scholarly journals KSR1 Modulates the Sensitivity of Mitogen-Activated Protein Kinase Pathway Activation in T Cells without Altering Fundamental System Outputs

2009 ◽  
Vol 29 (8) ◽  
pp. 2082-2091 ◽  
Author(s):  
Joseph Lin ◽  
Angus Harding ◽  
Emanuele Giurisato ◽  
Andrey S. Shaw
Keyword(s):  
T Cells ◽  
T Cell ◽  
Protein Kinase ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Mapk Activation ◽  
Cell Fate Decisions ◽  
Mapk Cascades ◽  
Wide Range ◽  
Mitogen Activated Protein

ABSTRACT Mitogen-activated protein kinase (MAPK) cascades are evolutionarily conserved signaling pathways that regulate cell fate decisions. They generate a wide range of signal outputs, including graded and digital responses. In T cells, MAPK activation is digital in response to T-cell-receptor stimulation; however, whether other receptors on T cells that lead to MAPK activation are graded or digital is unknown. Here we evaluate MAPK activation in T cells at the single-cell level. We show that T cells responded digitally to stimulation with superantigen-loaded antigen-presenting cells, whereas they responded in a graded manner to the chemokine SDF-1, demonstrating that the system output of the MAPK module is highly plastic and determined by components upstream of the MAPK module. These findings also confirm that different MAPK system outputs are used by T cells to control discrete biological functions. Scaffold proteins are essential for proper MAPK signaling and function as they physically assemble multiple components and regulators of MAPK cascades. We found that the scaffold protein KSR1 regulated the threshold required for MAPK activation in T cells without affecting the nature of the response. We conclude that KSR1 plays a central role in determining the sensitivity of T-cell responses and is thus well positioned as a key control point.

scholarly journals Mitogen-Activated Protein Kinase Inhibitors and T-Cell-Dependent Immunotherapy in Cancer

2020 ◽  
Vol 13 (1) ◽  
pp. 9 ◽  
Author(s):  
Sandeep Kumar ◽  
Daniel R. Principe ◽  
Sunil Kumar Singh ◽  
Navin Viswakarma ◽  
Gautam Sondarva ◽  
...  
Keyword(s):  
T Cell ◽  
Protein Kinase ◽  
Tumor Cells ◽  
Cell Biology ◽  
Kinase Inhibitors ◽  
Mapk Signaling ◽  
Protein Kinase Inhibitors ◽  
Mitogen Activated Protein Kinase ◽  
Wide Range ◽  
Mitogen Activated Protein

Mitogen-activated protein kinase (MAPK) signaling networks serve to regulate a wide range of physiologic and cancer-associated cell processes. For instance, a variety of oncogenic mutations often lead to hyperactivation of MAPK signaling, thereby enhancing tumor cell proliferation and disease progression. As such, several components of the MAPK signaling network have been proposed as viable targets for cancer therapy. However, the contributions of MAPK signaling extend well beyond the tumor cells, and several MAPK effectors have been identified as key mediators of the tumor microenvironment (TME), particularly with respect to the local immune infiltrate. In fact, a blockade of various MAPK signals has been suggested to fundamentally alter the interaction between tumor cells and T lymphocytes and have been suggested a potential adjuvant to immune checkpoint inhibition in the clinic. Therefore, in this review article, we discuss the various mechanisms through which MAPK family members contribute to T-cell biology, as well as circumstances in which MAPK inhibition may potentiate or limit cancer immunotherapy.

scholarly journals APPL1 mediates adiponectin-stimulated p38 MAPK activation by scaffolding the TAK1-MKK3-p38 MAPK pathway

2011 ◽  
Vol 300 (1) ◽  
pp. E103-E110 ◽  
Author(s):  
Xiaoban Xin ◽  
Lijun Zhou ◽  
Caleb M. Reyes ◽  
Feng Liu ◽  
Lily Q. Dong
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Mapk Pathway ◽  
Adaptor Protein ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Scaffolding Protein ◽  
Mapk Activation ◽  
P38 Mapk Pathway ◽  
Mitogen Activated Protein

