International Journal of Molecular Sciences

Editorial

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Open AccessEditorial

Editorial of the Special Issue: Signaling Molecules and Signal Transduction in Cells

by Jens Schlossmann

Int. J. Mol. Sci. 2013, 14(6), 11438-11443; https://doi.org/10.3390/ijms140611438 - 29 May 2013

Cited by 2 | Viewed by 6090

Abstract

In the special issue “Signaling Molecules and Signal Transduction in Cells” authors were invited to submit papers regarding important and novel aspects of extra- and intracellular signaling which have implications on physiological and pathophysiological processes. These aspects included compounds which are involved in [...] Read more.

In the special issue “Signaling Molecules and Signal Transduction in Cells” authors were invited to submit papers regarding important and novel aspects of extra- and intracellular signaling which have implications on physiological and pathophysiological processes. These aspects included compounds which are involved in these processes, elucidation of signaling pathways, as well as novel techniques for the analysis of signaling pathways. In response, various novel and important topics are elucidated in this special issue. Full article

(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells)

Research

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NS5ATP9 Contributes to Inhibition of Cell Proliferation by Hepatitis C Virus (HCV) Nonstructural Protein 5A (NS5A) via MEK/Extracellular Signal Regulated Kinase (ERK) Pathway

by Qi Wang, Yongsheng Wang, Yue Li, Xuesong Gao, Shunai Liu and Jun Cheng

Int. J. Mol. Sci. 2013, 14(5), 10539-10551; https://doi.org/10.3390/ijms140510539 - 21 May 2013

Cited by 8 | Viewed by 7780

Abstract

Hepatitis C virus (HCV) nonstructural protein 5A (NS5A) is a remarkable protein as it clearly plays multiple roles in mediating viral replication, host-cell interactions and viral pathogenesis. However, on the impact of cell growth, there have been different study results. NS5ATP9, also known [...] Read more.

Hepatitis C virus (HCV) nonstructural protein 5A (NS5A) is a remarkable protein as it clearly plays multiple roles in mediating viral replication, host-cell interactions and viral pathogenesis. However, on the impact of cell growth, there have been different study results. NS5ATP9, also known as KIAA0101, p15PAF, L5, and OEACT-1, was first identified as a proliferating cell nuclear antigen-binding protein. Earlier studies have shown that NS5ATP9 might play an important role in HCV infection. The aim of this study is to investigate the function of NS5ATP9 on hepatocellular carcinoma (HCC) cell lines proliferation under HCV NS5A expression. The results showed that overexpression of NS5ATP9 inhibited the proliferation of Bel7402 cells, whereas knockdown of NS5ATP9 by interfering RNA promoted the growth of HepG2 cells. Under HCV NS5A expression, RNA interference (RNAi) targeting of NS5ATP9 could reverse the inhibition of HepG2 cell proliferation, suggesting that NS5ATP9 might be an anti-proliferation gene that plays an important role in the suppression of cell growth mediated by HCV NS5A via MEK/ERK signaling pathway. These findings might provide new insights into HCV NS5A and NS5ATP9. Full article

(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells)

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Vascular Endothelial Growth Factor Induces CXCL1 Chemokine Release via JNK and PI-3K-Dependent Pathways in Human Lung Carcinoma Epithelial Cells

by Huey-Ming Lo, Jiunn-Min Shieh, Chih-Li Chen, Chih-Jen Tsou and Wen-Bin Wu

Int. J. Mol. Sci. 2013, 14(5), 10090-10106; https://doi.org/10.3390/ijms140510090 - 10 May 2013

Cited by 32 | Viewed by 8393

Abstract

Lung cancer cells express different chemokines and chemokine receptors that modulate leukocyte infiltration within tumor microenvironment. In this study we screened several mediators/growth factors on CXCL1 release in human carcinoma epithelial cells. Of the tested mediators, VEGF was found to have a robust [...] Read more.

Lung cancer cells express different chemokines and chemokine receptors that modulate leukocyte infiltration within tumor microenvironment. In this study we screened several mediators/growth factors on CXCL1 release in human carcinoma epithelial cells. Of the tested mediators, VEGF was found to have a robust increase in causing CXCL1 release. VEGF stimulated CXCL1 release and mRNA expression in a time- and concentration-dependent manner. The release was inhibited by the VEGF receptor antagonists and the JNK, PI-3K, tyrosine kinase, and transcription inhibitors. In parallel, VEGF induced JNK, PI3K and Akt activation. Strikingly, among these inhibitors only the JNK inhibitor could reduce VEGF-induced CXCL1 mRNA expression, suggesting that JNK participated in VEGF-induced CXCL1 synthesis, whereas PI-3K was responsible for cellular CXCL1 secretory process. In addition, the steroid dexamethasone and TGF-β suppressed CXCL1 release through a transcriptional regulation. We also showed that cells stimulated with VEGF significantly attracted monocyte migration, which could be abolished by CXCL1 B/N Ab, CXC receptor 2 antagonist, TGF-β, and dexamethasone. In summary, we provide here evidence showing JNK activation for VEGF-induced CXCL1 DNA transcription and PI-3K pathway for extracellular CXCL1 release in human carcinoma epithelial cells. The released CXCL1 was functionally linked to recruiting monocytes into lung cancer cell microenvironment. Full article

(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells)

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Open AccessArticle

Excitation and Adaptation in Bacteria–a Model Signal Transduction System that Controls Taxis and Spatial Pattern Formation

by Hans G. Othmer, Xiangrong Xin and Chuan Xue

Int. J. Mol. Sci. 2013, 14(5), 9205-9248; https://doi.org/10.3390/ijms14059205 - 26 Apr 2013

Cited by 18 | Viewed by 9015

Abstract

The machinery for transduction of chemotactic stimuli in the bacterium E. coli is one of the most completely characterized signal transduction systems, and because of its relative simplicity, quantitative analysis of this system is possible. Here we discuss models which reproduce many of [...] Read more.

The machinery for transduction of chemotactic stimuli in the bacterium E. coli is one of the most completely characterized signal transduction systems, and because of its relative simplicity, quantitative analysis of this system is possible. Here we discuss models which reproduce many of the important behaviors of the system. The important characteristics of the signal transduction system are excitation and adaptation, and the latter implies that the transduction system can function as a “derivative sensor” with respect to the ligand concentration in that the DC component of a signal is ultimately ignored if it is not too large. This temporal sensing mechanism provides the bacterium with a memory of its passage through spatially- or temporally-varying signal fields, and adaptation is essential for successful chemotaxis. We also discuss some of the spatial patterns observed in populations and indicate how cell-level behavior can be embedded in population-level descriptions. Full article

(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells)

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Role of UPR Pathway in Defense Response of Aedes aegypti against Cry11Aa Toxin from Bacillus thuringiensis

by Leidy P. Bedoya-Pérez, Angeles Cancino-Rodezno, Biviana Flores-Escobar, Mario Soberón and Alejandra Bravo

Int. J. Mol. Sci. 2013, 14(4), 8467-8478; https://doi.org/10.3390/ijms14048467 - 17 Apr 2013

Cited by 24 | Viewed by 7189

Abstract

The insecticidal Cry toxins are pore-forming toxins produced by the bacteria Bacillus thuringiensis that disrupt insect-midgut cells. Cells can trigger different survival mechanisms to counteract the effects of sub-lytic doses of pore forming toxins. Particularly, two signaling pathways have been demonstrated to play [...] Read more.

The insecticidal Cry toxins are pore-forming toxins produced by the bacteria Bacillus thuringiensis that disrupt insect-midgut cells. Cells can trigger different survival mechanisms to counteract the effects of sub-lytic doses of pore forming toxins. Particularly, two signaling pathways have been demonstrated to play a role in the defense mechanism to other toxins in Caenorhabditis elegans and in mammalian cells. These are the unfolded protein response (UPR) and the sterol regulatory element binding proteins (SREBP) pathways, which are proposed to facilitate membrane repair responses. In this work we analyzed the role of these pathways in Aedes aegypti response to intoxication with Cry11Aa toxin. We show that UPR is activated upon toxin ingestion. The role of these two pathways was analyzed in vivo by using RNA interference. We silenced the expression of specific proteins in A. aegypti larvae. Gene silencing of Ire-1 and Xbp-1 proteins from UPR system, resulted in hypersensitive to Cry11Aa toxin action. In contrast, silencing of Cas-1, Scap and S2P from SREBP pathway had no affect on Cry11Aa toxicity in A. aegypti larvae. However, the role of SREBP pathway requires further studies to be conclusive. Our data indicate that the UPR pathway is involved in the insect defense against Cry toxins. Full article

(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells)

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Loss of SUMOylation on ATF3 Inhibits Proliferation of Prostate Cancer Cells by Modulating CCND1/2 Activity

by Chiung-Min Wang and Wei-Hsiung Yang

Int. J. Mol. Sci. 2013, 14(4), 8367-8380; https://doi.org/10.3390/ijms14048367 - 16 Apr 2013

Cited by 17 | Viewed by 7161

Abstract

SUMOylation plays an important role in regulating a wide range of cellular processes. Previously, we showed that ATF3, a stress response mediator, can be SUMOylated and lysine 42 is the major SUMO site. However, the significance of ATF3 SUMOylation in biological processes is [...] Read more.

