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Advances in Cell Signaling Pathways and Signal Transduction
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Advances in Cell Signaling Pathways and Signal Transduction

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: 20 July 2025 | Viewed by 10733

Special Issue Editors

Prof. Dr. Katsuhiko Muraki

E-Mail Website
Guest Editor
Cellular Pharmacology, School of Pharmacy, Aichi Gakuin University, Nagoya 464-8650, Japan
Interests: ion channel and transporter research
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Susumu Ohya

E-Mail Website
Guest Editor
Department of Pharmacology, Graduate School of Medical Sciences, Nagoya City University, Mizuho-ku, Nagoya 467-8601, Japan
Interests: molecular pharmacological study of ion channel related diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue will focus on recent advances in signaling pathways and signal transduction in a variety of cell types, including neuronal cells, cardiovascular cells, immune cells, and cancer cells, reshaping our understanding of cellular communications. The authors will share breakthrough research on receptor types (G-protein-coupled, enzyme-linked, ion channel-coupled, and nuclear receptors), ion channels and transporters, intracellular signaling mechanisms, and transcriptional and post-transcriptional regulation. Additionally, this Special Issue will highlight innovative techniques for studying signal transduction, including living cell/tissue imaging and computational modeling, and cover novel approaches to targeting signaling pathways in the treatment of diseases such as neurodegenerative, cardiovascular, and immune diseases, as well as cancers, emphasizing their therapeutic potential.

We invite you to submit regular articles, short communications, and review articles.

Topics to address:

  • Recent insights into cell signaling networks and cell communications;
  • Molecular mechanisms of cellular signaling and signal transduction (amplification and termination);
  • Therapeutic implications of cell signaling and signal transduction and the development of drugs that specifically target malfunctioning signaling pathways in a variety of diseases.

Prof. Dr. Katsuhiko Muraki
Prof. Dr. Susumu Ohya
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Ca2+ signaling
  • transcriptional and post-transcriptional pathways
  • growth factors
  • second messengers
  • cell metabolism
  • cell senescence
  • protein phosphorylation/dephosphorylation
  • membrane trafficking
  • cell proliferation, differentiation, and apoptosis
  • cytokine/chemokine signaling

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Further information on MDPI's Special Issue policies can be found here.

Published Papers (6 papers)

