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Mechanical stress activates protein kinase cascade of phosphorylation in neonatal rat cardiac myocytes

Mechanical stress activates protein kinase cascade of phosphorylation in neonatal rat cardiac myocytes

We have previously shown that stretching cardiac myocytes evokes activation of protein kinase C (PKC), mitogen-activated protein kinases (MAPKs), and 90-kD ribosomal S6 kinase (p90rsk). To clarify the signal transduction pathways from external mechanical stress to nuclear gene expression in stretch-induced cardiac hypertrophy, we have elucidated protein kinase cascade of phosphorylation by examining the time course of activation of MAP kinase kinase kinases (MAPKKKs), MAP kinase kinase (MAPKK), MAPKs, and p90rsk in neonatal rat cardiac myocytes. Mechanical stretch transiently increased the activity of MAPKKKs. An increase in MAPKKKs activity was first detected at 1 min and maximal activation was observed at 2 min after stretch. The activity of MAPKK was
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The GRIK-SnRK1 Kinase Cascade: Characterizing Phosphorylation of TCP Transcription Factors and Motifs in Arabidopsis Proteins.

The GRIK-SnRK1 Kinase Cascade: Characterizing Phosphorylation of TCP Transcription Factors and Motifs in Arabidopsis Proteins.

The GRIK-SnRK1 Kinase Cascade: Characterizing Phosphorylation of TCP Transcription Factors and Motifs in Arabidopsis Proteins.. (Under the direction of Drs. Goshe and Linda Hanley-Bowd[r]

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Protein-protein interactions in the yeast pheromone response pathway: Ste5p interacts with all members of the MAP kinase cascade.

Protein-protein interactions in the yeast pheromone response pathway: Ste5p interacts with all members of the MAP kinase cascade.

Interaction between Ste5p and members of the MAP kinase cascade: The finding that Ste5p interacts with Stel l p , Ste7p and Fus3p suggests that one role of Ste5p in [r]

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The calcium/calmodulin regulated kinase cascade in learning and memory

The calcium/calmodulin regulated kinase cascade in learning and memory

A prelim inary study revealed reduced S e ri33 phosphorylation o f CREB after spatial learning in the water maze. In this study a single male mutant and WT control only were analysed and the results have to be considered carefully. M ore mutants and controls need to be studied and the results need to be quantified by densiometry. However, it should be noted that activation o f CREB in comparison to WT littermates was also impaired in two further male mutants trained and analysed by Keiko Mizuno, suggesting that activation o f CREB after spatial learning is impaired in Camkk2 null m utant males. S e ri33 phosphorylation o f CREB is required for CREB mediated transcription. Hence, activation o f CREB mediated transcription is expected to be impaired in the null mutants. Hence, CaMKK(3 functions as a CREB kinase in spatial LTM formation in vivo. However, CREB is most likely not to be the only transcription factor activated by CaM KKp. In particular, the CaM kinase cascade has been shown to activate the transcriptional co-activator CBP (Chawla et al., 1998; Impey et al., 2002). In neurons, CBP also works as a transcriptional co-activator to other transcription factors, for example cJun (Hardingham et al., 1999). Thus, the impact o f the null mutation on neuronal gene expression is likely to be far more complex than expected from interference with activation o f CREB only.
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Rho kinase cascade activation in circulating leukocytes in patients with diabetes mellitus type 2