SUMOylation plays an important role in regulating a wide range of cellular processes. Previously, we showed that ATF3, a stress response mediator, can be SUMOylated and lysine 42 is the major SUMO site. However, the significance of ATF3 SUMOylation in biological processes is still poorly understood. In the present study, we investigated the role of ATF3 SUMOylation on CCND activity and cellular proliferation in human prostate cancer cells. First, we showed that ATF3 can be SUMOylated endogenously in the overexpression system, and lysine 42 is the major SUMO site. Unlike normal prostate tissue and androgen-responsive LNCaP cancer cells, androgen-independent PC3 and DU145 cancer cells did not express ATF3 endogenously. Overexpression of ATF3 increased CCND1/2 expression in PC3 and DU145 cancer cells. Interestingly, we observed that SUMOylation is essential for ATF3-mediated CCND1/2 activation. Finally, we observed that SUMOylation plays a functional role in ATF3-mediated cellular proliferation in PC3 and DU145 cells. Taken together, our results demonstrate that SUMO modification of ATF3 influences CCND1/2 activity and cellular proliferation of prostate cancer PC3 and DU145 cells and explains at least in part how ATF3 functions to regulate cancer development. Full article

(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells)

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Characterization and Expression of the Gene Encoding En-MAPK1, an Intestinal Cell Kinase (ICK)-like Kinase Activated by the Autocrine Pheromone-Signaling Loop in the Polar Ciliate, Euplotes nobilii

by Annalisa Candelori, Pierangelo Luporini, Claudio Alimenti and Adriana Vallesi

Int. J. Mol. Sci. 2013, 14(4), 7457-7467; https://doi.org/10.3390/ijms14047457 - 3 Apr 2013

Cited by 5 | Viewed by 6205

Abstract

In the protozoan ciliate Euplotes, a transduction pathway resulting in a mitogenic cell growth response is activated by autocrine receptor binding of cell type-specific, water-borne signaling protein pheromones. In Euplotes raikovi, a marine species of temperate waters, this transduction pathway was [...] Read more.

In the protozoan ciliate Euplotes, a transduction pathway resulting in a mitogenic cell growth response is activated by autocrine receptor binding of cell type-specific, water-borne signaling protein pheromones. In Euplotes raikovi, a marine species of temperate waters, this transduction pathway was previously shown to involve the phosphorylation of a nuclear protein kinase structurally similar to the intestinal-cell and male germ cell-associated kinases described in mammals. In E. nobilii, which is phylogenetically closely related to E. raikovi but inhabits Antarctic and Arctic waters, we have now characterized a gene encoding a structurally homologous kinase. The expression of this gene requires +1 translational frameshifting and a process of intron splicing for the production of the active protein, designated En-MAPK1, which contains amino acid substitutions of potential significance for cold-adaptation. Full article

(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells)

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Analysis of Epithelial Growth Factor-Receptor (EGFR) Phosphorylation in Uterine Smooth Muscle Tumors: Correlation to Mucin-1 and Galectin-3 Expression

by Tobias Weissenbacher, Thomas Vrekoussis, David Roeder, Antonis Makrigiannakis, Doris Mayr, Nina Ditsch, Klaus Friese, Udo Jeschke and Darius Dian

Int. J. Mol. Sci. 2013, 14(3), 4783-4792; https://doi.org/10.3390/ijms14034783 - 28 Feb 2013

Cited by 6 | Viewed by 7111

Abstract

Uterine fibroids are the commonest uterine benign tumors. A potential mechanism of malignant transformation from leiomyomas to leiomyosarcomas has been described. Tyrosine phosphorylation is a key mechanism that controls biological functions, such as proliferation and cell differentiation. The aim of the current study [...] Read more.

Uterine fibroids are the commonest uterine benign tumors. A potential mechanism of malignant transformation from leiomyomas to leiomyosarcomas has been described. Tyrosine phosphorylation is a key mechanism that controls biological functions, such as proliferation and cell differentiation. The aim of the current study was to evaluate the phosphorylation of epithelial growth factor-receptor (EGFR) in normal myometrium, uterine myomas and uterine leiomyosarcomas. Formalin-fixed paraffin-embedded tissue samples from normal myometrium, leiomyomas and leiomyosarcomas were studied. Samples were immunohistochemically (IHC) assessed using the anti-EGFR phosphorylation of Y845 (pEGFR-Y845) and anti-pEGFR-Y1173 phosphorylation-specific antibodies. IHC staining was evaluated using a semiquantitative score. The expression of pEGFR-Y845 was significantly upregulated in leiomyosarcomas (p < 0.001) compared to leiomyomas and normal myometrium. In contrast, pEGFR-Y1173 did not differ significantly between the three groups of the study. Correlation analysis revealed an overall positive correlation between pEGFR Y845 and mucin 1 (MUC1). Further subgroup analysis within the tumoral group (myomas and leiomyosarcomas) revealed an additional negative correlation between pEGFR Y845 and galectin-3 (gal-3) staining. On the contrary no significant correlation was noted within the non-tumoral group. An upregulated EGFR phosphorylation of Y845 in leiomyosarcomas compared to leiomyomas implicates EGFR activation at this special receptor site. Due to these pEGFR-Y845 variations, it can be postulated that MUC1 interacts with it, whereas gal-3 seems to be cleaved from Y845 phosphorylated EGFR. Further research on this field could focus on differences in EGFR pathways as a potentially advantageous diagnostic tool for investigation of benign and malignant signal transduction processes. Full article

(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells)

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Cesium Inhibits Plant Growth through Jasmonate Signaling in Arabidopsis thaliana

by Eri Adams, Parisa Abdollahi and Ryoung Shin

Int. J. Mol. Sci. 2013, 14(3), 4545-4559; https://doi.org/10.3390/ijms14034545 - 25 Feb 2013

Cited by 37 | Viewed by 9831

Abstract

It has been suggested that cesium is absorbed from the soil through potassium uptake machineries in plants; however, not much is known about perception mechanism and downstream response. Here, we report that the jasmonate pathway is required in plant response to cesium. Jasmonate [...] Read more.

It has been suggested that cesium is absorbed from the soil through potassium uptake machineries in plants; however, not much is known about perception mechanism and downstream response. Here, we report that the jasmonate pathway is required in plant response to cesium. Jasmonate biosynthesis mutant aos and jasmonate-insensitive mutant coi1-16 show clear resistance to root growth inhibition caused by cesium. However, the potassium and cesium contents in these mutants are comparable to wild-type plants, indicating that jasmonate biosynthesis and signaling are not involved in cesium uptake, but involved in cesium perception. Cesium induces expression of a high-affinity potassium transporter gene HAK5 and reduces potassium content in the plant body, suggesting a competitive nature of potassium and cesium uptake in plants. It has also been found that cesium-induced HAK5 expression is antagonized by exogenous application of methyl-jasmonate. Taken together, it has been indicated that cesium inhibits plant growth via induction of the jasmonate pathway and likely modifies potassium uptake machineries. Full article

(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells)

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Evidence for the Involvement of RhoA Signaling in the Ethanol-Induced Increase in Intestinal Epithelial Barrier Permeability

by Jing Tong, Ying Wang, Bing Chang, Dai Zhang and Bingyuan Wang

Int. J. Mol. Sci. 2013, 14(2), 3946-3960; https://doi.org/10.3390/ijms14023946 - 18 Feb 2013

Cited by 23 | Viewed by 7789

Abstract

In this work, we investigated the potential role of the small G protein RhoA in ethanol-induced tight junction (TJ) protein disassembly and increased intestinal epithelial barrier (IEB) permeability. Our study used Caco-2 cells as an in vitro IEB model and RhoA short hairpin [...] Read more.

In this work, we investigated the potential role of the small G protein RhoA in ethanol-induced tight junction (TJ) protein disassembly and increased intestinal epithelial barrier (IEB) permeability. Our study used Caco-2 cells as an in vitro IEB model and RhoA short hairpin RNA (shRNA) interference to establish whether RhoA plays a role in ethanol-induced TJ opening. RhoA shRNA interference partially inhibited epithelial leakage and restored normal transepithelial electrical resistance (TEER) values in the IEB. Moreover, RhoA shRNA interference prevented a shift in occludin distribution from insoluble to soluble fractions. Additionally, RhoA shRNA interference inhibited the ethanol-induced expression of zonula occludens-1 (ZO-1). Finally, RhoA shRNA interference inhibited an ethanol-induced increase in RhoA activity. The contributions of RhoA to an ethanol-induced increase in IEB permeability are associated with TJ disassembly. Full article

(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells)

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Epidermal Growth Factor Stimulates Extracellular-Signal Regulated Kinase Phosphorylation of a Novel Site on Cytoplasmic Dynein Intermediate Chain 2

by Ashok K. Pullikuth, Aysun Ozdemir, Daviel Cardenas, Evangeline Bailey, Nicholas E. Sherman, K. Kevin Pfister and Andrew D. Catling

Int. J. Mol. Sci. 2013, 14(2), 3595-3620; https://doi.org/10.3390/ijms14023595 - 7 Feb 2013

Cited by 8 | Viewed by 7210

Abstract

Extracellular-signal regulated kinase (ERK) signaling is required for a multitude of physiological and patho-physiological processes. However, the identities of the proteins that ERK phosphorylates to elicit these responses are incompletely known. Using an affinity purification methodology of general utility, here we identify cytoplasmic [...] Read more.