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Research

13 pages, 2200 KiB  
Article
Detection of Human GPCR Activity in Drosophila S2 Cells Using the Tango System
by Emil Salim, Aki Hori, Kohei Matsubara, Toshiyuki Takano-Shimizu, Andre Rizky Pratomo, Marianne Marianne, Armia Syahputra, Dadang Irfan Husori, Asuka Inoue, Maryam Aisyah Abdullah, Nur Farisya Shamsudin, Kamal Rullah and Takayuki Kuraishi
Int. J. Mol. Sci. 2025, 26(1), 202; https://doi.org/10.3390/ijms26010202 - 29 Dec 2024
Viewed by 1290
Abstract
G protein-coupled receptors (GPCRs) are essential cell surface proteins involved in transducing extracellular signals into intracellular responses, regulating various physiological processes. This study validated the use of the Tango assay, a sensitive method for detecting GPCR activation, in Drosophila Schneider 2 (S2) cells, [...] Read more.
G protein-coupled receptors (GPCRs) are essential cell surface proteins involved in transducing extracellular signals into intracellular responses, regulating various physiological processes. This study validated the use of the Tango assay, a sensitive method for detecting GPCR activation, in Drosophila Schneider 2 (S2) cells, focusing on the human Dopamine Receptor D4 (DRD4). Plasmids encoding the LexA-tagged human DRD4 receptor and a luciferase reporter were co-transfected into Drosophila S2 cells and stimulated with dopamine. Receptor activation was measured by quantifying the luciferase activity. The system showed high specificity for dopamine, with no activation in response to octopamine, a non-ligand for DRD4. Furthermore, the system effectively detects activation by a novel compound. These results demonstrate that Drosophila S2 cells, coupled with the Tango assay, provide a viable model for studying human GPCR function and ligand specificity. This system enables the rapid screening of potential GPCR ligands in a cost-effective cellular model. Full article
(This article belongs to the Special Issue Advances in Cell Signaling Pathways and Signal Transduction)
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13 pages, 3241 KiB  
Article
Up-Regulated Expression of Thioredoxin-Interacting Protein (TXNIP) in Mesenchymal Stem Cells Associated with Severe Aplastic Anemia in Children
by Ying-Hsuan Peng, Chang-Wei Li, Kang-Hsi Wu, Ju-Pi Li, Shun-Fa Yang and Yu-Hua Chao
Int. J. Mol. Sci. 2024, 25(22), 12298; https://doi.org/10.3390/ijms252212298 - 15 Nov 2024
Viewed by 1354
Abstract
The pathogenic mechanisms of severe aplastic anemia (SAA) in children are not completely elucidated. The insufficiency of the bone marrow microenvironment, in which mesenchymal stem cells (MSCs) are an important element, can be a potential factor associated with hematopoietic impairment in SAA. In [...] Read more.
The pathogenic mechanisms of severe aplastic anemia (SAA) in children are not completely elucidated. The insufficiency of the bone marrow microenvironment, in which mesenchymal stem cells (MSCs) are an important element, can be a potential factor associated with hematopoietic impairment in SAA. In the present study, we compared bone marrow MSCs from five children with SAA and five controls. We found a higher intensity of senescence-associated β-galactosidase activity in SAA MSCs, indicating the increased senescence in these cells. Further RNA sequencing analysis identified a distinctive profile of transcriptomes in SAA MSCs. After conducting a survey of the differentially expressed genes, we found that the up-regulated expression of TXNIP may compromise the proliferative potential of MSCs and probably relate to the pathogenesis of SAA. These results were validated by qPCR. To explore the molecular mechanism involving aberrant TXNIP regulation in SAA MSCs, the expression levels of IGF-1 and IGFBP-1 were measured. A significant increase in IGFBP-1 expression was noted in SAA MSCs despite the wide range of IGF-1 expressions. Accordingly, we postulated a novel pathogenic mechanism of SAA: a compensated increase in the expression of IGF-1 in MSCs to down-regulate TXNIP expression in the face of SAA, which is offset by the up-regulated expression of IGFBP-1. Full article
(This article belongs to the Special Issue Advances in Cell Signaling Pathways and Signal Transduction)
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18 pages, 739 KiB  
Article
Basal State Calibration of a Chemical Reaction Network Model for Autophagy
by Bence Hajdú, Orsolya Kapuy and Tibor Nagy
Int. J. Mol. Sci. 2024, 25(20), 11316; https://doi.org/10.3390/ijms252011316 - 21 Oct 2024
Viewed by 1027
Abstract
The modulation of autophagy plays a dual role in tumor cells, with the potential to both promote and suppress tumor proliferation. In order to gain a deeper understanding of the nature of autophagy, we have developed a chemical reaction kinetic model of autophagy [...] Read more.