Rho kinase cascade activation in circulating leukocytes in patients with diabetes mellitus type 2

target subunit 1 (anti-MYPT-1 antibody, rabbit poly- clonal, 1/500 cell signaling, Cat 2634); anti-p-MYPT-1 antibody (phospho-MYPT1-Thr 853 rabbit polyclonal, 1/500, cyclex, Cat CY-P1025) [14, 16]; anti ezrin, radixin, moesin (anti-ERM antibody, total-ERM, rabbit poly- clonal, 1/700, Cell Signaling, Cat 3142); anti-p-ERM antibody (phospho-ERM, ezrin Thr567, radixin Thr564, moesin Thr558, rabbit polyclonal, 1/700, Cell Signal- ing, Cat 3141); anti p-38 mitogen-activated protein kinase (anti-p38 MAPK antibody, p-38, rabbit poly- clonal, 1/1000, Cell Signaling, Cat 9212); anti-phospho- p38 MAPK antibody (Thr180/Tyr182) (phospho-p-38, rabbit monoclonal, 1/1000, Cell Signaling, Cat 4511); anti-ROCK-1 antibody (mouse monoclonal, 1/500, BD Bioscience, Cat 611136); anti-ROCK-2 antibody (mouse monoclonal, 1/2000, BD Bioscience, Cat 610623); anti- p65 nuclear factor κB antibody (NFκB, rabbit polyclonal, 1/1000, Cell Signaling, Cat 8242); anti-vascular cell adhe- sion molecule 1 antibody (VCAM-1, goat polyclonal, 1/1000, Santa Cruz, Cat sc1504); anti-intracellular adhe- sion molecule 1 antibody (ICAM-1, mouse monoclo- nal, 1/1000, Santa Cruz, Cat sc8439); anti-interleukin 6 antibody (IL-6, rabbit polyclonal, 1/500, Abcam, Cat ab6672); anti-interleukin 8 antibody (IL-8, rabbit poly- clonal, 1/500, Abcam, Cat ab7747); anti-myosin light chain 2 antibody (MLC-2, rabbit polyclonal, 1/1000, Cell Signaling, Cat cs3672) and anti-phospho-MLC-2 anti- body (Thr18/Ser19) (p-MLC-2, rabbit polyclonal, 1/500, Cell Signaling, Cat cs3674); anti Janus kinase (anti JAK antibody, JAK, rabbit polyclonal, 1:1000 Cell signal- ing Cat cs3230); anti-phospho JAK2 antibody (p-JAK, 1:500 Rabbit polyclonal Cell signaling Cat sc3776); anti JNK antibody (JNK, rabbit polyclonal, 1:1000 cell signaling cs9252) and anti phospho c-Jun N-terminal kinase (anti-phospho JNK antibody, p-JNK, 1:500 rab- bit polyclonal Cell signaling cat cs9251). The blots were then washed and incubated with a secondary antibody horseradish peroxidase conjugated goat anti-rabbit IgG (1:7500, Thermo Scientific, Cat) or a goat anti-mouse IgG (1:10.000, Santa Cruz, Cat sc2005) for 2 h. As a protein loading control, β-actin (β-actin, mouse monoclonal, 1/10,000, Sigma, Cat A2228) was used.
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The G Protein-Coupled Receptor Gpr1 Is a Nutrient Sensor That Regulates Pseudohyphal Differentiation in Saccharomyces cerevisiae

The G Protein-Coupled Receptor Gpr1 Is a Nutrient Sensor That Regulates Pseudohyphal Differentiation in Saccharomyces cerevisiae

Pseudohyphal differentiation in the budding yeast Saccharomyces cerevisiae is induced in diploid cells in response to nitrogen starvation and abundant fermentable carbon source. Filamentous growth requires at least two signaling pathways: the pheromone responsive MAP kinase cascade and the Gpa2p-cAMP-PKA signaling pathway. Recent studies have established a physical and functional link between the Ga protein Gpa2 and the G protein-coupled receptor homolog Gpr1. We report here that the Gpr1 receptor is required for filamentous and haploid invasive growth and regulates expression of the cell surface flocculin Flo11. Epistasis analysis supports a model in which the Gpr1 receptor regulates pseudohyphal growth via the Gpa2p-cAMP-PKA pathway and independently of both the MAP kinase cascade and the PKA related kinase Sch9. Genetic and physiological studies indicate that the Gpr1 receptor is activated by glucose and other structurally related sugars. Because expression of the GPR1 gene is known to be induced by nitrogen starvation, the Gpr1 receptor may serve as a dual sensor of abundant carbon source (sugar ligand) and nitrogen starvation. In summary, our studies reveal a novel G protein-coupled receptor senses nutrients and regulates the dimorphic transition to filamentous growth via a Ga protein-cAMP-PKA signal transduction cascade.
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Genome-wide genetic analyses highlight mitogen-activated protein kinase (MAPK) signaling in the pathogenesis of endometriosis