Extracellular-signal regulated kinase (ERK) signaling is required for a multitude of physiological and patho-physiological processes. However, the identities of the proteins that ERK phosphorylates to elicit these responses are incompletely known. Using an affinity purification methodology of general utility, here we identify cytoplasmic dynein intermediate chain 2 (DYNC1I-2, IC-2) as a novel substrate for ERK following epidermal growth factor receptor stimulation of fibroblasts. IC-2 is a subunit of cytoplasmic dynein, a minus-end directed motor protein necessary for transport of diverse cargos along microtubules. Emerging data support the hypothesis that post-translational modification regulates dynein but the signaling mechanisms used are currently unknown. We find that ERK phosphorylates IC-2 on a novel, highly conserved Serine residue proximal to the binding site for the p150^Glued subunit of the cargo adapter dynactin. Surprisingly, neither constitutive phosphorylation nor a phosphomimetic substitution of this Serine influences binding of p150^Glued to IC-2. These data suggest that ERK phosphorylation of IC-2 regulates dynein function through mechanisms other than its interaction with dynactin. Full article

(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells)

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Regulation of Erythropoietin Receptor Activity in Endothelial Cells by Different Erythropoietin (EPO) Derivatives: An in Vitro Study

by Maria Letizia Trincavelli, Eleonora Da Pozzo, Osele Ciampi, Serena Cuboni, Simona Daniele, Maria Pia Abbracchio and Claudia Martini

Int. J. Mol. Sci. 2013, 14(2), 2258-2281; https://doi.org/10.3390/ijms14022258 - 24 Jan 2013

Cited by 32 | Viewed by 8167

Abstract

In endothelial cells, erythropoietin receptors (EPORs) mediate the protective, proliferative and angiogenic effects of EPO and its analogues, which act as EPOR agonists. Because hormonal receptors undergo functional changes upon chronic exposure to agonists and because erythropoiesis-stimulating agents (ESAs) are used for the [...] Read more.

In endothelial cells, erythropoietin receptors (EPORs) mediate the protective, proliferative and angiogenic effects of EPO and its analogues, which act as EPOR agonists. Because hormonal receptors undergo functional changes upon chronic exposure to agonists and because erythropoiesis-stimulating agents (ESAs) are used for the long-term treatment of anemia, it is critical to determine the mechanism by which EPOR responsiveness is regulated at the vascular level after prolonged exposure to ESAs. Here, we investigated EPOR desensitization/resensitization in human umbilical vein endothelial cells (HUVECs) upon exposure to three ESAs with different pharmacokinetic profiles, epoetin alpha (EPOα), darbepoetin alpha (DarbEPO) and continuous EPOR activator (CERA). These agonists all induced activation of the transcription factor STAT-5, which is a component of the intracellular pathway associated with EPORs. STAT-5 activation occurred with either monophasic or biphasic kinetics for EPOα/DarbEPO and CERA, respectively. ESAs, likely through activation of the STAT-5 pathway, induced endothelial cell proliferation and stimulated angiogenesis in vitro, demonstrating a functional role for epoetins on endothelial cells. All epoetins induced EPOR desensitization with more rapid kinetics for CERA compared to EPOα and DarbEPO. However, the recovery of receptor responsiveness was strictly dependent on the type of epoetin, the agonist concentration and the time of exposure to the agonist. EPOR resensitization occurred with more rapid kinetics after exposure to low epoetin concentrations for a short period of desensitization. When the highest concentration of agonists was tested, the recovery of receptor responsiveness was more rapid with CERA compared to EPOα and was completely absent with DarbEPO. Our results demonstrate that these three ESAs regulate EPOR resensitization by very different mechanisms and that both the type of molecule and the length of EPOR stimulation are factors that are critical for the control of EPOR functioning in endothelial cells. The differences observed in receptor resensitization after stimulation with the structurally different ESAs are most likely due different control mechanisms of receptor turnover at the intracellular level. Full article

(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells)

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Ochratoxin A Inhibits Mouse Embryonic Development by Activating a Mitochondrion-Dependent Apoptotic Signaling Pathway

by Yan-Der Hsuuw, Wen-Hsiung Chan and Jau-Song Yu

Int. J. Mol. Sci. 2013, 14(1), 935-953; https://doi.org/10.3390/ijms14010935 - 7 Jan 2013

Cited by 45 | Viewed by 6848

Abstract

Ochratoxin A (OTA), a mycotoxin found in many foods worldwide, causes nephrotoxicity, hepatotoxicity, and immunotoxicity, both in vitro and in vivo. In the present study, we explored the cytotoxic effects exerted by OTA on the blastocyst stage of mouse embryos, on subsequent [...] Read more.

Ochratoxin A (OTA), a mycotoxin found in many foods worldwide, causes nephrotoxicity, hepatotoxicity, and immunotoxicity, both in vitro and in vivo. In the present study, we explored the cytotoxic effects exerted by OTA on the blastocyst stage of mouse embryos, on subsequent embryonic attachment, on outgrowth in vitro, and following in vivo implantation via embryo transfer. Mouse blastocysts were incubated with or without OTA (1, 5, or 10 μM) for 24 h. Cell proliferation and growth were investigated using dual differential staining; apoptosis was measured using the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay; and embryo implantation and post-implantation development were assessed by examination of in vitro growth and the outcome of in vivo embryo transfer, respectively. Blastocysts treated with 10 μM OTA displayed a significantly increased level of apoptosis and a reduction in total cell number. Interestingly, we observed no marked difference in implantation success rate between OTA-pretreated and control blastocysts either during in vitro embryonic development (following implantation in a fibronectin-coated culture dish) or after in vivo embryo transfer. However, in vitro treatment with 10 μM OTA was associated with increased resorption of post-implantation embryos by the mouse uterus, and decreased fetal weight upon embryo transfer. Our results collectively indicate that in vitro exposure to OTA triggers apoptosis and retards early post-implantation development after transfer of embryos to host mice. In addition, OTA induces apoptosis-mediated injury of mouse blastocysts, via reactive oxygen species (ROS) generation, and promotes mitochondrion-dependent apoptotic signaling processes that impair subsequent embryonic development. Full article

(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells)

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Apoptosis is Induced in Cancer Cells via the Mitochondrial Pathway by the Novel Xylocydine-Derived Compound JRS-15

by Chao Sun, Xiao-Xi Guo, Dan Zhu, Chuan Xiao, Xiao Bai, Yang Li, Zhuo Zhan, Xiang-Long Li, Zhi-Guang Song and Ying-Hua Jin

Int. J. Mol. Sci. 2013, 14(1), 850-870; https://doi.org/10.3390/ijms14010850 - 4 Jan 2013

Cited by 14 | Viewed by 7413

Abstract

The novel compound JRS-15 was obtained through the chemical modification of xylocydine. JRS-15 exhibited much stronger cytotoxic and pro-apoptotic activity than its parent compound in various cancer cell lines, with IC₅₀ values in HeLa, HepG2, SK-HEP-1, PC-3M and A549 cells ranging from [...] Read more.

The novel compound JRS-15 was obtained through the chemical modification of xylocydine. JRS-15 exhibited much stronger cytotoxic and pro-apoptotic activity than its parent compound in various cancer cell lines, with IC₅₀ values in HeLa, HepG2, SK-HEP-1, PC-3M and A549 cells ranging from 12.42 to 28.25 µM. In addition, it is more potent for killing cancer than non-cancerous cells. Mechanistic studies showed that JRS-15 treatment arrested cell cycle at the G1/S phase, which further triggered the translocation of Bax and Bak to the mitochondria, resulting in mitochondrial membrane potential (MMP) depolarization and the subsequent release of cytochrome c and the second mitochondria-derived activator of caspase (Smac). The sequential activation of caspase-9 and caspase-3/7 and the cleavage of poly (ADP-ribose) polymerase (PARP) were observed following these mitochondrial events. Caspase-8, an initiator caspase that is required to activate the membrane receptor-mediated extrinsic apoptosis pathway was not activated in JRS-15-treated cells. Further analysis showed that the levels of the anti-apoptotic proteins Bcl-xL and XIAP were significantly reduced upon JRS-15 treatment. Furthermore, the caspase-9 inhibitor z-LEHD-fmk, the pan-caspase inhibitor z-VAD-fmk, and Bcl-xL or XIAP overexpression all effectively prevented JRS-15-induced apoptosis. Taken together, these results indicate that JRS-15 induces cancer cell apoptosis by regulating multiple apoptosis-related proteins, and this compound may therefore be a good candidate reagent for anticancer therapy. Full article

(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells)

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Antitumor Effects of Rapamycin in Pancreatic Cancer Cells by Inducing Apoptosis and Autophagy

by Zhi-Jun Dai, Jie Gao, Xiao-Bin Ma, Hua-Feng Kang, Bao-Feng Wang, Wang-Feng Lu, Shuai Lin, Xi-Jing Wang and Wen-Ying Wu

Int. J. Mol. Sci. 2013, 14(1), 273-285; https://doi.org/10.3390/ijms14010273 - 21 Dec 2012

Cited by 39 | Viewed by 8371

Abstract

Rapamycin (Rapa), an inhibitor of mammalian target of Rapamycin (mTOR), is an immunosuppressive agent that has anti-proliferative effects on some tumors. This study aims to investigate the effects of Rapa suppressing proliferation of pancreatic carcinoma PC-2 cells in vitro and its molecular mechanism [...] Read more.