The adaptor protein APPL1 mediates the stimulatory effect of adiponectin on p38 mitogen-activated protein kinase (MAPK) signaling, yet the underlying mechanism remains unclear. Here we show that, in C2C12 cells, overexpression or suppression of APPL1 enhanced or suppressed, respectively, adiponectin-stimulated p38 MAPK upstream kinase cascade, consisting of transforming growth factor-β-activated kinase 1 (TAK1) and mitogen-activated protein kinase kinase 3 (MKK3). In vitro affinity binding and coimmunoprecipitation experiments revealed that TAK1 and MKK3 bind to different regions of APPL1, suggesting that APPL1 functions as a scaffolding protein to facilitate adiponectin-stimulated p38 MAPK activation. Interestingly, suppressing APPL1 had no effect on TNFα-stimulated p38 MAPK phosphorylation in C2C12 myotubes, indicating that the stimulatory effect of APPL1 on p38 MAPK activation is selective. Taken together, our study demonstrated that the TAK1-MKK3 cascade mediates adiponectin signaling and uncovers a scaffolding role of APPL1 in regulating the TAK1-MKK3-p38 MAPK pathway, specifically in response to adiponectin stimulation.

scholarly journals Estrogen Receptor (ER)α and ERβ Exhibit Unique Pharmacologic Properties When Coupled to Activation of the Mitogen-Activated Protein Kinase Pathway*

Endocrinology ◽  
2001 ◽  
Vol 142 (6) ◽  
pp. 2336-2342 ◽  
Author(s):  
Christian B. Wade ◽  
Siobhan Robinson ◽  
Robert A. Shapiro ◽  
Daniel M. Dorsa
Keyword(s):  
Protein Kinase ◽  
Mapk Signaling ◽  
Model System ◽  
Mitogen Activated Protein Kinase ◽  
Mapk Activation ◽  
Transfected Cells ◽  
Ici 182,780 ◽  
Mediated Effects ◽  
Estrogen Response ◽  
Mitogen Activated Protein

Abstract The rapid, nongenomic effects of estrogen are increasingly recognized as playing an important role in several aspects of estrogen action. Rapid activation of the mitogen-activated protein kinase (MAPK) signaling pathway by estrogen is among the more recently identified of these effects. To explore the role of estrogen receptors (ERs) in mediating these effects, we have transfected ER-negative Rat-2 fibroblasts with complementary DNA clones encoding either human ERα or rat ERβ and examined their ability to couple to activation of MAPK in response to 17β-estradiol (17β-E2) and other ligands. For both receptors, addition of E2 resulted in a rapid phosphorylation of MAPK. Activation of MAPK in ERα-transfected cells was partially and completely blocked by the antiestrogens tamoxifen and ICI 182,780, respectively. In ERβ-transfected cells, MAPK activation was less sensitive to inhibition by tamoxifen and ICI 182,780. We have also observed that, in this model system, a membrane-impermeable estrogen (BSA-E2) and 17α-E2 were both able to activate MAPK in a manner similar to E2 alone. Here also, ICI 182,780 blocked the ability of BSA-E2 to activate MAPK through ERα, but failed to block ERβ-mediated effects. BSA-E2 treatment, however, failed to activate nuclear estrogen-response-element-mediated gene transcription. These data show that these nuclear ERs are necessary for estrogen’s effects at the membrane. This model system will be useful in identifying molecular interactions involved in the rapid effects mediated by the ERs.

