International Journal of Molecular Sciences

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19 pages, 5931 KiB

Open AccessArticle

Poly(ADP-Ribose) Polymerase-3 Regulates Regeneration in Planarians

by Paul G. Barghouth, Peter Karabinis, Andie Venegas and Néstor J. Oviedo

Int. J. Mol. Sci. 2020, 21(3), 875; https://doi.org/10.3390/ijms21030875 - 29 Jan 2020

Cited by 3 | Viewed by 3633

Abstract

Protein ADP-ribosylation is a reversible post-translational modification (PTM) process that plays fundamental roles in cell signaling. The covalent attachment of ADP ribose polymers is executed by PAR polymerases (PARP) and it is essential for chromatin organization, DNA repair, cell cycle, transcription, and replication, [...] Read more.

Protein ADP-ribosylation is a reversible post-translational modification (PTM) process that plays fundamental roles in cell signaling. The covalent attachment of ADP ribose polymers is executed by PAR polymerases (PARP) and it is essential for chromatin organization, DNA repair, cell cycle, transcription, and replication, among other critical cellular events. The process of PARylation or polyADP-ribosylation is dynamic and takes place across many tissues undergoing renewal and repair, but the molecular mechanisms regulating this PTM remain mostly unknown. Here, we introduce the use of the planarian Schmidtea mediterranea as a tractable model to study PARylation in the complexity of the adult body that is under constant renewal and is capable of regenerating damaged tissues. We identified the evolutionary conservation of PARP signaling that is expressed in planarian stem cells and differentiated tissues. We also demonstrate that Smed-PARP-3 homolog is required for proper regeneration of tissues in the anterior region of the animal. Furthermore, our results demonstrate, Smed-PARP-3(RNAi) disrupts the timely location of injury-induced cell death near the anterior facing wounds and also affects the regeneration of the central nervous system. Our work reveals novel roles for PARylation in large-scale regeneration and provides a simplified platform to investigate PARP signaling in the complexity of the adult body. Full article

(This article belongs to the Special Issue Signaling: From Past to Future)

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17 pages, 2113 KiB

Open AccessArticle

Streptococcal Pyrogenic Exotoxin A-Stimulated Monocytes Mediate Regulatory T-Cell Accumulation through PD-L1 and Kynurenine

by Katharina Giesbrecht, Sandra Förmer, Aline Sähr, Klaus Heeg and Dagmar Hildebrand

Int. J. Mol. Sci. 2019, 20(16), 3933; https://doi.org/10.3390/ijms20163933 - 13 Aug 2019

Cited by 15 | Viewed by 9319

Abstract

Bacterial superantigens (SAgs) are exotoxins that promote a fulminant activation of the immune system. The subsequent intense release of inflammatory cytokines often results in hypotension, shock, and organ failure with high mortality rates. In the current paradigm, the direct and simultaneous binding of [...] Read more.

Bacterial superantigens (SAgs) are exotoxins that promote a fulminant activation of the immune system. The subsequent intense release of inflammatory cytokines often results in hypotension, shock, and organ failure with high mortality rates. In the current paradigm, the direct and simultaneous binding of SAgs with T-cell receptor (TCR)-bearing Vβ regions and conserved structures on major histocompatibility complex class II (MHC class II) on antigen-presenting cells (APCs) induces the activation of both cell types. However, by crosslinking MHC class II molecules, APCs can be activated by SAgs independently of T lymphocytes. Recently, we showed that streptococcal pyrogenic exotoxin A (SPEA) of Streptococcus pyogenes stimulates an immunogenic APC phenotype with upregulated costimulatory molecules and inflammatory cytokines. Additionally, we revealed that SPEA triggers immunosuppressive programs in monocytes that facilitate the accumulation of regulatory T cells (Tregs) in in vitro monocyte/CD4⁺ T-cell cocultures. Immunosuppressive factors include anti-inflammatory interleukin 10 (IL-10), co-inhibitory surface molecule programmed cell death 1 ligand 1 (PD-L1), and the inhibitory indoleamine 2,3-dioxygenase (IDO)/kynurenine effector system. In the present study, we investigated the underlying mechanism of SPEA-stimulated monocyte-mediated accumulation of Tregs. Blood-derived monocytes from healthy donors were stimulated with SPEA for 48 h (SPEA-monocytes). For the evaluation of SPEA-monocyte-mediated modulation of CD4⁺ T lymphocytes, SPEA was removed from the culture through extensive washing of cells before adding allogeneic CD3/CD28-activated T cells. Results: In coculture with allogeneic CD4⁺ T cells, SPEA-monocytes mediate apoptosis of CD4⁺Foxp3⁻ lymphocytes and accumulation of CD4⁺Foxp3⁺ Tregs. PD-L1 and kynurenine are critically involved in the mediated cell death because blocking both factors diminished apoptosis and decreased the proportion of the CD25⁺/Foxp3⁺ Treg subpopulation significantly. Upregulation of PD-L1 and kynurenine as well as SPEA-monocyte-mediated effects on T cells depend on inflammatory IL-1β. Our study shows that monocytes activated by SPEA mediate apoptosis of CD4⁺Foxp3⁻ T effector cells through PD-L1 and kynurenine. CD4⁺Foxp3⁺ T cells are resistant to apoptosis and accumulate in SPEA-monocyte/CD4⁺ T-cell coculture. Full article