Genome-wide genetic analyses highlight mitogen-activated protein kinase (MAPK) signaling in the pathogenesis of endometriosis

MAPKs comprise a kinase enzyme family that add phosphate groups to other proteins to activate, triggering a cascade of downstream sig- naling reactions that are involved in many physiological processes, such as gene expression, mitosis, cell movement, metabolism, cell survival and apoptosis. The protein kinase cascade consists of enzyme compo- nents; MAPK kinase kinase (MAPKKK), MAPK kinase (MAPKK) and MAP kinase (MAPK), that are activated consecutively (Fig. 3). Extracellular stimuli activate the Grb2-Sos complex, which then pro- motes Ras protein activation and which in turn activate the cytosolic MAPK pathway that fi nally leads to intranuclear events and cellular responses. Three main MAPK classes are distinguished by their bio- logical function: ERKs acting in the control of cell division; JNKs regulat- ing transcription; and p38 MAPK playing important roles in immune response, cell survival and differentiation regulation. They are mostly activated by in fl ammatory cytokines and environmental stresses, while other stimuli include growth factors, neurotransmitters, steroid
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Emerging role of Hpo signaling and YAP in hepatocellular carcinoma

Emerging role of Hpo signaling and YAP in hepatocellular carcinoma

Abstract: Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third most common cause of cancer-related mortality worldwide. Due to the poor prognosis and limited therapeutic options, there is great interest in further understanding better the molecu- lar underpinnings and potential molecular targets associated with HCC. The Hippo (Hpo) signaling pathway and YAP, its principal downstream effector, represent an innovative area of research in HCC. Pioneered in Drosophila melanogaster, the Hpo cascade controls tissue homeostasis including organ size, cell proliferation, apoptosis, as well as cell-cycle regulation and differentiation. This conserved kinase cascade in mammals depends on central control by the tumor suppressor mammalian sterile 20-like kinase 1/2 (Mst1/2). The Mst1/2 commences the downstream kinase cascade, ultimately activating the oncoprotein YAP and allowing its physical association with downstream targets to enhance the gene expression signatures that are involved in proliferation and survival. Alterations in YAP expression and defective regu- lation of other key Hpo pathway members, such as Mst1/2, Salvador, neurofibromatosis and Mer (Nf2/mer), large tumor suppressor homolog 1/2 (Lats1/2), and Mps one binder kinase activator-like 1A and 1B (Mob1) drive carcinogenesis in animal models. The dysregulation of the Hpo pathway – resulting in an unchecked activation of YAP – culminates in the development of a broad range of human tumor types, including HCC. The abrogation of Mst1/2-mediated YAP phosphorylation permits YAP entry into the nucleus in murine models and functions similarly in human HCCs. Chemoresistance mechanisms displayed by HCC tumors occur in a YAP-dependent manner. The HCC specimens exhibit YAP overexpression, and YAP serves as an independent prognostic marker for disease-free survival and overall survival in patients with HCC. Recently, the small molecule inhibitor, verteporfin has been shown to attenuate YAP activity in murine models, perhaps offering a novel therapeutic approach for patients with advanced HCC.
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umi-unc-2281.pdf