Role of nuclear factor κB and mitogen-activated protein kinase signaling in exercise-induced antioxidant enzyme adaptation

2007 ◽  
Vol 32 (5) ◽  
pp. 930-935 ◽  
Author(s):  
Li Li Ji ◽  
Maria-Carmen Gomez-Cabrera ◽  
Jose Vina
Keyword(s):  
Protein Kinase ◽  
Nuclear Factor Κb ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Ros Generation ◽  
Nuclear Factor ◽  
Adaptive Responses ◽  
Wide Range ◽  
Mitogen Activated Protein ◽  
Exercise Induced

Activation of nuclear factor (NF) κB and mitogen-activated protein kinase (MAPK) pathways in skeletal muscle has been shown to enhance the gene expression of several enzymes that play an important role in maintaining oxidant–antioxidant homeostasis, such as mitochondrial superoxide dismutase (MnSOD) and inducible nitric oxide synthase (iNOS). While an acute bout of exercise activates NFκB and MAPK signaling and upregulates MnSOD and iNOS, administration of chemical agents that suppress reactive oxygen species (ROS) production can cause attenuation of exercise-induced MnSOD and iNOS expression. Thus, ROS generation during exercise may have duel effects: the infliction of oxidative stress and damage, and the stimulation of adaptive responses favoring long-term protection. This scenario explains why animals and humans involved in exercise training have demonstrated increased resistance to oxidative damage under a wide range of physiological and pathological stresses.

scholarly journals Regulation of FAS Ligand Expression during Activation-Induced Cell Death in T Cells by p38 Mitogen-Activated Protein Kinase and C-Jun Nh2-Terminal Kinase

2000 ◽  
Vol 191 (6) ◽  
pp. 1017-1030 ◽  
Author(s):  
Jian Zhang ◽  
Jian-Xin Gao ◽  
Kostantin Salojin ◽  
Qing Shao ◽  
Marsha Grattan ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Protein Kinase ◽  
P38 Mapk ◽  
Fas Ligand ◽  
Mitogen Activated Protein Kinase ◽  
Fasl Expression ◽  
Activation Induced Cell Death ◽  
Mitogen Activated Protein

Activation-induced cell death (AICD) is a mechanism of peripheral T cell tolerance that depends upon an interaction between Fas and Fas ligand (FasL). Although c-Jun NH2-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) may be involved in apoptosis in various cell types, the mode of regulation of FasL expression during AICD in T cells by these two MAPKs is incompletely understood. To investigate the regulatory roles of these two MAPKs, we analyzed the kinetics of TCR-induced p38 MAPK and JNK activity and their regulation of FasL expression and AICD. We report that both JNK and p38 MAPK regulate AICD in T cells. Our data suggest a novel model of T cell AICD in which p38 MAPK acts early to initiate FasL expression and the Fas-mediated activation of caspases. Subsequently, caspases stimulate JNK to further upregulate FasL expression. Thus, p38 MAPK and downstream JNK converge to regulate FasL expression at different times after T cell receptor stimulation to elicit maximum AICD.

scholarly journals The Repertoire of Fos and Jun Proteins Expressed during the G1 Phase of the Cell Cycle Is Determined by the Duration of Mitogen-Activated Protein Kinase Activation

1999 ◽  
Vol 19 (1) ◽  
pp. 330-341 ◽  
Author(s):  
Simon J. Cook ◽  
Natasha Aziz ◽  
Martin McMahon
Keyword(s):  
Protein Kinase ◽  
Cell Fate ◽  
Active Form ◽  
Mapk Cascade ◽  
Mitogen Activated Protein Kinase ◽  
Mapk Activation ◽  
Cell Fate Decisions ◽  
Mitogen Activated Protein ◽  
Early Expression ◽  
Fos Expression