Rapamycin (Rapa), an inhibitor of mammalian target of Rapamycin (mTOR), is an immunosuppressive agent that has anti-proliferative effects on some tumors. This study aims to investigate the effects of Rapa suppressing proliferation of pancreatic carcinoma PC-2 cells in vitro and its molecular mechanism involved in antitumor activities. MTT assays showed that the inhibition of proliferation of PC-2 cells in vitro was in a time- and dose-dependent manner. By using transmission electron microscopy, apoptosis bodies and formation of abundant autophagic vacuoles were observed in PC-2 cells after Rapa treatment. Flow cytometry assays also showed Rapa had a positive effect on apoptosis. MDC staining showed that the fluorescent density was higher and the number of MDC-labeled particles in PC-2 cells was greater in the Rapa treatment group than in the control group. RT-PCR revealed that the expression levels of p53, Bax and Beclin 1 were up-regulated in a dose-dependent manner, indicating that Beclin 1 was involved in Rapa induced autophagy and Rapa induced apoptosis as well as p53 up-regulation in PC-2 cells. The results demonstrated that Rapa could effectively inhibit proliferation and induce apoptosis and autophagy in PC-2 cells. Full article

(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells)

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Ginsenoside Rh2 Induces Human Hepatoma Cell Apoptosisvia Bax/Bak Triggered Cytochrome C Release and Caspase-9/Caspase-8 Activation

by Xiao-Xi Guo, Qiao Guo, Yang Li, Seung Ki Lee, Xue-Ning Wei and Ying-Hua Jin

Int. J. Mol. Sci. 2012, 13(12), 15523-15535; https://doi.org/10.3390/ijms131215523 - 22 Nov 2012

Cited by 40 | Viewed by 7558

Abstract

Ginsenoside Rh2 (G-Rh2) has been shown to induce apoptotic cell death in a variety of cancer cells. However, the details of the signal transduction cascade involved in G-Rh2-induced cell death is unclear. In this manuscript we elucidate the molecular mechanism of G-Rh2-induced apoptosis [...] Read more.

Ginsenoside Rh2 (G-Rh2) has been shown to induce apoptotic cell death in a variety of cancer cells. However, the details of the signal transduction cascade involved in G-Rh2-induced cell death is unclear. In this manuscript we elucidate the molecular mechanism of G-Rh2-induced apoptosis in human hepatoma SK-HEP-1 cells by demonstrating that G-Rh2 causes rapid and dramatic translocation of both Bak and Bax, which subsequently triggers mitochondrial cytochrome c release and consequent caspase activation. Interestingly, siRNA-based gene inactivation of caspase-8 effectively delays caspase-9 activation and apoptosis induced by G-Rh2, indicating that caspase-8 also plays an important role in the G-Rh2-induced apoptosis program. Taken together, our results indicate that G-Rh2 employs a multi pro-apoptotic pathway to execute cancer cell death, suggesting a potential role for G-Rh2 as a powerful chemotherapeutic agent. Full article

(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells)

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Review

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Toll-Like Receptors in Atherosclerosis

by Mika Falck-Hansen, Christina Kassiteridi and Claudia Monaco

Int. J. Mol. Sci. 2013, 14(7), 14008-14023; https://doi.org/10.3390/ijms140714008 - 4 Jul 2013

Cited by 105 | Viewed by 10417

Abstract

Atherosclerosis, the leading cause of cardiovascular disease (CVD), is driven by inflammation. Increasing evidence suggests that toll-like receptors (TLRs) are key orchestrators of the atherosclerotic disease process. Interestingly, a distinct picture is being revealed for individual receptors in atherosclerosis. TLRs exhibit a complex [...] Read more.

Atherosclerosis, the leading cause of cardiovascular disease (CVD), is driven by inflammation. Increasing evidence suggests that toll-like receptors (TLRs) are key orchestrators of the atherosclerotic disease process. Interestingly, a distinct picture is being revealed for individual receptors in atherosclerosis. TLRs exhibit a complex nature enabling the detection of multiple motifs named danger-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs). Activation of these receptors triggers an intracellular signalling cascade mediated through MyD88 or TRIF, leading to the production of pro- and anti-inflammatory cytokines. In this review we explore key novel findings pertaining to TLR signalling in atherosclerosis, including recently described endosomal TLRs and future directions in TLR research. Full article

(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells)

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Role of Cytokine Signaling during Nervous System Development

by Alyaa Mousa and Moiz Bakhiet

Int. J. Mol. Sci. 2013, 14(7), 13931-13957; https://doi.org/10.3390/ijms140713931 - 4 Jul 2013

Cited by 68 | Viewed by 9012

Abstract

Cytokines are signaling proteins that were first characterized as components of the immune response, but have been found to have pleiotropic effects in diverse aspects of body function in health and disease. They are secreted by numerous cells and are used extensively in [...] Read more.

Cytokines are signaling proteins that were first characterized as components of the immune response, but have been found to have pleiotropic effects in diverse aspects of body function in health and disease. They are secreted by numerous cells and are used extensively in intercellular communications to produce different activities, including intricate processes engaged in the ontogenetic development of the brain. This review discusses factors involved in brain growth regulation and recent findings exploring cytokine signaling pathways during development of the central nervous system. In view of existing data suggesting roles for neurotropic cytokines in promoting brain growth and repair, these molecules and their signaling pathways might become targets for therapeutic intervention in neurodegenerative processes due to diseases, toxicity, or trauma. Full article

(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells)

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Cellular Functions Regulated by Phosphorylation of EGFR on Tyr845

by Ken-ichi Sato

Int. J. Mol. Sci. 2013, 14(6), 10761-10790; https://doi.org/10.3390/ijms140610761 - 23 May 2013

Cited by 75 | Viewed by 13418

Abstract

The Src gene product (Src) and the epidermal growth factor receptor (EGFR) are prototypes of oncogene products and function primarily as a cytoplasmic non-receptor tyrosine kinase and a transmembrane receptor tyrosine kinase, respectively. The identification of Src and EGFR, and the subsequent extensive [...] Read more.

The Src gene product (Src) and the epidermal growth factor receptor (EGFR) are prototypes of oncogene products and function primarily as a cytoplasmic non-receptor tyrosine kinase and a transmembrane receptor tyrosine kinase, respectively. The identification of Src and EGFR, and the subsequent extensive investigations of these proteins have long provided cutting edge research in cancer and other molecular and cellular biological studies. In 1995, we reported that the human epidermoid carcinoma cells, A431, contain a small fraction of Src and EGFR in which these two kinase were in physical association with each other, and that Src phosphorylates EGFR on tyrosine 845 (Y845) in the Src-EGFR complex. Y845 of EGFR is located in the activation segment of the kinase domain, where many protein kinases contain kinase-activating autophosphorylation sites (e.g., cAMP-dependent protein kinase, Src family kinases, transmembrane receptor type tyrosine kinases) or trans-phosphorylation sites (e.g., cyclin-dependent protein kinase, mitogen-activated protein kinase, Akt protein kinase). A number of studies have demonstrated that Y845 phosphorylation serves an important role in cancer as well as normal cells. Here we compile the experimental facts involving Src phosphorylation of EGFR on Y845, by which cell proliferation, cell cycle control, mitochondrial regulation of cell metabolism, gamete activation and other cellular functions are regulated. We also discuss the physiological relevance, as well as structural insights of the Y845 phosphorylation. Full article

(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells)

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MAPKs and Signal Transduction in the Control of Gastrointestinal Epithelial Cell Proliferation and Differentiation

by Luciana H. Osaki and Patrícia Gama

Int. J. Mol. Sci. 2013, 14(5), 10143-10161; https://doi.org/10.3390/ijms140510143 - 13 May 2013

Cited by 119 | Viewed by 11983

Abstract

Mitogen-activated protein kinase (MAPK) pathways are activated by several stimuli and transduce the signal inside cells, generating diverse responses including cell proliferation, differentiation, migration and apoptosis. Each MAPK cascade comprises a series of molecules, and regulation takes place at different levels. They communicate [...] Read more.