umi-unc-2281.pdf

Although the overall 5-year survival for NSCLC is only 15%, recent advances in our understanding of cancer genetics and biology will undoubtedly lead to vast improvements in our ability to effectively treat this disease. Proof of these advancements is evidenced by the recent incorporation of novel target-based therapies into our treatment paradigms, such as of bevacizumab (Avastin) and erlotinib (Tarceva) (Sebolt-Leopold and English, 2006). Another recent advancement has been the validation that adjuvant chemotherapy increases overall survival of patients following surgical resection (Arriagada et al., 2004; Douillard et al., 2006; Kato et al., 2004; Strauss et al., 2004; Winton et al., 2005). Previously, up to 60% of surgically resected stage IB-IIIA patients relapsed and died following surgical resection (Johnson and Rabin, 2005). While it is clear that certain patients receive great benefit from adjuvant chemotherapy, the overall impact on the entire patient population is relatively small, with an overall risk reduction of approximately 10%. Thus in the current state of the art many patients receive adjuvant chemotherapy while only a few receive benefit. The other patients are exposed to the toxicities of chemotherapy without a positive impact on survival either because they were the patients who would not have relapsed or because the adjuvant chemotherapy regimen was not effective for their disease. Since it is currently not possible to select patients likely to relapse or likely to benefit from adjuvant therapy, it is imperative that clinical and molecular markers be identified in order to select those patients who should receive adjuvant chemotherapy. In this study, we evaluated the importance of the ERK protein kinase cascade as a clinical correlate and as a drug target for NSCLC treatment. Our results support the importance of ERK-targeted therapies for NSCLC treatment.
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Organization of kinases, phosphatases, and receptor signaling complexes

Organization of kinases, phosphatases, and receptor signaling complexes

similar to those in yeast. Each kinase binds to a distinct region of JIP-1, and overexpression of the scaffold pro- tein specifically enhances the transduction of signals through the pathway (5). Mammalian MAP kinase path- ways may also be ordered by the adapter protein MP1. MP1 enhances activation of the classical MAP kinase cas- cade by bringing together MEK1 and ERK1. Overex- pression of MP1 favors the formation of MEK1/ERK1 complexes with a concomitant increase in ELK1 tran- scription, a commonly used index of MAP kinase activa- tion (6). MP1 seems to represent a novel class of MAP kinase adapter protein, as it only binds two members of the kinase cascade, whereas JIP-1, Pbs2, and Ste5 organ- ize and segregate complete MAP kinase pathways. As yet, it is unclear what the functional role of MP1 may be, but it has been proposed to facilitate interactions specifical- ly involving MEK1. It will be of interest to establish whether MP1 has other binding partners.
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Mating in Saccharomyces cerevisiae: The Role of the Pheromone Signal Transduction Pathway in the Chemotropic Response to Pheromone

Mating in Saccharomyces cerevisiae: The Role of the Pheromone Signal Transduction Pathway in the Chemotropic Response to Pheromone

Cells mutant for compo- nents of the mitogen-activated protein ( M A P ) kinase cascade (ste5, ste20, stell, ste7or fm? kssl) formed diploids at a frequency 1% that [r]

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Mec1 Dependent Phosphorylation of the Scc3 Subunit of Cohesin during Mitosis in Budding Yeast

Mec1 Dependent Phosphorylation of the Scc3 Subunit of Cohesin during Mitosis in Budding Yeast

after expressing a mec1 kinase-dead mutation from MEC1 genomic locus (Figure 4(b)). Therefore, Mec1 alone appears to be sufficient to phosphorylate Scc3 in response to DNA damage. The signal was also basically sup- pressed in a rad24 null background (Figure 4(b)), a mutation that prevents loading of the Rad17-Mec3-Ddc1 checkpoint complex and altogether prevents activation of the DNA damage checkpoint kinase cascade. It is worth recalling here that Mec1-Rad53-Chk1 and Rad24-Rad17-Mec3-Ddc1 represent two parallel pathways in the DNA damage checkpoint network and that, although both are essential for checkpoint activation, the Rad24 module is not needed for activation of the Mec1 module. Therefore, in the absence of Rad24, Mec1 was still ac- tive, yet the Scc3 S/T-Q signal was absent, thus suggesting that the absence of G2/M arrest in rad24Δ cells, rather than the absence of Mec1 activation, was likely responsible for the absence of Scc3 phosphorylation.
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In-silico Interaction Studies of Alternaria brassicae Toxin
Destruxin B and Potential Partners of MAPK4 Cascade