(This article belongs to the Special Issue Signaling: From Past to Future)

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12 pages, 2949 KiB

Open AccessArticle

Changes in uPA, PAI-1, and TGF-β Production during Breast Cancer Cell Interaction with Human Mesenchymal Stroma/Stem-Like Cells (MSC)

by Catharina Melzer, Juliane von der Ohe, Hannah Otterbein, Hendrik Ungefroren and Ralf Hass

Int. J. Mol. Sci. 2019, 20(11), 2630; https://doi.org/10.3390/ijms20112630 - 28 May 2019

Cited by 17 | Viewed by 4284

Abstract

The interactions of cancer cells with neighboring non-malignant cells in the microenvironment play an important role for progressive neoplastic development and metastasis. Long-term direct co-culture of human MDA-MB-231^cherry breast cancer cells with benign human mesenchymal stroma/stem-like cells (MSC) MSC544^GFP stably expressing [...] Read more.

The interactions of cancer cells with neighboring non-malignant cells in the microenvironment play an important role for progressive neoplastic development and metastasis. Long-term direct co-culture of human MDA-MB-231^cherry breast cancer cells with benign human mesenchymal stroma/stem-like cells (MSC) MSC544^GFP stably expressing mCherry and eGFP fluorescence proteins, respectively, was associated with the formation of three-dimensional (3D) tumor spheroids in vitro. The quantification of the breast tumor marker urokinase plasminogen activator (uPA) in mono-cultured MDA-MB-231 cells revealed an approximately 14-fold enhanced expression when compared to five different normal human MSC mono-cultures. Moreover, uPA levels in 3D tumor spheroids remained elevated 9.4-fold above the average of five different human MSC cultures. In contrast, the expression of the corresponding plasminogen activator inhibitor type-1 (PAI-1) declined by 2.6-fold in the breast cancer cells and was even further reduced by 3.2-fold in the MDA-MB-231^cherry/MSC544^GFP 3D co-culture spheroids when compared to the various MSC populations. The supportive data were obtained for the production of TGF-β1, which is an important growth factor in the regulation of tumor growth and metastasis formation. Whereas, TGF-β1 release in MDA-MB-231^cherry/MSC544^GFP co-cultures was elevated by 1.56-fold as compared to MSC544 mono-cultures after 24 h; this ratio further increased to 2.19-fold after 72 h. Quantitative PCR analyses in MSC544 and MDA-MB-231 cells revealed that MSC, rather than the breast cancer cells, are responsible for TGF-β1 synthesis and that TGF-β1 contributes to its own synthesis in these cells. These findings suggested potential synergistic effects in the expression/secretion of uPA, PAI-1, and TGF-β during the co-culture of breast cancer cells with MSC. Full article

(This article belongs to the Special Issue Signaling: From Past to Future)

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18 pages, 2649 KiB

Open AccessArticle

Short-Term Protocols to Obtain Insulin-Producing Cells from Rat Adipose Tissue: Signaling Pathways and In Vivo Effect

by Krista Minéia Wartchow, Letícia Rodrigues, Lucas Zingano Suardi, Barbara Carolina Federhen, Nicholas Guerini Selistre, Carlos-Alberto Gonçalves and Patrícia Sesterheim

Int. J. Mol. Sci. 2019, 20(10), 2458; https://doi.org/10.3390/ijms20102458 - 18 May 2019

Cited by 10 | Viewed by 4235

Abstract

Studies using mesenchymal stromal cells (MSCs) as a source of insulin-secreting cells (IPCs) are a promising path in the pursuit for diabetes therapy. Here, we investigate three short-term differentiation protocols in order to generate IPCs from autologous adipose-derived stromal cells (ADSCs) with an [...] Read more.

Studies using mesenchymal stromal cells (MSCs) as a source of insulin-secreting cells (IPCs) are a promising path in the pursuit for diabetes therapy. Here, we investigate three short-term differentiation protocols in order to generate IPCs from autologous adipose-derived stromal cells (ADSCs) with an expressive insulin-secreting profile in vitro and in vivo, as well as the signaling pathways involved in the chosen differentiation protocols. We extracted and cultured ADSCs and differentiated them into IPCs, using three different protocols with different inductors. Afterwards, the secretory profile was analyzed and IPCs differentiated in exendin-4/activin A medium, which presented the best secretory profile, was implanted in the kidney subcapsular region of diabetic rats. All protocols induced the differentiation, but media supplemented with exendin-4/activin A or resveratrol induced the expression and secretion of insulin more efficiently, and only the exendin-4/activin-A-supplemented medium generated an insulin secretion profile more like β-cells, in response to glucose. The PI3K/Akt pathway seems to play a negative role in IPC differentiation; however, the differentiation of ADSCs with exendin-4/activin A positively modulated the p38/MAPK pathway. Resveratrol medium activated the Jak/STAT3 pathway and generated IPCs apparently less sensitive to insulin and insulin-like receptors. Finally, the implant of IPCs with the best secretory behavior caused a decrease in hyperglycemia after one-week implantation in diabetic rats. Our data provide further information regarding the generation of IPCs from ADSCs and strengthen evidence to support the use of MSCs in regenerative medicine, specially the use of exendin-4/activin A to produce rapid and effectively IPCs with significant in vivo effects. Full article