Mitogen-activated protein kinase (MAPK) pathways are activated by several stimuli and transduce the signal inside cells, generating diverse responses including cell proliferation, differentiation, migration and apoptosis. Each MAPK cascade comprises a series of molecules, and regulation takes place at different levels. They communicate with each other and with additional pathways, creating a signaling network that is important for cell fate determination. In this review, we focus on ERK, JNK, p38 and ERK5, the major MAPKs, and their interactions with PI3K-Akt, TGFβ/Smad and Wnt/β-catenin pathways. More importantly, we describe how MAPKs regulate cell proliferation and differentiation in the rapidly renewing epithelia that lines the gastrointestinal tract and, finally, we highlight the recent findings on nutritional aspects that affect MAPK transduction cascades. Full article

(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells)

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Calcium in Red Blood Cells—A Perilous Balance

by Anna Bogdanova, Asya Makhro, Jue Wang, Peter Lipp and Lars Kaestner

Int. J. Mol. Sci. 2013, 14(5), 9848-9872; https://doi.org/10.3390/ijms14059848 - 8 May 2013

Cited by 188 | Viewed by 14794

Abstract

Ca²⁺ is a universal signalling molecule involved in regulating cell cycle and fate, metabolism and structural integrity, motility and volume. Like other cells, red blood cells (RBCs) rely on Ca²⁺ dependent signalling during differentiation from precursor cells. Intracellular Ca²⁺ levels [...] Read more.

Ca²⁺ is a universal signalling molecule involved in regulating cell cycle and fate, metabolism and structural integrity, motility and volume. Like other cells, red blood cells (RBCs) rely on Ca²⁺ dependent signalling during differentiation from precursor cells. Intracellular Ca²⁺ levels in the circulating human RBCs take part not only in controlling biophysical properties such as membrane composition, volume and rheological properties, but also physiological parameters such as metabolic activity, redox state and cell clearance. Extremely low basal permeability of the human RBC membrane to Ca²⁺ and a powerful Ca²⁺ pump maintains intracellular free Ca²⁺ levels between 30 and 60 nM, whereas blood plasma Ca²⁺ is approximately 1.8 mM. Thus, activation of Ca²⁺ uptake has an impressive impact on multiple processes in the cells rendering Ca²⁺ a master regulator in RBCs. Malfunction of Ca²⁺ transporters in human RBCs leads to excessive accumulation of Ca²⁺ within the cells. This is associated with a number of pathological states including sickle cell disease, thalassemia, phosphofructokinase deficiency and other forms of hereditary anaemia. Continuous progress in unravelling the molecular nature of Ca²⁺ transport pathways allows harnessing Ca²⁺ uptake, avoiding premature RBC clearance and thrombotic complications. This review summarizes our current knowledge of Ca²⁺ signalling in RBCs emphasizing the importance of this inorganic cation in RBC function and survival. Full article

(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells)

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Cell Signaling Experiments Driven by Optical Manipulation

by Francesco Difato, Giulietta Pinato and Dan Cojoc

Int. J. Mol. Sci. 2013, 14(5), 8963-8984; https://doi.org/10.3390/ijms14058963 - 25 Apr 2013

Cited by 13 | Viewed by 10988

Abstract

Cell signaling involves complex transduction mechanisms in which information released by nearby cells or extracellular cues are transmitted to the cell, regulating fundamental cellular activities. Understanding such mechanisms requires cell stimulation with precise control of low numbers of active molecules at high spatial [...] Read more.

Cell signaling involves complex transduction mechanisms in which information released by nearby cells or extracellular cues are transmitted to the cell, regulating fundamental cellular activities. Understanding such mechanisms requires cell stimulation with precise control of low numbers of active molecules at high spatial and temporal resolution under physiological conditions. Optical manipulation techniques, such as optical tweezing, mechanical stress probing or nano-ablation, allow handling of probes and sub-cellular elements with nanometric and millisecond resolution. PicoNewton forces, such as those involved in cell motility or intracellular activity, can be measured with femtoNewton sensitivity while controlling the biochemical environment. Recent technical achievements in optical manipulation have new potentials, such as exploring the actions of individual molecules within living cells. Here, we review the progress in optical manipulation techniques for single-cell experiments, with a focus on force probing, cell mechanical stimulation and the local delivery of active molecules using optically manipulated micro-vectors and laser dissection. Full article

(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells)

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Intercellular Signaling Pathway among Endothelia, Astrocytes and Neurons in Excitatory Neuronal Damage

by Takako Takemiya and Kanato Yamagata

Int. J. Mol. Sci. 2013, 14(4), 8345-8357; https://doi.org/10.3390/ijms14048345 - 16 Apr 2013

Cited by 19 | Viewed by 7788

Abstract

Neurons interact closely with astrocytes via glutamate; this neuron-glia circuit may play a pivotal role in synaptic transmission. On the other hand, astrocytes contact vascular endothelial cells with their end-feet. It is becoming obvious that non-neuronal cells play a critical role in regulating [...] Read more.

Neurons interact closely with astrocytes via glutamate; this neuron-glia circuit may play a pivotal role in synaptic transmission. On the other hand, astrocytes contact vascular endothelial cells with their end-feet. It is becoming obvious that non-neuronal cells play a critical role in regulating the neuronal activity in the brain. We find that kainic acid (KA) administration induces the expression of microsomal prostaglandin E synthase-1 (mPGES-1) in venous endothelial cells and the prostaglandin E₂ (PGE₂) receptor prostaglandin E receptor (EP)-3 on astrocytes. Endothelial mPGES-1 exacerbates KA-induced neuronal damage in in vivo experiments. In in vitro experiments, mPGES-1 produces PGE₂, which enhances astrocytic Ca²⁺ levels via the EP3 receptor and increases Ca²⁺-dependent glutamate release, thus aggravating neuronal injury. This novel endothelium-astrocyte-neuron signaling pathway may be crucial for driving neuronal damage after repetitive seizures and could be a new therapeutic target for epilepsy and other brain disorders. Full article

(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells)

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Biophysical Techniques for Detection of cAMP and cGMP in Living Cells

by Julia U. Sprenger and Viacheslav O. Nikolaev

Int. J. Mol. Sci. 2013, 14(4), 8025-8046; https://doi.org/10.3390/ijms14048025 - 12 Apr 2013

Cited by 62 | Viewed by 10548

Abstract

Cyclic nucleotides cAMP and cGMP are ubiquitous second messengers which regulate myriads of functions in virtually all eukaryotic cells. Their intracellular effects are often mediated via discrete subcellular signaling microdomains. In this review, we will discuss state-of-the-art techniques to measure cAMP and cGMP [...] Read more.

Cyclic nucleotides cAMP and cGMP are ubiquitous second messengers which regulate myriads of functions in virtually all eukaryotic cells. Their intracellular effects are often mediated via discrete subcellular signaling microdomains. In this review, we will discuss state-of-the-art techniques to measure cAMP and cGMP in biological samples with a particular focus on live cell imaging approaches, which allow their detection with high temporal and spatial resolution in living cells and tissues. Finally, we will describe how these techniques can be applied to the analysis of second messenger dynamics in subcellular signaling microdomains. Full article

(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells)

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Emerging Roles for Intersectin (ITSN) in Regulating Signaling and Disease Pathways

by Michael P. Hunter, Angela Russo and John P. O'Bryan

Int. J. Mol. Sci. 2013, 14(4), 7829-7852; https://doi.org/10.3390/ijms14047829 - 10 Apr 2013

Cited by 42 | Viewed by 8769

Abstract

Intersectins (ITSNs) represent a family of multi-domain adaptor proteins that regulate endocytosis and cell signaling. ITSN genes are highly conserved and present in all metazoan genomes examined thus far. Lower eukaryotes have only one ITSN gene, whereas higher eukaryotes have two ITSN genes. [...] Read more.

Intersectins (ITSNs) represent a family of multi-domain adaptor proteins that regulate endocytosis and cell signaling. ITSN genes are highly conserved and present in all metazoan genomes examined thus far. Lower eukaryotes have only one ITSN gene, whereas higher eukaryotes have two ITSN genes. ITSN was first identified as an endocytic scaffold protein, and numerous studies reveal a conserved role for ITSN in endocytosis. Subsequently, ITSNs were found to regulate multiple signaling pathways including receptor tyrosine kinases (RTKs), GTPases, and phosphatidylinositol 3-kinase Class 2beta (PI3KC2β). ITSN has also been implicated in diseases such as Down Syndrome (DS), Alzheimer Disease (AD), and other neurodegenerative disorders. This review summarizes the evolutionary conservation of ITSN, the latest research on the role of ITSN in endocytosis, the emerging roles of ITSN in regulating cell signaling pathways, and the involvement of ITSN in human diseases such as DS, AD, and cancer. Full article

(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells)

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Distinct Signaling Cascades Elicited by Different Formyl Peptide Receptor 2 (FPR2) Agonists

by Fabio Cattaneo, Melania Parisi and Rosario Ammendola

Int. J. Mol. Sci. 2013, 14(4), 7193-7230; https://doi.org/10.3390/ijms14047193 - 2 Apr 2013

Cited by 143 | Viewed by 17463

Abstract

The formyl peptide receptor 2 (FPR2) is a remarkably versatile transmembrane protein belonging to the G-protein coupled receptor (GPCR) family. FPR2 is activated by an array of ligands, which include structurally unrelated lipids and peptide/proteins agonists, resulting in different intracellular responses in a [...] Read more.