ABSTRACT In Rat-1 fibroblasts nonmitogenic doses of lysophosphatidic acid (LPA) stimulate a transient activation of mitogen-activated protein kinase (MAPK), whereas mitogenic doses elicit a sustained response. This sustained phase of MAPK activation regulates cell fate decisions such as proliferation or differentiation, presumably by inducing a program of gene expression which is not observed in response to transient MAPK activation. We have examined the expression of members of the AP-1 transcription factor complex in response to stimulation with different doses of LPA. c-Fos, c-Jun, and JunB are induced rapidly in response to LPA stimulation, whereas Fra-1 and Fra-2 are induced after a significant lag. The expression of c-Fos is transient, whereas the expression of c-Jun, JunB, Fra-1, and Fra-2 is sustained. The early expression of c-Fos can be reconstituted with nonmitogenic doses of LPA, but the response is transient compared to that observed with mitogenic doses. In contrast, expression of Fra-1, Fra-2, and JunB and optimal expression of c-Jun are observed only with doses of LPA which induce sustained MAPK activation and DNA synthesis. LPA-stimulated expression of c-Fos, Fra-1, Fra-2, c-Jun, and JunB is inhibited by the MEK1 inhibitor PD098059, indicating that the Raf-MEK-MAPK cascade is required for their expression. In cells expressing a conditionally active form of Raf-1 (ΔRaf-1:ER), we observed that selective, sustained activation of Raf-MEK-MAPK was sufficient to induce expression of Fra-1, Fra-2, and JunB but, interestingly, induced little or no c-Fos or c-Jun. The induction of c-Fos observed in response to LPA was strongly inhibited by buffering the intracellular [Ca2+]. Moreover, although Raf activation or calcium ionophores induced little c-Fos expression, we observed a synergistic induction in response to the combination of ΔRaf-1:ER and ionomycin. These results suggest that kinetically distinct phases of MAPK activation serve to regulate the expression of distinct AP-1 components such that sustained MAPK activation is required for the induced expression of Fra-1, Fra-2, c-Jun, and JunB. However, in contrast to the case for Fra-1, Fra-2, and JunB, activation of the MAPK cascade alone is not sufficient to induce c-Fos expression, which rather requires cooperation with other signals such as Ca2+mobilization. Finally, the identification of the Fra-1, Fra-2, c-Jun, and JunB genes as genes which are selectively regulated by sustained MAPK activation or in response to activated Raf suggests that they are candidates to mediate certain of the effects of Ras proteins in oncogenic transformation.

scholarly journals Graded Mitogen-Activated Protein Kinase Activity Precedes Switch-Like c-Fos Induction in Mammalian Cells

2005 ◽  
Vol 25 (11) ◽  
pp. 4676-4682 ◽  
Author(s):  
Jeffrey P. MacKeigan ◽  
Leon O. Murphy ◽  
Christopher A. Dimitri ◽  
John Blenis
Keyword(s):  
Protein Kinase ◽  
Cell Fate ◽  
Oocyte Maturation ◽  
Mammalian Cells ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Cell Fate Decisions ◽  
Graded Response ◽  
Mitogen Activated Protein

ABSTRACT The mitogen-activated protein kinase (MAPK) pathway is an evolutionarily conserved signaling module that controls important cell fate decisions in a variety of physiological contexts. During Xenopus oocyte maturation, the MAPK cascade converts an increasing progesterone stimulus into a switch-like, all-or-nothing response. While the importance of such switch-like behavior is widely discussed in the literature, it is not known whether the MAPK pathway in mammalian cells exhibits a switch-like or graded response. For this study, we used flow cytometry and immunofluorescence to generate single-cell measurements of MAPK signaling in Swiss 3T3 fibroblasts. In contrast to the case in Xenopus oocytes, we found that ERK activation in individual mammalian cells is not ultrasensitive and shows a graded response to changes in agonist concentration. Thus, the conserved MAPK signaling module exhibits different systems-level properties in different cellular contexts. Furthermore, the graded ERK response was converted into a more switch-like behavior at the level of immediate-early gene induction and cell cycle progression. Thus, while MAPK signaling is involved in all-or-nothing cell fate decisions for both Xenopus oocyte maturation and mammalian fibroblast proliferation, the underlying mechanisms responsible for the switch-like nature of the cellular responses are different in these two systems, with the mechanism appearing to lie downstream of the kinase cascade in mammalian fibroblasts.