(This article belongs to the Special Issue Signaling: From Past to Future)

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18 pages, 3564 KiB

Open AccessArticle

Involvement of p38 Activation and Mitochondria in Death of Human Leukemia Cells Induced by an Agonistic Human Monoclonal Antibody Fab Specific to TRAIL Receptor 1

by You-Ri Lee, Eunjoo Hwang and Young-Ju Jang

Int. J. Mol. Sci. 2019, 20(8), 1967; https://doi.org/10.3390/ijms20081967 - 22 Apr 2019

Viewed by 2882

Abstract

The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces cancer cell death with minimal damage to normal cells; however, some cancer cells are resistant to TRAIL. TRAIL resistance may be overcome by agonistic antibodies to TRAIL receptors. In this study, we report the toxic [...] Read more.

The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces cancer cell death with minimal damage to normal cells; however, some cancer cells are resistant to TRAIL. TRAIL resistance may be overcome by agonistic antibodies to TRAIL receptors. In this study, we report the toxic effects of a novel recombinant agonistic human anti–TRAIL receptor 1 (DR4) monoclonal antibody Fab fragment, DR4-4, on various TRAIL-resistant and -sensitive cancer cell lines. The mechanisms of DR4-4 Fab–induced cell death in a human T cell leukemia cell line (Jurkat) were investigated using cell viability testing, immunoblotting, immunoassays, flow cytometry, and morphological observation. DR4-4 Fab–induced caspase-independent necrosis was observed to occur in Jurkat cells in association with p38 mitogen-activated protein kinase activation, cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein degradation, decreased mitochondrial membrane potential, and increased mitochondrial reactive oxygen species production. Increased cytotoxic effects of DR4-4 Fab were observed in combination with TRAIL or γ-irradiation. Our results indicate that the novel DR4-4 Fab might overcome TRAIL-resistance and induce death in leukemia cells via cellular mechanisms different from those activated by TRAIL. DR4-4 Fab may have application as a potential therapeutic antibody fragment in single or combination therapy for cancer. Full article

(This article belongs to the Special Issue Signaling: From Past to Future)

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14 pages, 2952 KiB

Open AccessArticle

Involvement of Actin Cytoskeletal Components in Breast Cancer Cell Fusion with Human Mesenchymal Stroma/Stem-Like Cells

by Catharina Melzer, Juliane von der Ohe and Ralf Hass

Int. J. Mol. Sci. 2019, 20(4), 876; https://doi.org/10.3390/ijms20040876 - 18 Feb 2019

Cited by 24 | Viewed by 5136

Abstract

Cell fusion as a rare event was observed following the co-culture of human MDA-MB-231^cherry breast cancer cells or benign neoplastic MCF10A^cherry breast epithelial cells together with different mesenchymal stroma/stem-like cells (MSC^GFP) cultures, respectively, resulting in the generation of double-fluorescing [...] Read more.

Cell fusion as a rare event was observed following the co-culture of human MDA-MB-231^cherry breast cancer cells or benign neoplastic MCF10A^cherry breast epithelial cells together with different mesenchymal stroma/stem-like cells (MSC^GFP) cultures, respectively, resulting in the generation of double-fluorescing hybrid cells. Analysis of potential molecular mechanisms for the formation of cancer hybrid cells revealed cytoskeletal components, including F-actin. Thus, a sub-lethal concentration of cytochalasin D, which blocks elongation of actin filaments, was able to significantly reduce cancer hybrid cell formation. Simultaneously, cell cycle progression of the different co-cultures remained unaffected following treatment with cytochalasin D, indicating continued proliferation. Moreover, exposure to 50 nM cytochalasin D revealed little if any effect on the expression of various integrins and cell adhesion molecules in the different co-cultures. However, LC-MS proteome analysis of the different control co-cultures compared to corresponding cytochalasin-treated co-cultures demonstrated predominant differences in the expression of actin-associated cytoskeletal proteins. In addition, the requirement of structured actin to provide an appropriate cytoskeletal network for enabling subsequent fusion processes was also substantiated by the actin filament disrupting latrunculin B, which inhibits the fusion process between the breast cancer populations and mesenchymal stroma/stem-like cells (MSC). Together, these findings suggest an important role of distinct actin structures and associated cytoskeletal components during cell fusion and the formation of breast cancer hybrid cells. Full article

(This article belongs to the Special Issue Signaling: From Past to Future)

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18 pages, 3398 KiB

Open AccessArticle

α-Melanocyte-Stimulating Hormone Attenuates Neovascularization by Inducing Nitric Oxide Deficiency via MC-Rs/PKA/NF-κB Signaling

by Wen-Tsan Weng, Chieh-Shan Wu, Feng-Sheng Wang, Chang-Yi Wu, Yi-Ling Ma, Hoi-Hung Chan, Den-Chiung Wu, Jian-Ching Wu, Tian-Huei Chu, Shih-Chung Huang and Ming-Hong Tai

Int. J. Mol. Sci. 2018, 19(12), 3823; https://doi.org/10.3390/ijms19123823 - 30 Nov 2018

Cited by 12 | Viewed by 4902

Abstract

α-melanocyte-stimulating hormone (α-MSH) has been characterized as a novel angiogenesis inhibitor. The homeostasis of nitric oxide (NO) plays an important role in neovascularization. However, it remains unclear whether α-MSH mitigates angiogenesis through modulation of NO and its signaling pathway. The present study elucidated [...] Read more.