The formyl peptide receptor 2 (FPR2) is a remarkably versatile transmembrane protein belonging to the G-protein coupled receptor (GPCR) family. FPR2 is activated by an array of ligands, which include structurally unrelated lipids and peptide/proteins agonists, resulting in different intracellular responses in a ligand-specific fashion. In addition to the anti-inflammatory lipid, lipoxin A4, several other endogenous agonists also bind FPR2, including serum amyloid A, glucocorticoid-induced annexin 1, urokinase and its receptor, suggesting that the activation of FPR2 may result in potent pro- or anti-inflammatory responses. Other endogenous ligands, also present in biological samples, include resolvins, amyloidogenic proteins, such as beta amyloid (Aβ)-42 and prion protein (Prp)_106–126, the neuroprotective peptide, humanin, antibacterial peptides, annexin 1-derived peptides, chemokine variants, the neuropeptides, vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating polypeptide (PACAP)-27, and mitochondrial peptides. Upon activation, intracellular domains of FPR2 mediate signaling to G-proteins, which trigger several agonist-dependent signal transduction pathways, including activation of phospholipase C (PLC), protein kinase C (PKC) isoforms, the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway, the mitogen-activated protein kinase (MAPK) pathway, p38MAPK, as well as the phosphorylation of cytosolic tyrosine kinases, tyrosine kinase receptor transactivation, phosphorylation and nuclear translocation of regulatory transcriptional factors, release of calcium and production of oxidants. FPR2 is an attractive therapeutic target, because of its involvement in a range of normal physiological processes and pathological diseases. Here, we review and discuss the most significant findings on the intracellular pathways and on the cross-communication between FPR2 and tyrosine kinase receptors triggered by different FPR2 agonists. Full article

(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells)

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Skeletal Muscle Function during Exercise—Fine-Tuning of Diverse Subsystems by Nitric Oxide

by Frank Suhr, Sebastian Gehlert, Marijke Grau and Wilhelm Bloch

Int. J. Mol. Sci. 2013, 14(4), 7109-7139; https://doi.org/10.3390/ijms14047109 - 28 Mar 2013

Cited by 57 | Viewed by 15377

Abstract

Skeletal muscle is responsible for altered acute and chronic workload as induced by exercise. Skeletal muscle adaptations range from immediate change of contractility to structural adaptation to adjust the demanded performance capacities. These processes are regulated by mechanically and metabolically induced signaling pathways, [...] Read more.

Skeletal muscle is responsible for altered acute and chronic workload as induced by exercise. Skeletal muscle adaptations range from immediate change of contractility to structural adaptation to adjust the demanded performance capacities. These processes are regulated by mechanically and metabolically induced signaling pathways, which are more or less involved in all of these regulations. Nitric oxide is one of the central signaling molecules involved in functional and structural adaption in different cell types. It is mainly produced by nitric oxide synthases (NOS) and by non-enzymatic pathways also in skeletal muscle. The relevance of a NOS-dependent NO signaling in skeletal muscle is underlined by the differential subcellular expression of NOS1, NOS2, and NOS3, and the alteration of NO production provoked by changes of workload. In skeletal muscle, a variety of highly relevant tasks to maintain skeletal muscle integrity and proper signaling mechanisms during adaptation processes towards mechanical and metabolic stimulations are taken over by NO signaling. The NO signaling can be mediated by cGMP-dependent and -independent signaling, such as S-nitrosylation-dependent modulation of effector molecules involved in contractile and metabolic adaptation to exercise. In this review, we describe the most recent findings of NO signaling in skeletal muscle with a special emphasis on exercise conditions. However, to gain a more detailed understanding of the complex role of NO signaling for functional adaptation of skeletal muscle (during exercise), additional sophisticated studies are needed to provide deeper insights into NO-mediated signaling and the role of non-enzymatic-derived NO in skeletal muscle physiology. Full article

(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells)

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Cytokines and the Skin Barrier

by Kai H. Hänel, Christian Cornelissen, Bernhard Lüscher and Jens Malte Baron

Int. J. Mol. Sci. 2013, 14(4), 6720-6745; https://doi.org/10.3390/ijms14046720 - 26 Mar 2013

Cited by 232 | Viewed by 22724

Abstract

The skin is the largest organ of the human body and builds a barrier to protect us from the harmful environment and also from unregulated loss of water. Keratinocytes form the skin barrier by undergoing a highly complex differentiation process that involves changing [...] Read more.

The skin is the largest organ of the human body and builds a barrier to protect us from the harmful environment and also from unregulated loss of water. Keratinocytes form the skin barrier by undergoing a highly complex differentiation process that involves changing their morphology and structural integrity, a process referred to as cornification. Alterations in the epidermal cornification process affect the formation of the skin barrier. Typically, this results in a disturbed barrier, which allows the entry of substances into the skin that are immunologically reactive. This contributes to and promotes inflammatory processes in the skin but also affects other organs. In many common skin diseases, including atopic dermatitis and psoriasis, a defect in the formation of the skin barrier is observed. In these diseases the cytokine composition within the skin is different compared to normal human skin. This is the result of resident skin cells that produce cytokines, but also because additional immune cells are recruited. Many of the cytokines found in defective skin are able to influence various processes of differentiation and cornification. Here we summarize the current knowledge on cytokines and their functions in healthy skin and their contributions to inflammatory skin diseases. Full article

(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells)

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Aptamers and Their Potential to Selectively Target Aspects of EGF, Wnt/β-Catenin and TGFβ–Smad Family Signaling

by Andrea Conidi, Veronique Van den Berghe and Danny Huylebroeck

Int. J. Mol. Sci. 2013, 14(4), 6690-6719; https://doi.org/10.3390/ijms14046690 - 26 Mar 2013

Cited by 32 | Viewed by 13242

Abstract

The smooth identification and low-cost production of highly specific agents that interfere with signaling cascades by targeting an active domain in surface receptors, cytoplasmic and nuclear effector proteins, remain important challenges in biomedical research. We propose that peptide aptamers can provide a very [...] Read more.

The smooth identification and low-cost production of highly specific agents that interfere with signaling cascades by targeting an active domain in surface receptors, cytoplasmic and nuclear effector proteins, remain important challenges in biomedical research. We propose that peptide aptamers can provide a very useful and new alternative for interfering with protein–protein interactions in intracellular signal transduction cascades, including those emanating from activated receptors for growth factors. By their targeting of short, linear motif type of interactions, peptide aptamers have joined nucleic acid aptamers for use in signaling studies because of their ease of production, their stability, their high specificity and affinity for individual target proteins, and their use in high-throughput screening protocols. Furthermore, they are entering clinical trials for treatment of several complex, pathological conditions. Here, we present a brief survey of the use of aptamers in signaling pathways, in particular of polypeptide growth factors, starting with the published as well as potential applications of aptamers targeting Epidermal Growth Factor Receptor signaling. We then discuss the opportunities for using aptamers in other complex pathways, including Wnt/β-catenin, and focus on Transforming Growth Factor-β/Smad family signaling. Full article

(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells)

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Diacylglycerol Kinases: Regulated Controllers of T Cell Activation, Function, and Development

by Rohan P. Joshi and Gary A. Koretzky

Int. J. Mol. Sci. 2013, 14(4), 6649-6673; https://doi.org/10.3390/ijms14046649 - 26 Mar 2013

Cited by 38 | Viewed by 10007

Abstract

Diacylglycerol kinases (DGKs) are a diverse family of enzymes that catalyze the conversion of diacylglycerol (DAG), a crucial second messenger of receptor-mediated signaling, to phosphatidic acid (PA). Both DAG and PA are bioactive molecules that regulate a wide set of intracellular signaling proteins [...] Read more.

Diacylglycerol kinases (DGKs) are a diverse family of enzymes that catalyze the conversion of diacylglycerol (DAG), a crucial second messenger of receptor-mediated signaling, to phosphatidic acid (PA). Both DAG and PA are bioactive molecules that regulate a wide set of intracellular signaling proteins involved in innate and adaptive immunity. Clear evidence points to a critical role for DGKs in modulating T cell activation, function, and development. More recently, studies have elucidated factors that control DGK function, suggesting an added complexity to how DGKs act during signaling. This review summarizes the available knowledge of the function and regulation of DGK isoforms in signal transduction with a particular focus on T lymphocytes. Full article

(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells)

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UPR Signal Activation by Luminal Sensor Domains

by Marta Carrara, Filippo Prischi and Maruf M. U. Ali

Int. J. Mol. Sci. 2013, 14(3), 6454-6466; https://doi.org/10.3390/ijms14036454 - 21 Mar 2013

Cited by 38 | Viewed by 10084

Abstract

The unfolded protein response (UPR) is a cell-signaling system that detects the accumulation of unfolded protein within the endoplasmic reticulum (ER) and initiates a number of cellular responses to restore ER homeostasis. The presence of unfolded protein is detected by the ER-luminal sensor [...] Read more.

The unfolded protein response (UPR) is a cell-signaling system that detects the accumulation of unfolded protein within the endoplasmic reticulum (ER) and initiates a number of cellular responses to restore ER homeostasis. The presence of unfolded protein is detected by the ER-luminal sensor domains of the three UPR-transducer proteins IRE1, PERK, and ATF6, which then propagate the signal to the cytosol. In this review, we discuss the various mechanisms of action that have been proposed on how the sensor domains detect the presence of unfolded protein to activate downstream UPR signaling. Full article

(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells)

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Ubiquitinations in the Notch Signaling Pathway

by Julien Moretti and Christel Brou

Int. J. Mol. Sci. 2013, 14(3), 6359-6381; https://doi.org/10.3390/ijms14036359 - 19 Mar 2013

Cited by 54 | Viewed by 11579

Abstract

The very conserved Notch pathway is used iteratively during development and adulthood to regulate cell fates. Notch activation relies on interactions between neighboring cells, through the binding of Notch receptors to their ligands, both transmembrane molecules. This inter-cellular contact initiates a cascade of [...] Read more.