In-silico Interaction Studies of Alternaria brassicae Toxin Destruxin B and Potential Partners of MAPK4 Cascade

Some members of WRKY transcription family are regulated by MAPKs at the transcriptional and posttranscriptional levels in defense related signaling pathways (Ishihama et al., 2011). It is possible that the PAMP of Alternaria brassicae and its toxin affects some of the key components of this highly conserved MAP kinase cascade. A current challenge in this research area is to determine which signaling pathways in the plant make use of which MAPK components during elicitation of plant defense response. Therefore, it would be logical to assume that knowledge of pathogen recognition and transmission of stimuli to the signaling pathway could play a crucial role in disease resistance. Although there are some wet lab methods for addressing protein-protein interaction or probing protein partners, these methods have some limitations like identification of correct solutions, proper dealing with ûexibility and conformational changes. For single protein in a cell various possible binding partners ranging from few to several hundred are reported (Zacharias 2010; Gavin et al., 2002; Rual et al., 2005). Nowadays computational approaches are often used to predict how two proteins interact and form a complex. Several protein-protein docking servers have been developed for this purpose. In the present study, attempt has been made to decipher the cascade regulated by MAPK 4 with the study of interaction of destruxin B, host selective toxin of Alternaria brassicae, with different receptor kinase reported for necrotrophic fungi like Lys-M RLK, CHRK1, LRPK1, WAK and ERECTA and the potential partners of cascade. It was realized that such studies will help in identification of members of MAPK cascade regulated by MAPK4.
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ras2 Controls Morphogenesis, Pheromone Response, and Pathogenicity in the Fungal Pathogen Ustilago maydis

ras2 Controls Morphogenesis, Pheromone Response, and Pathogenicity in the Fungal Pathogen Ustilago maydis

Mutants deficient in components of the putative pheromone response pathway exhibit phenotypes that are similar to that of the ras2 mutant. Much like the ras2 mutant, ubc3 mutants fail to produce aerial hyphae when cospotted on mating medium (36). Further analysis by drop mating and RNA blot assays confirmed that ubc3 mutants produce less pheromone and are incapable of responding to pheromone produced by compati- ble mating partners (36, 40). In addition, haploid fuz7 mutants show reduced filament formation during mating interactions, and diploid fuz7 mutants are yeastlike after 24 h of growth on charcoal agar (4). Furthermore, pheromone signaling through the MAP kinase cascade leads to the activation of the phero- mone response factor encoded by the prf1 gene (21, 36, 40). FIG. 8. Ras2 promotes tumor formation. Anthocyanin production and the formation of very small tumors are the major symptoms of disease in maize seedlings infected with the P6D strain (left), while multiple tumors of various sizes are induced upon infection with the P6D strain carrying the activated ras2 Val16 allele in prV16Hyg (right).
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Regulators of Pseudohyphal Differentiation in Saccharomyces cerevisiae Identified Through Multicopy Suppressor Analysis in Ammonium Permease Mutant Strains

Regulators of Pseudohyphal Differentiation in Saccharomyces cerevisiae Identified Through Multicopy Suppressor Analysis in Ammonium Permease Mutant Strains

