap-70 in activated T lymphocytes. The results of our analyses showed that p120 is largely encoded by the c-cbl protooncogene. Furthermore, the association of Zap-70 with c-Cbl was shown to be induced by T cell receptor stimulation, implying that it required posttranslational modification of one or both of these products. FynT, but not Lck, also associated with c-Cbl in activated T cells. Finally, using a heterologous system, it was demonstrated that the ability of Zap-70 to cause tyrosine phosphorylation of p120c-cbl was dependent on Lck- or FynT-mediated signals. As c-Cbl can associate with several other signaling molecules, it may couple Zap-70 to downstream effectors during T cell activation.

scholarly journals Differential regulation of T cell antigen responsiveness by isoforms of the src-related tyrosine protein kinase p59fyn.

1992 ◽  
Vol 175 (6) ◽  
pp. 1483-1492 ◽  
Author(s):  
D Davidson ◽  
L M Chow ◽  
M Fournel ◽  
A Veillette
Keyword(s):  
T Cell ◽  
Protein Kinase ◽  
T Lymphocytes ◽  
T Cell Activation ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Lymphocyte Activation ◽  
Cell Receptor ◽  
Kinase Domain ◽  
Tyrosine Protein Kinase

Recent observations suggest that the src-related tyrosine protein kinase p59fyn may be involved in antigen-induced T lymphocyte activation. As a result of alternative splicing, p59fyn exists as two isoforms that differ exclusively within a short sequence spanning the end of the Src Homology 2 (SH2) region and the beginning of the tyrosine protein kinase domain. While one p59fyn isoform (fynB) is highly expressed in brain, the alternative product (fynT) is principally found in T lymphocytes. To further understand the role of p59fyn in T cell activation and to test the hypothesis that p59fynT serves a tissue-specific function in T lymphocytes, we have examined the effects of expression of activated versions (tyrosine 528 to phenylalanine 528 mutants) of either form of p59fyn on the physiology of an antigen-specific mouse T cell hybridoma. Our results demonstrated that the two forms of fyn, expressed in equivalent amounts, efficiently enhanced antibody-induced T cell receptor (TCR)-mediated signals. In contrast, only p59fynT increased interleukin 2 production in response to antigen stimulation. This finding implies that the distinct p59fyn isoform expressed in T lymphocytes regulates the coupling of TCR stimulation by antigen/major histocompatibility complex to lymphokine production.

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