scholarly journals Dissociation of Intracellular Signaling Pathways in Response to Partial Agonist Ligands of the T Cell Receptor

1998 ◽  
Vol 187 (10) ◽  
pp. 1699-1709 ◽  
Author(s):  
Luan A. Chau ◽  
Jeffrey A. Bluestone ◽  
Joaquín Madrenas
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Intracellular Signaling ◽  
Mapk Pathway ◽  
Partial Agonist ◽  
Cell Receptor ◽  
Mitogen Activated Protein Kinase ◽  
Mapk Activation ◽  
Partial Agonists ◽  
Mitogen Activated Protein

The T cell receptor (TCR) is a versatile receptor able to generate different signals that result in distinct T cell responses. The pattern of early signals is determined by the TCR binding kinetics that control the ability of the ligand to coengage TCR and coreceptor. Coengagement of TCR and CD4 results in an agonist signaling pattern with complete tyrosine phosphorylation of TCR subunits, and recruitment and activation of ZAP-70. In contrast, TCR engagement without CD4 coengagement causes a partial agonist type of signaling, characterized by distinct phosphorylation of TCR subunits and recruitment but no activation of ZAP-70. The pathways triggered by partial agonist signaling are unknown. Here, we show that agonists cause association of active lck and active ZAP-70 with p120-GTPase–activating protein (p120-GAP). These associations follow engagement of CD4 or CD3, respectively. In contrast, partial agonists do not activate lck or ZAP-70, but induce association of p120-GAP with inactive ZAP-70. Despite these differences, both agonist and partial agonist signals activate the mitogen-activated protein kinase (MAPK) pathway. However, MAPK activation by partial agonists is transient, supporting a kinetic, CD4-dependent model for the mechanism of action of variant TCR ligands. Transient MAPK activation may explain some of the responses to TCR partial agonists and antagonists.

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 Positive and negative selection invoke distinct signaling pathways.

1996 ◽  
Vol 184 (1) ◽  
pp. 9-18 ◽  
Author(s):  
J Alberola-Ila ◽  
K A Hogquist ◽  
K A Swan ◽  
M J Bevan ◽  
R M Perlmutter
Keyword(s):  
T Cell ◽  
Positive Selection ◽  
Negative Selection ◽  
Mapk Pathway ◽  
Cell Receptor ◽  
Dominant Negative ◽  
Mapk Cascade ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein

During T cell development, interaction of the T cell receptor (TCR) with cognate ligands in the thymus may result in either maturation (positive selection) or death (negative selection). The intracellular pathways that control these opposed outcomes are not well characterized. We have generated mice expressing dominant-negative Ras (dnRas) and Mek-1 (dMek) transgenes simultaneously, either in otherwise normal animals, or in animals expressing a transgenic TCR, thereby permitting a comprehensive analysis of peptide-specific selection. In this system, thymocyte maturation beyond the CD4+8+ stage is blocked almost completely, whereas negative selection, assessed using an in vitro deletion protocol, is quantitatively intact. This suggests that activation of the mitogen-activated protein kinase (MAPK) cascade is necessary for positive selection, but irrelevant for negative selection. Generation of gamma/delta and of CD4-8- alpha/beta T cells proceeds normally despite blockade of the MAPK cascade. Hence, only cells that mature via conventional, TCR-mediated repertoire selection require activation of the MAPK pathway to complete their maturation.

scholarly journals The Phosphotyrosine Phosphatase SHP-2 Participates in a Multimeric Signaling Complex and Regulates T Cell Receptor (TCR) coupling to the Ras/Mitogen-activated Protein Kinase (MAPK) Pathway in Jurkat T Cells

1998 ◽  
Vol 187 (9) ◽  
pp. 1417-1426 ◽  
Author(s):  
Julie A. Frearson ◽  
Denis R. Alexander
Keyword(s):  
T Cells ◽  
Protein Kinase ◽  
Tyrosine Phosphorylation ◽  
T Cell Receptor ◽  
Mapk Pathway ◽  
Cell Receptor ◽  
Mitogen Activated Protein Kinase ◽  
Wild Type ◽  
Jurkat T Cells ◽  
Mitogen Activated Protein