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 Selective Regulation of c-jun Gene Expression by Mitogen-Activated Protein Kinases via the 12-O-Tetradecanoylphorbol-13-Acetate- Responsive Element and Myocyte Enhancer Factor 2 Binding Sites

2005 ◽  
Vol 25 (9) ◽  
pp. 3784-3792 ◽  
Author(s):  
Midori Kayahara ◽  
Xin Wang ◽  
Cathy Tournier
Keyword(s):  
Gene Expression ◽  
Protein Kinase ◽  
Cell Fate ◽  
P38 Mapk ◽  
Physiological Role ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Mapk Cascades ◽  
Mitogen Activated Protein

ABSTRACT To further understand how the mitogen-activated protein kinase (MAPK) signaling pathways regulate AP-1 activity, we have elucidated the physiological role of these cascades in the regulation of c-jun gene expression. c-Jun is a crucial component of AP-1 complexes and has been shown in vitro to be a point of integration of numerous signals that can differentially affect its expression as well as its transcriptional activity. Our strategy was based on the use of (i) genetically modified fibroblasts deficient in components of the MAPK cascades and (ii) pharmacological reagents. The results demonstrate that c-Jun NH2-terminal protein kinase (JNK) is essential for a basal level of c-Jun expression and for c-Jun phosphorylation in response to stress. In addition to JNK, p38 MAPK or ERK1/2 and ERK5 are required for mediating UV radiation- or epidermal growth factor (EGF)-induced c-Jun expression, respectively. Further studies indicate that p38 MAPK inhibits the activation of JNK in response to EGF, causing a down-regulation of c-Jun. Overall, these data provide important insights into the mechanisms that ultimately determine the function of c-Jun as a regulator of cell fate.

scholarly journals Diketoacetonylphenalenone, Derived from Hawaiian Volcanic Soil-Associated Fungus Penicillium herquei FT729, Regulates T Cell Activation via Nuclear Factor-κB and Mitogen-Activated Protein Kinase Pathway

Molecules ◽  
2020 ◽  
Vol 25 (22) ◽  
pp. 5374
Author(s):  
Hyun-Su Lee ◽  
Jae Sik Yu ◽  
Ki Hyun Kim ◽  
Gil-Saeng Jeong
Keyword(s):  
T Cells ◽  
T Cell ◽  
Protein Kinase ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Activity ◽  
Mitogen Activated Protein Kinase ◽  
Volcanic Soil ◽  
Activated T Cells ◽  
Mitogen Activated Protein

In immunological responses, controlling excessive T cell activity is critical for immunological homeostasis maintenance. Diketoacetonylphenalenone, derived from Hawaiian volcanic soil-associated fungus Penicillium herquei FT729, possesses moderate anti-inflammatory activity in RAW 264.7 cells but its immunosuppressive effect on T cell activation is unknown. In the present study, diketoacetonylphenalenone (up to 40 μM) did not show cytotoxicity in T cells. Western blot analysis showed treatment with diketoacetonylphenalenone did not alter the expression of anti-apoptotic proteins. Pretreatment with diketoacetonylphenalenone suppressed the interleukin-2 production in activated T cells induced by T cell receptor-mediated stimulation and PMA/A23187. The CFSE-proliferation assay revealed the inhibitory effect of diketoacetonylphenalenone on the proliferation of T cells. The expression of surface molecules on activated T cells was also reduced. We discovered the suppression of the TAK1-IKKα-NF-κB pathway by pretreatment with diketoacetonylphenalenone abrogated mitogen-activated protein kinase (MAPK) signaling in activated T cells. These results suggest that diketoacetonylphenalenone effectively downregulates T cell activity via the MAPK pathway and provides insight into the therapeutic potential of immunosuppressive reagents.

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