Nitrogen-starved diploid cells of the yeast Saccharomyces cerevisiae differentiate into a filamentous, pseu- dohyphal growth form. Recognition of nitrogen starvation is mediated, at least in part, by the ammonium permease Mep2p and the Ga subunit Gpa2p. Genetic activation of the pheromone-responsive MAP kinase cascade, which is also required for filamentous growth, only weakly suppresses the filamentation defect of Dmep2/Dmep2 and Dgpa2/Dgpa2 strain. Surprisingly, deletion of Mep1p, an ammonium permease not previously thought to regulate differentiation, significantly enhances the potency of MAP kinase activation, such that the STE11-4 allele induces filamentation to near wild-type levels in Dmep1/Dmep1 Dmep2/Dmep2 and Dmep1/Dmep1 Dgpa2/Dgpa2 strains. To identify additional regulatory components, we isolated high- copy suppressors of the filamentation defect of the Dmep1/Dmep1 Dmep2/Dmep2 mutant. Multicopy expres- sion of TEC1, PHD1, PHD2 (MSS10/MSN1/FUP4), MSN5, CDC6, MSS11, MGA1, SKN7, DOT6, HMS1, HMS2, or MEP2 each restored filamentation in a Dmep1/Dmep1 Dmep2/Dmep2 strain. Overexpression of SRK1 (SSD1), URE2, DAL80, MEP1, or MEP3 suppressed only the growth defect of the Dmep1/Dmep1 Dmep2/Dmep2 mutant strain. Characterization of these genes through deletion analysis and epistasis under- scores the complexity of this developmental pathway and suggests that stress conditions other than nitrogen deprivation may also promote filamentous growth.
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Mcs4, a Two-Component System Response Regulator Homologue, Regulates the Schizosaccharomyces pombe Cell Cycle Control

Mcs4, a Two-Component System Response Regulator Homologue, Regulates the Schizosaccharomyces pombe Cell Cycle Control

RUSSELL, 1997 Mcs4 mitotic catas- trophe suppressor regulates the fission yeast cell cycle through the Wikl-WislSpcl kinase cascade. HIETER, 1989 A system of shuttle vecto[r]

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Supplementing L-isoleucine increases medium protein and alters the expression of genes and proteins involved in milk protein synthesis and energy metabolism in bovine mammary cells

Supplementing L-isoleucine increases medium protein and alters the expression of genes and proteins involved in milk protein synthesis and energy metabolism in bovine mammary cells

Abstract: The objective of this study was to determine the effects of supplementing L-isoleucine (L- Ile) on milk protein synthesis, using an immortalized bovine mammary epithelial (MAC-T) cell line. In this case, the cells were treated with 0, 0.3, 0.6, 0.9, 1.2 and 1.5 mM of supplemental Isoleucine (Ile), and the most efficient time for protein synthesis for each amino acid was determined by measuring the cell, medium and total protein at 0, 24, 48, 72 and 96 h. Confirmatory tests showed that 48h incubation time and 0.6 mM dosage of L-Ile are considered as the optimal time and dosage. The mechanism of milk protein synthesis was elucidated through proteomics analysis to clarify the metabolic pathway. When the L-Ile was supplemented, extracellular protein (medium protein) reached a peak at 48h, whereas in the case of the intracellular cell protein, it was shown to have reached to its peak at 24h in all L-Ile dosage treatments. In total, it is noted that there were 63 upregulated and 52 downregulated proteins. The results of the protein pathway analysis showed that the L-Ile group stimulated insulin/IGF pathway-mitogen activated protein kinase kinase/MAP kinase cascade, insulin/IGF pathway-protein kinase B signaling cascade, p53 pathway, de novo purine biosynthesis, Wnt signaling pathway, glycolysis, pentose phosphate pathway, and ATP synthesis which are pathways involved and related to protein and energy metabolism. Together, these results demonstrate that L-Ile supplementation was effective in stimulating β-casein synthesis by stimulating genes and pathways which are significantly related to protein and energy metabolism.
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Proteomic and histopathological characterisation of sicca subjects and primary Sjögren’s syndrome patients reveals promising tear, saliva and extracellular vesicle disease biomarkers

Proteomic and histopathological characterisation of sicca subjects and primary Sjögren’s syndrome patients reveals promising tear, saliva and extracellular vesicle disease biomarkers