Src homology 2 (SH2) domain–containing phosphotyrosine phosphatases (SHPs) are increasingly being shown to play critical roles in protein tyrosine kinase–mediated signaling pathways. The role of SHP-1 as a negative regulator of T cell receptor (TCR) signaling has been established. To further explore the function of the other member of this family, SHP-2, in TCR-mediated events, a catalytically inactive mutant SHP-2 was expressed under an inducible promoter in Jurkat T cells. Expression of the mutant phosphatase significantly inhibited TCR-induced activation of the extracellular-regulated kinase (ERK)-2 member of the mitogen-activated protein kinase (MAPK) family, but had no effect on TCR-ζ chain tyrosine phosphorylation or TCR-elicited Ca2+ transients. Inactive SHP-2 was targeted to membranes resulting in the selective increase in tyrosine phosphorylation of three membrane-associated candidate SHP-2 substrates of 110 kD, 55-60 kD, and 36 kD, respectively. Analysis of immunoprecipitates containing inactive SHP-2 also indicated that the 110-kD and 36-kD Grb-2–associated proteins were putative substrates for SHP-2. TCR-stimulation of Jurkat T cells expressing wild-type SHP-2 resulted in the formation of a multimeric cytosolic complex composed of SHP-2, Grb-2, phosphatidylinositol (PI) 3′-kinase, and p110. A significant proportion of this complex was shown to be membrane associated, presumably as a result of translocation from the cytosol. Catalytically inactive SHP-2, rather than the wild-type PTPase, was preferentially localized in complex with Grb-2 and the p85 subunit of PI 3′-kinase, suggesting that the dephosphorylating actions of SHP-2 may regulate the association of these signaling molecules to the p110 complex. Our results show that SHP-2 plays a critical role in linking the TCR to the Ras/MAPK pathway in Jurkat T cells, and also provide some insight into the molecular interactions of SHP-2 that form the basis of this signal transduction process.

scholarly journals A Role for Neutral Sphingomyelinase-mediated Ceramide Production in T Cell Receptor–induced Apoptosis and Mitogen-activated Protein Kinase–mediated Signal Transduction

1999 ◽  
Vol 189 (10) ◽  
pp. 1581-1589 ◽  
Author(s):  
Laura Tonnetti ◽  
Maria-Concetta Verí ◽  
Ezio Bonvini ◽  
Luciano D'Adamio
Keyword(s):  
T Cell ◽  
Protein Kinase ◽  
T Cell Receptor ◽  
Fumonisin B1 ◽  
Cell Receptor ◽  
Mitogen Activated Protein Kinase ◽  
Tcr Signaling ◽  
Neutral Sphingomyelinase ◽  
Mitogen Activated Protein ◽  
Ceramide Production

Studying apoptosis induced by T cell receptor (TCR) cross-linking in the T cell hybridoma, 3DO, we found both neutral sphingomyelinase activation and production of ceramide upon receptor engagement. Pharmacological inhibition of ceramide production by the fungal toxin, fumonisin B1, impaired TCR-induced interleukin (IL)-2 production and programmed cell death. Addition of either exogenous ceramide or bacterial sphingomyelinase reconstituted both responses. Moreover, specific inactivation of neutral sphingomyelinase by antisense RNA inhibited IL-2 production and mitogen-activated protein kinase activation after TCR triggering. These results suggest that ceramide production by activation of neutral sphingomyelinase is an essential component of the TCR signaling machinery.

scholarly journals Lck Regulates the Threshold of Activation in Primary T Cells, While both Lck and Fyn Contribute to the Magnitude of the Extracellular Signal-Related Kinase Response

2006 ◽  
Vol 26 (22) ◽  
pp. 8655-8665 ◽  
Author(s):  
Matthew Lovatt ◽  
Andrew Filby ◽  
Valentino Parravicini ◽  
Guy Werlen ◽  
Ed Palmer ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Protein Kinase ◽  
Mapk Pathway ◽  
Cell Receptor ◽  
Mitogen Activated Protein Kinase ◽  
Differentiation Potential ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Proximal Signaling