α-melanocyte-stimulating hormone (α-MSH) has been characterized as a novel angiogenesis inhibitor. The homeostasis of nitric oxide (NO) plays an important role in neovascularization. However, it remains unclear whether α-MSH mitigates angiogenesis through modulation of NO and its signaling pathway. The present study elucidated the function and mechanism of NO signaling in α-MSH-induced angiogenesis inhibition using cultured human umbilical vein endothelial cells (HUVECs), rat aorta rings, and transgenic zebrafish. By Griess reagent assay, it was found α-MSH dose-dependently reduced the NO release in HUVECs. Immunoblotting and immunofluorescence analysis revealed α-MSH potently suppressed endothelial and inducible nitric oxide synthase (eNOS/iNOS) expression, which was accompanied with inhibition of nuclear factor kappa B (NF-κB) activities. Excessive supply of NO donor l-arginine reversed the α-MSH-induced angiogenesis inhibition in vitro and in vivo. By using antibody neutralization and RNA interference, it was delineated that melanocortin-1 receptor (MC1-R) and melanocortin-2 receptor (MC2-R) participated in α-MSH-induced inhibition of NO production and NF-κB/eNOS/iNOS signaling. This was supported by pharmaceutical inhibition of protein kinase A (PKA), the downstream effector of MC-Rs signaling, using H89 abolished the α-MSH-mediated suppression of NO release and eNOS/iNOS protein level. Therefore, α-MSH exerts anti-angiogenic function by perturbing NO bioavailability and eNOS/iNOS expression in endothelial cells. Full article

(This article belongs to the Special Issue Signaling: From Past to Future)

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18 pages, 3838 KiB

Open AccessArticle

Secondary Unconjugated Bile Acids Induce Hepatic Stellate Cell Activation

by Kunihiro Saga, Yukio Iwashita, Shinya Hidano, Yuiko Aso, Kenji Isaka, Yasutoshi Kido, Kazuhiro Tada, Hiroomi Takayama, Takashi Masuda, Teijiro Hirashita, Yuichi Endo, Masayuki Ohta, Takashi Kobayashi and Masafumi Inomata

Int. J. Mol. Sci. 2018, 19(10), 3043; https://doi.org/10.3390/ijms19103043 - 5 Oct 2018

Cited by 20 | Viewed by 6193

Abstract

Hepatic stellate cells (HSCs) are key players in liver fibrosis, cellular senescence, and hepatic carcinogenesis. Bile acids (BAs) are involved in the activation of HSCs, but the detailed mechanism of this process remains unclear. We conducted a comprehensive DNA microarray study of the [...] Read more.

Hepatic stellate cells (HSCs) are key players in liver fibrosis, cellular senescence, and hepatic carcinogenesis. Bile acids (BAs) are involved in the activation of HSCs, but the detailed mechanism of this process remains unclear. We conducted a comprehensive DNA microarray study of the human HSC line LX-2 treated with deoxycholic acid (DCA), a secondary unconjugated BA. Additionally, LX-2 cells were exposed to nine BAs and studied using immunofluorescence staining, enzyme-linked immunosorbent assay, and flow cytometry to examine the mechanisms of HSC activation. We focused on the tumor necrosis factor (TNF) pathway and revealed upregulation of genes related to nuclear factor kappa B (NF-κB) signaling and senescence-associated secretory phenotype factors. α-Smooth muscle actin (α-SMA) was highly expressed in cells treated with secondary unconjugated BAs, including DCA, and a morphological change associated with radial extension of subendothelial protrusion was observed. Interleukin-6 level in culture supernatant was significantly higher in cells treated with secondary unconjugated BAs. Flow cytometry showed that the proportion of cells highly expressing α-SMA was significantly increased in HSCs cultured with secondary unconjugated BAs. We demonstrated that secondary unconjugated BAs induced the activation of human HSCs. Full article

(This article belongs to the Special Issue Signaling: From Past to Future)

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19 pages, 4561 KiB

Open AccessArticle

Guanidinoacetic Acid Regulates Myogenic Differentiation and Muscle Growth Through miR-133a-3p and miR-1a-3p Co-mediated Akt/mTOR/S6K Signaling Pathway

by Yujie Wang, Jideng Ma, Wanling Qiu, Jinwei Zhang, Siyuan Feng, Xiankun Zhou, Xun Wang, Long Jin, Keren Long, Lingyan Liu, Weihang Xiao, Qianzi Tang, Li Zhu, Yanzhi Jiang, Xuewei Li and Mingzhou Li

Int. J. Mol. Sci. 2018, 19(9), 2837; https://doi.org/10.3390/ijms19092837 - 19 Sep 2018

Cited by 43 | Viewed by 6692

Abstract

Guanidinoacetic acid (GAA), an amino acid derivative that is endogenous to animal tissues including muscle and nerve, has been reported to enhance muscular performance. MicroRNA (miRNA) is a post-transcriptional regulator that plays a key role in nutrient-mediated myogenesis. However, the effects of GAA [...] Read more.