The very conserved Notch pathway is used iteratively during development and adulthood to regulate cell fates. Notch activation relies on interactions between neighboring cells, through the binding of Notch receptors to their ligands, both transmembrane molecules. This inter-cellular contact initiates a cascade of events eventually transforming the cell surface receptor into a nuclear factor acting on the transcription of specific target genes. This review highlights how the various processes undergone by Notch receptors and ligands that regulate the pathway are linked to ubiquitination events. Full article

(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells)

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Integration of Multiple Signaling Pathways Determines Differences in the Osteogenic Potential and Tissue Regeneration of Neural Crest-Derived and Mesoderm-Derived Calvarial Bones

by Kshemendra Senarath-Yapa, Shuli Li, Nathaniel P. Meyer, Michael T. Longaker and Natalina Quarto

Int. J. Mol. Sci. 2013, 14(3), 5978-5997; https://doi.org/10.3390/ijms14035978 - 15 Mar 2013

Cited by 26 | Viewed by 9623

Abstract

The mammalian skull vault, a product of a unique and tightly regulated evolutionary process, in which components of disparate embryonic origin are integrated, is an elegant model with which to study osteoblast biology. Our laboratory has demonstrated that this distinct embryonic origin of [...] Read more.

The mammalian skull vault, a product of a unique and tightly regulated evolutionary process, in which components of disparate embryonic origin are integrated, is an elegant model with which to study osteoblast biology. Our laboratory has demonstrated that this distinct embryonic origin of frontal and parietal bones confer differences in embryonic and postnatal osteogenic potential and skeletal regenerative capacity, with frontal neural crest derived osteoblasts benefitting from greater osteogenic potential.We outline how this model has been used to elucidate some of the molecular mechanisms which underlie these differences and place these findings into the context of our current understanding of the key, highly conserved, pathways which govern the osteoblast lineage including FGF, BMP, Wnt and TGFβ signaling. Furthermore, we explore recent studies which have provided a tantalizing insight into way these pathways interact, with evidence accumulating for certain transcription factors, such as Runx2, acting as a nexus for cross-talk. Full article

(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells)

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Functions and Mechanisms of Fibroblast Growth Factor (FGF) Signalling in Drosophila melanogaster

by Villö Muha and Hans-Arno J. Müller

Int. J. Mol. Sci. 2013, 14(3), 5920-5937; https://doi.org/10.3390/ijms14035920 - 14 Mar 2013

Cited by 49 | Viewed by 13254

Abstract

Intercellular signalling via growth factors plays an important role in controlling cell differentiation and cell movements during the development of multicellular animals. Fibroblast Growth Factor (FGF) signalling induces changes in cellular behaviour allowing cells in the embryo to move, to survive, to divide [...] Read more.

Intercellular signalling via growth factors plays an important role in controlling cell differentiation and cell movements during the development of multicellular animals. Fibroblast Growth Factor (FGF) signalling induces changes in cellular behaviour allowing cells in the embryo to move, to survive, to divide or to differentiate. Several examples argue that FGF signalling is used in multi-step morphogenetic processes to achieve and maintain a transitional state of the cells required for the control of cell fate. In the genetic model Drosophila melanogaster, FGF signalling via the receptor tyrosine kinases Heartless (Htl) and Breathless (Btl) is particularly well studied. These FGF receptors affect gene expression, cell shape and cell–cell interactions during mesoderm layer formation, caudal visceral muscle (CVM) formation, tracheal morphogenesis and glia differentiation. Here, we will address the current knowledge of the biological functions of FGF signalling in the fly on the tissue, at a cellular and molecular level. Full article

(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells)

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Understanding Resolvin Signaling Pathways to Improve Oral Health

by David Keinan, Noel J. Leigh, Joel W. Nelson, Laura De Oleo and Olga J. Baker

Int. J. Mol. Sci. 2013, 14(3), 5501-5518; https://doi.org/10.3390/ijms14035501 - 8 Mar 2013

Cited by 26 | Viewed by 9932

Abstract

The discovery of resolvins has been a major breakthrough for understanding the processes involved in resolution of inflammation. Resolvins belong to a family of novel lipid mediators that possess dual anti-inflammatory and pro-resolution actions. Specifically, they protect healthy tissue during immune-inflammatory responses to [...] Read more.

The discovery of resolvins has been a major breakthrough for understanding the processes involved in resolution of inflammation. Resolvins belong to a family of novel lipid mediators that possess dual anti-inflammatory and pro-resolution actions. Specifically, they protect healthy tissue during immune-inflammatory responses to infection or injury, thereby aiding inflammation resolution and promoting tissue healing. One of the major concerns in modern medicine is the management and treatment of oral diseases, as they are related to systemic outcomes impacting the quality of life of many patients. This review summarizes known signaling pathways utilized by resolvins to regulate inflammatory responses associated with the oral cavity. Full article

(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells)

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Exosomes as Intercellular Signaling Organelles Involved in Health and Disease: Basic Science and Clinical Applications

by Chiara Corrado, Stefania Raimondo, Antonio Chiesi, Francesco Ciccia, Giacomo De Leo and Riccardo Alessandro

Int. J. Mol. Sci. 2013, 14(3), 5338-5366; https://doi.org/10.3390/ijms14035338 - 6 Mar 2013

Cited by 326 | Viewed by 19332

Abstract

Cell to cell communication is essential for the coordination and proper organization of different cell types in multicellular systems. Cells exchange information through a multitude of mechanisms such as secreted growth factors and chemokines, small molecules (peptides, ions, bioactive lipids and nucleotides), cell-cell [...] Read more.

Cell to cell communication is essential for the coordination and proper organization of different cell types in multicellular systems. Cells exchange information through a multitude of mechanisms such as secreted growth factors and chemokines, small molecules (peptides, ions, bioactive lipids and nucleotides), cell-cell contact and the secretion of extracellular matrix components. Over the last few years, however, a considerable amount of experimental evidence has demonstrated the occurrence of a sophisticated method of cell communication based on the release of specialized membranous nano-sized vesicles termed exosomes. Exosome biogenesis involves the endosomal compartment, the multivesicular bodies (MVB), which contain internal vesicles packed with an extraordinary set of molecules including enzymes, cytokines, nucleic acids and different bioactive compounds. In response to stimuli, MVB fuse with the plasma membrane and vesicles are released in the extracellular space where they can interact with neighboring cells and directly induce a signaling pathway or affect the cellular phenotype through the transfer of new receptors or even genetic material. This review will focus on exosomes as intercellular signaling organelles involved in a number of physiological as well as pathological processes and their potential use in clinical diagnostics and therapeutics. Full article

(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells)

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Wnt Secretion and Gradient Formation

by Gonzalo P. Solis, Anne-Marie Lüchtenborg and Vladimir L. Katanaev

Int. J. Mol. Sci. 2013, 14(3), 5130-5145; https://doi.org/10.3390/ijms14035130 - 1 Mar 2013

Cited by 24 | Viewed by 8181

Abstract

Concentration gradients formed by the lipid-modified morphogens of the Wnt family are known for their pivotal roles during embryogenesis and adult tissue homeostasis. Wnt morphogens are also implicated in a variety of human diseases, especially cancer. Therefore, the signaling cascades triggered by Wnts [...] Read more.

Concentration gradients formed by the lipid-modified morphogens of the Wnt family are known for their pivotal roles during embryogenesis and adult tissue homeostasis. Wnt morphogens are also implicated in a variety of human diseases, especially cancer. Therefore, the signaling cascades triggered by Wnts have received considerable attention during recent decades. However, how Wnts are secreted and how concentration gradients are formed remains poorly understood. The use of model organisms such as Drosophila melanogaster has provided important advances in this area. For instance, we have previously shown that the lipid raft-associated reggie/flotillin proteins influence Wnt secretion and spreading in Drosophila. Our work supports the notion that producing cells secrete Wnt molecules in at least two pools: a poorly diffusible one and a reggie/flotillin-dependent highly diffusible pool which allows morphogen spreading over long distances away from its source of production. Here we revise the current views of Wnt secretion and spreading, and propose two models for the role of the reggie/flotillin proteins in these processes: (i) reggies/flotillins regulate the basolateral endocytosis of the poorly diffusible, membrane-bound Wnt pool, which is then sorted and secreted to apical compartments for long-range diffusion, and (ii) lipid rafts organized by reggies/flotillins serve as “dating points” where extracellular Wnt transiently interacts with lipoprotein receptors to allow its capture and further spreading via lipoprotein particles. We further discuss these processes in the context of human breast cancer. A better understanding of these phenomena may be relevant for identification of novel drug targets and therapeutic strategies. Full article

(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells)

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775 KiB

Open AccessReview

Mitogen-Activated Protein (MAP) Kinase Scaffolding Proteins: A Recount

by Melanie Meister, Ana Tomasovic, Antje Banning and Ritva Tikkanen

Int. J. Mol. Sci. 2013, 14(3), 4854-4884; https://doi.org/10.3390/ijms14034854 - 1 Mar 2013

Cited by 62 | Viewed by 24793

Abstract

The mitogen-activated protein kinase (MAPK) pathway is the canonical signaling pathway for many receptor tyrosine kinases, such as the Epidermal Growth Factor Receptor. Downstream of the receptors, this pathway involves the activation of a kinase cascade that culminates in a transcriptional response and [...] Read more.