ABSTRACT The src family kinases p56lck (Lck) and p59fyn (Fyn) are the most proximal signaling molecules to be activated downstream of the T-cell receptor. Using an inducible transgenic model, we can regulate the expression of Lck in primary T cells and ask how the signaling cascade and differentiation potential are affected by the absence or the presence of reduced levels of Lck. We show that in naïve T cells, Lck controls the threshold of activation by preferentially regulating multiple signaling pathways that result in the mobilization of Ca2+ through activation of phospholipase C-gamma and protein kinase C as well as activation of the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway. Fyn is also able to stimulate the ERK/MAPK pathway in primary T cells but has little influence on the mobilization of Ca2+. Only Lck efficiently stimulates production of diacylglycerol and therefore RasGRP1 recruitment to the plasma membrane and phosphorylation of Shc, suggesting that Fyn activates ERK via a different upstream signaling route. Finally, we show that signals through Lck are essential for the development of T-cell-effector potential, particularly for effective cytokine transcription.

scholarly journals T-cell receptor early signalling complex activation in response to interferon-α receptor stimulation

2010 ◽  
Vol 428 (3) ◽  
pp. 429-437 ◽  
Author(s):  
Claire N. Stevens ◽  
Ann-Marie Simeone ◽  
Susan John ◽  
Zamal Ahmed ◽  
Orso M. Lucherini ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Mapk Pathway ◽  
Transcriptional Response ◽  
Cell Receptor ◽  
Janus Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Interferon Α ◽  
Mapk Activity ◽  
Stimulation Of

Signalling through the IFNαR (interferon-α receptor) and TCR (T-cell receptor) in Jurkat T lymphocytes results in distinct immune responses. Despite this both receptors elicit ERK (extracellular-signal-regulated kinase)/MAPK (mitogen-activated protein kinase) phosphorylation. Vav and Slp76 are shown to be required for IFNα (interferon-α)-stimulated ERK activity. These form a subset of proteins which behave identically on stimulation of both receptors. TCR deletion abrogates IFNαR-stimulated MAPK activity, whereas the canonical JAK/STAT (Janus kinase/signal transducer and activator of transcription) pathway is unaffected. Thus recruitment of the intact TCR ESC (early signalling complex) is necessary for this downstream MAPK response. Despite using a common ESC, stimulation of the IFNαR does not produce the transcriptional response associated with TCR. Up-regulation of the MAPK pathway by IFNαR might be important to ensure that the cell responds to only one stimulant.

scholarly journals T cell receptor zeta/CD3-p59fyn(T)-associated p120/130 binds to the SH2 domain of p59fyn(T).

1993 ◽  
Vol 178 (6) ◽  
pp. 2107-2113 ◽  
Author(s):  
A J da Silva ◽  
O Janssen ◽  
C E Rudd
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Intracellular Signaling ◽  
Cell Activation ◽  
Cell Receptor ◽  
Sh2 Domain ◽  
T Complex

Intracellular signaling from the T cell receptor (TCR)zeta/CD3 complex is likely to be mediated by associated protein tyrosine kinases such as p59fyn(T), ZAP-70, and the CD4:p56lck and CD8:p56lck coreceptors. The nature of the signaling cascade initiated by these kinases, their specificities, and downstream targets remain to be elucidated. The TCR-zeta/CD3:p59fyn(T) complex has previously been noted to coprecipitate a 120/130-kD doublet (p120/130). This intracellular protein of unknown identity associates directly with p59fyn(T) within the receptor complex. In this study, we have shown that this interaction with p120/130 is specifically mediated by the SH2 domain (not the fyn-SH3 domain) of p59fyn(T). Further, based on the results of in vitro kinase assays, p120/130 appears to be preferentially associated with p59fyn(T) in T cells, and not with p56lck. Antibody reprecipitation studies identified p120/130 as a previously described 130-kD substrate of pp60v-src whose function and structure is unknown. TCR-zeta/CD3 induced activation of T cells augmented the tyrosine phosphorylation of p120/130 in vivo as detected by antibody and GST:fyn-SH2 fusion proteins. p120/130 represents the first identified p59fyn(T):SH2 binding substrate in T cells, and as such is likely to play a key role in the early events of T cell activation.

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