Guanidinoacetic acid (GAA), an amino acid derivative that is endogenous to animal tissues including muscle and nerve, has been reported to enhance muscular performance. MicroRNA (miRNA) is a post-transcriptional regulator that plays a key role in nutrient-mediated myogenesis. However, the effects of GAA on myogenic differentiation and skeletal muscle growth, and the potential regulatory mechanisms of miRNA in these processes have not been elucidated. In this study, we investigated the effects of GAA on proliferation, differentiation, and growth in C2C12 cells and mice. The results showed that GAA markedly inhibited the proliferation of myoblasts, along with the down-regulation of cyclin D1 (CCND1) and cyclin dependent kinase 4 (CDK4) mRNA expression, and the upregulation of cyclin dependent kinase inhibitor 1A (P21) mRNA expression. We also demonstrated that GAA treatment stimulated myogenic differentiation 1 (MyoD) and myogenin (MyoG) mRNA expression, resulting in an increase in the myotube fusion rate. Meanwhile, GAA supplementation promoted myotube growth through increase in total myosin heavy chain (MyHC) protein level, myotubes thickness and gastrocnemius muscle cross-sectional area. Furthermore, small RNA sequencing revealed that a total of eight miRNAs, including miR-133a-3p and miR-1a-3p cluster, showed differential expression after GAA supplementation. To further study the function of miR-133a-3p and miR-1a-3p in GAA-induced skeletal muscle growth, we transfected miR-133a-3p and miR-1a-3p mimics into myotube, which also induced muscle growth. Through bioinformatics and a dual-luciferase reporter system, the target genes of miR-133a-3p and miR-1a-3p were determined. These two miRNAs were shown to modulate the Akt/mTOR/S6K signaling pathway by restraining target gene expression. Taken together, these findings suggest that GAA supplementation can promote myoblast differentiation and skeletal muscle growth through miR-133a-3p- and miR-1a-3p-induced activation of the AKT/mTOR/S6K signaling pathway. Full article

(This article belongs to the Special Issue Signaling: From Past to Future)

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22 pages, 4258 KiB

Open AccessArticle

Leukocyte Immunoglobulin-Like Receptors A2 and A6 are Expressed in Avian Macrophages and Modulate Cytokine Production by Activating Multiple Signaling Pathways

by Anh Duc Truong, Deivendran Rengaraj, Yeojin Hong, Ha Thi Thanh Tran, Hoang Vu Dang, Viet Khong Nguyen, Hyun S. Lillehoj and Yeong Ho Hong

Int. J. Mol. Sci. 2018, 19(9), 2710; https://doi.org/10.3390/ijms19092710 - 11 Sep 2018

Cited by 8 | Viewed by 5537

Abstract

The activating leukocyte immunoglobulin-like receptors (LILRAs) play an important role in innate immunity. However, most of the LILRA members have not been characterized in avian species including chickens. The present study is the first attempt at cloning, structural analysis and functional characterization of [...] Read more.

The activating leukocyte immunoglobulin-like receptors (LILRAs) play an important role in innate immunity. However, most of the LILRA members have not been characterized in avian species including chickens. The present study is the first attempt at cloning, structural analysis and functional characterization of two LILRAs (LILRA2 and LILRA6) in chickens. Multiple sequence alignments and construction of a phylogenetic tree of chicken LILRA2 and LILRA6 with mammalian proteins revealed high conservation between chicken LILRA2 and LILRA6 and a close relationship between the chicken and mammalian proteins. The mRNA expression of LILRA2 and LILRA6 was high in chicken HD11 macrophages and the small intestine compared to that in several other tissues and cells tested. To examine the function of LILRA2 and LILRA6 in chicken immunity, LILRA2 and LILRA6 were transfected into HD11 cells. Our findings indicated that LILRA2 and LILRA6 are associated with the phosphorylation of Src kinases and SHP2, which play a regulatory role in immune functions. Moreover, LILRA6 associated with and activated MHC class I, β2-microglobulin and induced the expression of transporters associated with antigen processing but LILRA2 did not. Furthermore, both LILRA2 and LILRA6 activated JAK-STAT, NF-κB, PI3K/AKT and ERK1/2 MAPK signaling pathways and induced Th1-, Th2- and Th17-type cytokines and Toll-like receptors. Collectively, this study indicates that LILRA2 and LILRA6 are essential for macrophage-mediated immune responses and they have the potential to complement the innate and adaptive immune system against pathogens. Full article

(This article belongs to the Special Issue Signaling: From Past to Future)

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Review

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44 pages, 4291 KiB

Open AccessReview

Conceptual Evolution of Cell Signaling

by Arathi Nair, Prashant Chauhan, Bhaskar Saha and Katharina F. Kubatzky

Int. J. Mol. Sci. 2019, 20(13), 3292; https://doi.org/10.3390/ijms20133292 - 4 Jul 2019

Cited by 103 | Viewed by 18877

Abstract

During the last 100 years, cell signaling has evolved into a common mechanism for most physiological processes across systems. Although the majority of cell signaling principles were initially derived from hormonal studies, its exponential growth has been supported by interdisciplinary inputs, e.g., from [...] Read more.