The mitogen-activated protein kinase (MAPK) pathway is the canonical signaling pathway for many receptor tyrosine kinases, such as the Epidermal Growth Factor Receptor. Downstream of the receptors, this pathway involves the activation of a kinase cascade that culminates in a transcriptional response and affects processes, such as cell migration and adhesion. In addition, the strength and duration of the upstream signal also influence the mode of the cellular response that is switched on. Thus, the same components can in principle coordinate opposite responses, such as proliferation and differentiation. In recent years, it has become evident that MAPK signaling is regulated and fine-tuned by proteins that can bind to several MAPK signaling proteins simultaneously and, thereby, affect their function. These so-called MAPK scaffolding proteins are, thus, important coordinators of the signaling response in cells. In this review, we summarize the recent advances in the research on MAPK/extracellular signal-regulated kinase (ERK) pathway scaffolders. We will not only review the well-known members of the family, such as kinase suppressor of Ras (KSR), but also put a special focus on the function of the recently identified or less studied scaffolders, such as fibroblast growth factor receptor substrate 2, flotillin-1 and mitogen-activated protein kinase organizer 1. Full article

(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells)

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Open AccessReview

Atypical Protein Phosphatases: Emerging Players in Cellular Signaling

by Daichi Sadatomi, Susumu Tanimura, Kei-ichi Ozaki and Kohsuke Takeda

Int. J. Mol. Sci. 2013, 14(3), 4596-4612; https://doi.org/10.3390/ijms14034596 - 26 Feb 2013

Cited by 27 | Viewed by 10340

Abstract

It has generally been considered that protein phosphatases have more diverse catalytic domain structures and mechanisms than protein kinases; however, gene annotation efforts following the human genome project appeared to have completed the whole array of protein phosphatases. Ser/Thr phosphatases are divided into [...] Read more.

It has generally been considered that protein phosphatases have more diverse catalytic domain structures and mechanisms than protein kinases; however, gene annotation efforts following the human genome project appeared to have completed the whole array of protein phosphatases. Ser/Thr phosphatases are divided into three subfamilies that have different structures from each other, whereas Tyr phosphatases and dual-specificity phosphatases targeting Tyr, Ser and Thr belong to a single large family based on their common structural features. Several years of research have revealed, however, the existence of unexpected proteins, designated here as “atypical protein phosphatases”, that have structural and enzymatic features different from those of the known protein phosphatases and are involved in important biological processes. In this review, we focus on the identification and functional characterization of atypical protein phosphatases, represented by eyes absent (EYA), suppressor of T-cell receptor signaling (Sts) and phosphoglycerate mutase family member 5 (PGAM5) and discuss their biological significance in cellular signaling. Full article

(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells)

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481 KiB

Open AccessReview

Cell Survival and Apoptosis Signaling as Therapeutic Target for Cancer: Marine Bioactive Compounds

by Senthilkumar Kalimuthu and Kim Se-Kwon

Int. J. Mol. Sci. 2013, 14(2), 2334-2354; https://doi.org/10.3390/ijms14022334 - 24 Jan 2013

Cited by 107 | Viewed by 16430

Abstract

Inhibition of apoptosis leads to activation of cell survival factors (e.g., AKT) causes continuous cell proliferation in cancer. Apoptosis, the major form of cellular suicide, is central to various physiological processes and the maintenance of homeostasis in multicellular organisms. A number of discoveries [...] Read more.

Inhibition of apoptosis leads to activation of cell survival factors (e.g., AKT) causes continuous cell proliferation in cancer. Apoptosis, the major form of cellular suicide, is central to various physiological processes and the maintenance of homeostasis in multicellular organisms. A number of discoveries have clarified the molecular mechanism of apoptosis, thus clarifying the link between apoptosis and cell survival factors, which has a therapeutic outcome. Induction of apoptosis and inhibition of cell survival by anticancer agents has been shown to correlate with tumor response. Cellular damage induces growth arrest and tumor suppression by inducing apoptosis, necrosis and senescence; the mechanism of cell death depends on the magnitude of DNA damage following exposure to various anticancer agents. Apoptosis is mainly regulated by cell survival and proliferating signaling molecules. As a new therapeutic strategy, alternative types of cell death might be exploited to control and eradicate cancer cells. This review discusses the signaling of apoptosis and cell survival, as well as the potential contribution of marine bioactive compounds, suggesting that new therapeutic strategies might follow. Full article

(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells)

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156 KiB

Open AccessReview

Spatial Regulation of Epidermal Growth Factor Receptor Signaling by Endocytosis

by Brian P. Ceresa

Int. J. Mol. Sci. 2013, 14(1), 72-87; https://doi.org/10.3390/ijms14010072 - 20 Dec 2012

Cited by 23 | Viewed by 9905

Abstract

Signaling by cell surface receptors appears to be relatively straight-forward: ligand binds to the extracellular domain of the receptor and biochemical changes are communicated into the cell. However, this process is more complex than it first seems due to the various mechanisms that [...] Read more.

Signaling by cell surface receptors appears to be relatively straight-forward: ligand binds to the extracellular domain of the receptor and biochemical changes are communicated into the cell. However, this process is more complex than it first seems due to the various mechanisms that regulate signaling. In order to effectively target these receptors for pharmacological purposes, a more complete understanding of how their signaling is regulated is needed. Here, how the endocytic pathway regulates receptor signaling is discussed, using the epidermal growth factor receptor (EGFR) as a model. In particular, the spatial regulation of signaling is examined. Areas of discussion include: how endocytic trafficking affects biology/pathology, varying approaches for studying the relationship between receptor endocytosis and signaling, and developments in how the endocytic pathway controls EGFR:effector communication and EGFR-mediated cell biology. Full article

(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells)

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269 KiB

Open AccessReview

RORα, a Potential Tumor Suppressor and Therapeutic Target of Breast Cancer

by Jun Du and Ren Xu

Int. J. Mol. Sci. 2012, 13(12), 15755-15766; https://doi.org/10.3390/ijms131215755 - 26 Nov 2012

Cited by 70 | Viewed by 7854

Abstract

The function of the nuclear receptor (NR) in breast cancer progression has been investigated for decades. The majority of the nuclear receptors have well characterized natural ligands, but a few of them are orphan receptors for which no ligand has been identified. RORα, [...] Read more.

The function of the nuclear receptor (NR) in breast cancer progression has been investigated for decades. The majority of the nuclear receptors have well characterized natural ligands, but a few of them are orphan receptors for which no ligand has been identified. RORα, one member of the retinoid orphan nuclear receptor (ROR) subfamily of orphan receptors, regulates various cellular and pathological activities. RORα is commonly down-regulated and/or hypoactivated in breast cancer compared to normal mammary tissue. Expression of RORα suppresses malignant phenotypes in breast cancer cells, in vitro and in vivo. Activity of RORα can be categorized into the canonical and non-canonical nuclear receptor pathways, which in turn regulate various breast cancer cellular function, including cell proliferation, apoptosis and invasion. This information suggests that RORα is a potent tumor suppressor and a potential therapeutic target for breast cancer. Full article

(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells)

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Open AccessConcept Paper

Overlapping ATP2C1 and ASTE1 Genes in Human Genome: Implications for SPCA1 Expression?

by Massimo Micaroni and Lorenzo Malquori

Int. J. Mol. Sci. 2013, 14(1), 674-683; https://doi.org/10.3390/ijms14010674 - 4 Jan 2013

Cited by 5 | Viewed by 6829

Abstract

The ATP2C1 gene encodes for the secretory pathway calcium (Ca²⁺)-ATPase pump (SPCA1), which localizes along the secretory pathway, mainly in the trans-Golgi. The loss of one ATP2C1 allele causes Hailey-Hailey disease in humans but not mice. Examining differences in genomic [...] Read more.

The ATP2C1 gene encodes for the secretory pathway calcium (Ca²⁺)-ATPase pump (SPCA1), which localizes along the secretory pathway, mainly in the trans-Golgi. The loss of one ATP2C1 allele causes Hailey-Hailey disease in humans but not mice. Examining differences in genomic organization between mouse and human we speculate that the overlap between ATP2C1 and ASTE1 genes only in humans could explain this different response to ATP2C1 dysregulation. We propose that ASTE1, overlapping with ATP2C1 in humans, affects alternative splicing, and potentially protein expression of the latter. If dysregulated, the composition of the SPCA1 isoform pool could diverge from the physiological status, affecting cytosolic Ca²⁺-signaling, and in turn perturbing cell division, leading to cell death or to neoplastic transformation. Full article

(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells)

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