To delineate cellular pathways involving the upregu- lated proteins identified with LC-MS in the tear fluid samples from pSS patients, in relation to non-SS sicca controls and healthy individuals, GO and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway overrepresentation analyses were performed using DA- VID. Our results demonstrated pathways in the pSS pa- tients involving inflammatory innate immune responses, such as MHC class I antigen processing and presenta- tion, TNF-mediated signalling and IL-1 mediated signal- ling. Additional T cell receptor signalling of the adaptive immune response, and apoptotic processes through MAP kinase cascade, were also detected (Fig. 2). Inter- estingly, similar cellular processes were observed as a re- sult of upregulated proteins in the pSS patients, when compared to both non-SS sicca subjects and healthy in- dividuals. Moreover, the three most upregulated pro- teins identified in tear fluid of pSS patients were similar, when compared to both non-SS subjects and healthy controls, namely LMO7, HUWE1 and TPD52 (Table 4, Additional file 1: Figure S1). Here, LMO7 and HUWE1 are both involved in the post-transla- tional modification processes of ubiquitination [47, 48], similar to the SS autoantigen Ro52 [49], also known as E3 ubiquitin ligase. Meanwhile, TPD52 plays a central role in adaptive immunity by regulat- ing B cell differentiation [50]. Taken together, these identified cellular pathways and proteins in tear fluid of pSS patients imply the involvement of innate and adaptive immune systems, where non-SS sicca sub- jects showed similar behavioural tendencies as healthy controls on a protein level.
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Balancing the immune response in the brain: IL-10 and its regulation

Balancing the immune response in the brain: IL-10 and its regulation

Importantly, several mechanisms operate as negative feedback loops to restrain IL-10 production by CNS cells (Fig. 2). Activation of the signalling cascade mediated by glycogen synthase kinase (GSK)-3 functions as an en- dogenous mechanism to inhibit IL-10 production, whilst enhancing the production of pro-inflammatory cytokines, by microglial cells upon TLR4 activation [127]. In line with this, abrogation of GSK-3, through chemical inhibi- tors or siRNA, was shown to restore TLR4-induced IL-10 production in microglia with a concomitant reduction in the levels of pro-inflammatory mediators [82, 128]. Fur- thermore, blockade of GSK-3 was shown to induce p38 and ERK, thus confirming the role for these MAPKs in enhancing IL-10 production [82]. A similar role for GSK-3 in regulating IL-10 was previously demonstrated for other immune cell types [6, 9]. In both microglia and astrocytes, IL-10 was found to down-regulate its own transcription and that of the IL-10R when exogenously provided to un- treated and LPS-treated cells [41].
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The p38 mitogen activated protein kinase signaling cascade in CD4 T cells

The p38 mitogen activated protein kinase signaling cascade in CD4 T cells

human acute inflammatory disorders, several clinical trials with p38 MAPK inhibitors have been discontinued because of serious side effects, in particular at the level of the central nervous system. New p38 MAPK inhibitors that are unable to cross the blood–brain barrier are now in clinical trials in rheumatoid arthritis and will delineate precisely the role of p38 MAPK in Th1-driven chronic inflammatory diseases. However, in view of recent advances underlining the essential role of p38 MAPK in IL-10 expression and in Th2 cell functions and of the regulatory capacities of IL-10 and Th2 cells in Th1-driven inflammation, p38 MAPK inhibitors might be associated with some unwanted effects on the immune system, enhancing rather than ameliorating the underlying inflammatory response in Th1-driven diseases. In contrast, these inhibitors may be useful as therapy in Th2-driven inflammatory disorders. However, as p38 MAPK also has essential functions in other organ systems beside the immune system, it may be necessary to characterize precisely the signal cascades downstream of p38 MAPK that control effector functions in the immune system to identify those that are involved in unwanted immune responses without interfering with essential physiologic functions of the p38 MAPK signaling cascade in other organ systems. This might provide therapeutic targets to specifically block, for example, TNF production by macrophages in autoimmune diseases or Th2 effector functions in allergic disorders.
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