During the last 100 years, cell signaling has evolved into a common mechanism for most physiological processes across systems. Although the majority of cell signaling principles were initially derived from hormonal studies, its exponential growth has been supported by interdisciplinary inputs, e.g., from physics, chemistry, mathematics, statistics, and computational fields. As a result, cell signaling has grown out of scope for any general review. Here, we review how the messages are transferred from the first messenger (the ligand) to the receptor, and then decoded with the help of cascades of second messengers (kinases, phosphatases, GTPases, ions, and small molecules such as cAMP, cGMP, diacylglycerol, etc.). The message is thus relayed from the membrane to the nucleus where gene expression ns, subsequent translations, and protein targeting to the cell membrane and other organelles are triggered. Although there are limited numbers of intracellular messengers, the specificity of the response profiles to the ligands is generated by the involvement of a combination of selected intracellular signaling intermediates. Other crucial parameters in cell signaling are its directionality and distribution of signaling strengths in different pathways that may crosstalk to adjust the amplitude and quality of the final effector output. Finally, we have reflected upon its possible developments during the coming years. Full article

(This article belongs to the Special Issue Signaling: From Past to Future)

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21 pages, 2615 KiB

Open AccessReview

Glycation of Plant Proteins: Regulatory Roles and Interplay with Sugar Signalling?

by Julia Shumilina, Alena Kusnetsova, Alexander Tsarev, Henry C. Janse van Rensburg, Sergei Medvedev, Vadim Demidchik, Wim Van den Ende and Andrej Frolov

Int. J. Mol. Sci. 2019, 20(9), 2366; https://doi.org/10.3390/ijms20092366 - 13 May 2019

Cited by 48 | Viewed by 7316

Abstract

Glycation can be defined as an array of non-enzymatic post-translational modifications of proteins formed by their interaction with reducing carbohydrates and carbonyl products of their degradation. Initial steps of this process rely on reducing sugars and result in the formation of early glycation [...] Read more.

Glycation can be defined as an array of non-enzymatic post-translational modifications of proteins formed by their interaction with reducing carbohydrates and carbonyl products of their degradation. Initial steps of this process rely on reducing sugars and result in the formation of early glycation products—Amadori and Heyns compounds via Schiff base intermediates, whereas their oxidative degradation or reactions of proteins with α-dicarbonyl compounds yield a heterogeneous group of advanced glycation end products (AGEs). These compounds accompany thermal processing of protein-containing foods and are known to impact on ageing, pathogenesis of diabetes mellitus and Alzheimer’s disease in mammals. Surprisingly, despite high tissue carbohydrate contents, glycation of plant proteins was addressed only recently and its physiological role in plants is still not understood. Therefore, here we summarize and critically discuss the first steps done in the field of plant protein glycation during the last decade. We consider the main features of plant glycated proteome and discuss them in the context of characteristic metabolic background. Further, we address the possible role of protein glycation in plants and consider its probable contribution to protein degradation, methylglyoxal and sugar signalling, as well as interplay with antioxidant defense. Full article

(This article belongs to the Special Issue Signaling: From Past to Future)

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16 pages, 1073 KiB

Open AccessReview

An Update on Interleukin-9: From Its Cellular Source and Signal Transduction to Its Role in Immunopathogenesis

by Sushmita Chakraborty, Katharina F. Kubatzky and Dipendra Kumar Mitra

Int. J. Mol. Sci. 2019, 20(9), 2113; https://doi.org/10.3390/ijms20092113 - 29 Apr 2019

Cited by 65 | Viewed by 12433

Abstract

Interleukin-9 (IL-9) is a pleiotropic cytokine and was primarily studied in the context of T helper 2 (T_H2)-associated immuno-pathological conditions such as asthma and parasitic infections. There was a paradigm shift in the biology of IL-9 after the recent discovery of [...] Read more.

Interleukin-9 (IL-9) is a pleiotropic cytokine and was primarily studied in the context of T helper 2 (T_H2)-associated immuno-pathological conditions such as asthma and parasitic infections. There was a paradigm shift in the biology of IL-9 after the recent discovery of T_H9 cells, a new subtype of T_H cells which secrete IL-9 in copious amounts. This has resulted in renewed interest in this cytokine, which was neglected since discovery because it was considered it to be just another T_H2 cytokine. Recent studies have shown that it has multiple cellular sources and is critically involved in the immune-pathogenesis of inflammatory diseases and in guarding immune tolerance. In this review, we will discuss its discovery, gene organization, cellular sources, and signaling pathways. Especially, we will give an update on the recent development regarding its relevance in the immune pathogenesis of human diseases. Full article

(This article belongs to the Special Issue Signaling: From Past to Future)

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22 pages, 1930 KiB

Open AccessReview

Differential Regulation of Type I and Type III Interferon Signaling

by Megan L. Stanifer, Kalliopi Pervolaraki and Steeve Boulant

Int. J. Mol. Sci. 2019, 20(6), 1445; https://doi.org/10.3390/ijms20061445 - 21 Mar 2019

Cited by 150 | Viewed by 21115

Abstract

Interferons (IFNs) are very powerful cytokines, which play a key role in combatting pathogen infections by controlling inflammation and immune response by directly inducing anti-pathogen molecular countermeasures. There are three classes of IFNs: type I, type II and type III. While type II [...] Read more.

Interferons (IFNs) are very powerful cytokines, which play a key role in combatting pathogen infections by controlling inflammation and immune response by directly inducing anti-pathogen molecular countermeasures. There are three classes of IFNs: type I, type II and type III. While type II IFN is specific for immune cells, type I and III IFNs are expressed by both immune and tissue specific cells. Unlike type I IFNs, type III IFNs have a unique tropism where their signaling and functions are mostly restricted to epithelial cells. As such, this class of IFN has recently emerged as a key player in mucosal immunity. Since the discovery of type III IFNs, the last 15 years of research in the IFN field has focused on understanding whether the induction, the signaling and the function of these powerful cytokines are regulated differently compared to type I IFN-mediated immune response. This review will cover the current state of the knowledge of the similarities and differences in the signaling pathways emanating from type I and type III IFN stimulation. Full article

(This article belongs to the Special Issue Signaling: From Past to Future)

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22 pages, 2815 KiB

Open AccessReview

Functional Annotation of Bacterial Signal Transduction Systems: Progress and Challenges

by David Martín-Mora, Matilde Fernández, Félix Velando, Álvaro Ortega, José A. Gavira, Miguel A. Matilla and Tino Krell

Int. J. Mol. Sci. 2018, 19(12), 3755; https://doi.org/10.3390/ijms19123755 - 26 Nov 2018

Cited by 19 | Viewed by 7762

Abstract

Bacteria possess a large number of signal transduction systems that sense and respond to different environmental cues. Most frequently these are transcriptional regulators, two-component systems and chemosensory pathways. A major bottleneck in the field of signal transduction is the lack of information on [...] Read more.

Bacteria possess a large number of signal transduction systems that sense and respond to different environmental cues. Most frequently these are transcriptional regulators, two-component systems and chemosensory pathways. A major bottleneck in the field of signal transduction is the lack of information on signal molecules that modulate the activity of the large majority of these systems. We review here the progress made in the functional annotation of sensor proteins using high-throughput ligand screening approaches of purified sensor proteins or individual ligand binding domains. In these assays, the alteration in protein thermal stability following ligand binding is monitored using Differential Scanning Fluorimetry. We illustrate on several examples how the identification of the sensor protein ligand has facilitated the elucidation of the molecular mechanism of the regulatory process. We will also discuss the use of virtual ligand screening approaches to identify sensor protein ligands. Both approaches have been successfully applied to functionally annotate a significant number of bacterial sensor proteins but can also be used to study proteins from other kingdoms. The major challenge consists in the study of sensor proteins that do not recognize signal molecules directly, but that are activated by signal molecule-loaded binding proteins. Full article

(This article belongs to the Special Issue Signaling: From Past to Future)

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12 pages, 961 KiB

Open AccessReview

Neglected Functions of TFCP2/TFCP2L1/UBP1 Transcription Factors May Offer Valuable Insights into Their Mechanisms of Action

by Agnieszka Taracha, Grzegorz Kotarba and Tomasz Wilanowski

Int. J. Mol. Sci. 2018, 19(10), 2852; https://doi.org/10.3390/ijms19102852 - 20 Sep 2018

Cited by 28 | Viewed by 5191

Abstract

In recent years, the TFCP2 (transcription factor cellular promoter 2)/TFCP2L1 (TFCP2-like 1)/UBP1 (upstream binding protein 1) subfamily of transcription factors has been attracting increasing attention in the scientific community. These factors are very important in cancer, Alzheimer’s disease, and other human conditions, and [...] Read more.

In recent years, the TFCP2 (transcription factor cellular promoter 2)/TFCP2L1 (TFCP2-like 1)/UBP1 (upstream binding protein 1) subfamily of transcription factors has been attracting increasing attention in the scientific community. These factors are very important in cancer, Alzheimer’s disease, and other human conditions, and they can be attractive targets for drug development. However, the interpretation of experimental results is complicated, as in principle, any of these factors could substitute for the lack of another. Thus, studying their hitherto little known functions should enhance our understanding of mechanisms of their functioning, and analogous mechanisms might govern their functioning in medically relevant contexts. For example, there are numerous parallels between placental development and cancer growth; therefore, investigating the roles of TFCP2, TFCP2L1, and UBP1 in the placenta may help us better understand their functioning in cancer, as is evidenced by the studies of various other proteins and pathways. Our review article aims to call the attention of the scientific community to these neglected functions, and encourage further research in this field. Here, we present a systematic review of current knowledge of the TFCP2/TFCP2L1/UBP1 subfamily in reproduction, embryonic development, renal function, blood-pressure regulation, brain function, and other processes, where their involvement has not been studied much until now. Full article

(This article belongs to the Special Issue Signaling: From Past to Future)

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23 pages, 2038 KiB

Open AccessReview

General Pathways of Pain Sensation and the Major Neurotransmitters Involved in Pain Regulation

by Mun Fei Yam, Yean Chun Loh, Chu Shan Tan, Siti Khadijah Adam, Nizar Abdul Manan and Rusliza Basir

Int. J. Mol. Sci. 2018, 19(8), 2164; https://doi.org/10.3390/ijms19082164 - 24 Jul 2018

Cited by 374 | Viewed by 46291

Abstract

Pain has been considered as a concept of sensation that we feel as a reaction to the stimulus of our surrounding, putting us in harm’s way and acting as a form of defense mechanism that our body has permanently installed into its system. [...] Read more.

Pain has been considered as a concept of sensation that we feel as a reaction to the stimulus of our surrounding, putting us in harm’s way and acting as a form of defense mechanism that our body has permanently installed into its system. However, pain leads to a huge chunk of finances within the healthcare system with continuous rehabilitation of patients with adverse pain sensations, which might reduce not only their quality of life but also their productivity at work setting back the pace of our economy. It may not look like a huge deal but factor in pain as an issue for majority of us, it becomes an economical burden. Although pain has been researched into and understood by numerous researches, from its definition, mechanism of action to its inhibition in hopes of finding an absolute solution for victims of pain, the pathways of pain sensation, neurotransmitters involved in producing such a sensation are not comprehensively reviewed. Therefore, this review article aims to put in place a thorough understanding of major pain conditions that we experience—nociceptive, inflammatory and physiologically dysfunction, such as neuropathic pain and its modulation and feedback systems. Moreover, the complete mechanism of conduction is compiled within this article, elucidating understandings from various researches and breakthroughs. Full article

(This article belongs to the Special Issue Signaling: From Past to Future)

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9 pages, 220 KiB

Open AccessMeeting Report

Report of the 23rd Meeting on Signal Transduction 2019—Trends in Cancer and Infection

by Bastian Schirmer, Klaudia Giehl and Katharina F. Kubatzky

Int. J. Mol. Sci. 2020, 21(8), 2728; https://doi.org/10.3390/ijms21082728 - 15 Apr 2020

Viewed by 2401

Abstract

The annual meeting “Signal Transduction–Receptors, Mediators and Genes” of the Signal Transduction Society (STS) is an interdisciplinary conference open to all scientists sharing the common interest in elucidating the signalling pathways underlying the physiological or pathological processes in health and disease of humans, [...] Read more.

The annual meeting “Signal Transduction–Receptors, Mediators and Genes” of the Signal Transduction Society (STS) is an interdisciplinary conference open to all scientists sharing the common interest in elucidating the signalling pathways underlying the physiological or pathological processes in health and disease of humans, animals, plants, fungi, prokaryotes and protists. The 23rd meeting on signal transduction was held from 4–6 November 2019 in Weimar, Germany, and focused on “Trends in Cancer and Infection”. As usual, keynote presentations by invited scientists introduced the respective workshops and were followed by speakers chosen from the submitted abstracts. Ample time had been reserved for discussion of the presented data during the workshops. In this report, we provide a concise summary of the various workshops and further aspects of the scientific program. Full article

(This article belongs to the Special Issue Signaling: From Past to Future)

6 pages, 204 KiB

Open AccessMeeting Report

Report of the Signal Transduction Society Meeting 2018—Signaling: From Past to Future

by Bastian Schirmer, Klaudia Giehl and Katharina F. Kubatzky

Int. J. Mol. Sci. 2019, 20(1), 227; https://doi.org/10.3390/ijms20010227 - 8 Jan 2019

Viewed by 8962

Abstract

The annual meeting “Signal Transduction—Receptors, Mediators, and Genes” of the Signal Transduction Society (STS) is an interdisciplinary conference open to all scientists sharing the common interest in elucidating signaling pathways in physiological or pathological processes in humans, animals, plants, fungi, prokaryotes, and protists. [...] Read more.

The annual meeting “Signal Transduction—Receptors, Mediators, and Genes” of the Signal Transduction Society (STS) is an interdisciplinary conference open to all scientists sharing the common interest in elucidating signaling pathways in physiological or pathological processes in humans, animals, plants, fungi, prokaryotes, and protists. On the occasion of the 20th anniversary of the STS, the 22nd joint meeting took place in Weimar from 5–7 November 2018. With the focus topic “Signaling: From Past to Future” the evolution of the multifaceted research concerning signal transduction since foundation of the society was highlighted. Invited keynote speakers introduced the respective workshop topics and were followed by numerous speakers selected from the submitted abstracts. All presentations were lively discussed during the workshops. Here, we provide a concise summary of the various workshops and further aspects of the scientific program. Full article

(This article belongs to the Special Issue Signaling: From Past to Future)

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