The modulation of autophagy plays a dual role in tumor cells, with the potential to both promote and suppress tumor proliferation. In order to gain a deeper understanding of the nature of autophagy, we have developed a chemical reaction kinetic model of autophagy and apoptosis based on the mass action kinetic models that have been previously described in the literature. It is regrettable that the authors did not provide all of the information necessary to reconstruct their model, which made their simulation results irreproducible. In this study, based on an extensive literature review, we have identified concentrations for each species in the stress-free, homeostatic state. These ranges were randomly sampled to generate sets of initial concentrations, from which the simulations were run. In every case, abnormal behavior was observed, with apoptosis and autophagy being activated, even in the absence of stress. Consequently, the model failed to reproduce even the basal conditions. Detailed examination of the model revealed erroneous reactions, which were corrected. The influential kinetic parameters of the corrected model were identified and optimized using the Optima++ code. The model is now capable of simulating homeostatic states, and provides a suitable basis for further model development to describe cell response to various stresses. Full article
(This article belongs to the Special Issue Advances in Cell Signaling Pathways and Signal Transduction)
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20 pages, 1974 KiB  
Article
Modulatory Effects of Chalcone Thio-Derivatives on NF-κB and STAT3 Signaling Pathways in Hepatocellular Carcinoma Cells: A Study on Selected Active Compounds
by Katarzyna Papierska, Eliza Judasz, Wiktoria Tonińska, Maciej Kubicki and Violetta Krajka-Kuźniak
Int. J. Mol. Sci. 2024, 25(19), 10739; https://doi.org/10.3390/ijms251910739 - 5 Oct 2024
Viewed by 1638
Abstract
Our previous studies demonstrated the modulatory effects of new synthetic thio-chalcone derivatives in dishes on the Nrf2, NF-κB, and STAT3 signaling pathways in colon cancer cells. This study aimed to evaluate the effect of four selected active chalcone thio-derivatives on the NF-κB and [...] Read more.
Our previous studies demonstrated the modulatory effects of new synthetic thio-chalcone derivatives in dishes on the Nrf2, NF-κB, and STAT3 signaling pathways in colon cancer cells. This study aimed to evaluate the effect of four selected active chalcone thio-derivatives on the NF-κB and STAT3 signaling pathways involved in inflammatory processes and cell proliferation in human liver cancer cells. Cell survival was assessed for cancer (HepG2) and normal (THLE-2) cell lines. Activation of NF-κB and STAT3 signaling pathways and the expression of proteins controlled by these pathways were estimated by Western blot, and qRT-PCR assessed the expression of NF-κB and STAT3 target genes. We also evaluated the impact on the selected kinases responsible for the phosphorylation of the studied transcription factors by MagneticBead-Based Multiplex Immunoassay. Among the thio-derivatives tested, especially derivatives 1 and 5, there was an impact on cell viability, cell cycle, apoptosis, and activation of NF-κB and STAT3 pathways in hepatocellular carcinoma (HCC), which confirms the possibilities of using them in combinatorial molecular targeted therapy of HCC. The tested synthetic thio-chalcones exhibit anticancer activity by initiating proapoptotic processes in HCC while showing low toxicity to non-cancerous cells. These findings confirm the possibility of using chalcone thio-derivatives in molecularly targeted combination therapy for HCC. Full article
(This article belongs to the Special Issue Advances in Cell Signaling Pathways and Signal Transduction)
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21 pages, 4661 KiB  
Article
Biased Signaling Agonists Promote Distinct Phosphorylation and Conformational States of the Dopamine D3 Receptor
by Binod Nepal, Jessica Barnett, Frank Bearoff and Sandhya Kortagere
Int. J. Mol. Sci. 2024, 25(19), 10470; https://doi.org/10.3390/ijms251910470 - 28 Sep 2024
Cited by 1 | Viewed by 2244
Abstract
Biased agonists of G-protein-coupled receptors (GPCRs) have emerged as promising selective modulators of signaling pathways by offering therapeutic advantages over unbiased agonists to minimize side effects. The dopamine D3 receptor (D3R), a pivotal GPCR in the central nervous system, has gained significant attention [...] Read more.
Biased agonists of G-protein-coupled receptors (GPCRs) have emerged as promising selective modulators of signaling pathways by offering therapeutic advantages over unbiased agonists to minimize side effects. The dopamine D3 receptor (D3R), a pivotal GPCR in the central nervous system, has gained significant attention as a therapeutic target for neurological diseases, including Parkinson’s disease (PD), addiction, psychosis, depression, and anxiety. We have recently designed and tested SK609, a G-protein biased D3R selective agonist, and demonstrated its efficacy in reducing motor impairment and improving cognitive effects in a rodent model of PD. The molecular mechanism by which SK609 recruits G-protein but not β-arrestin pathways is poorly understood. Utilizing all-atom molecular dynamics simulations, we investigated the distinct conformational dynamics imparted by SK609 and the reference unbiased agonist Pramipexole (PRX). Results from these studies show that the flexibility of transmembrane 3 is key to unbiased signaling, with a ~30° and ~17° shift in tilt angle in the D3R-Gi and D3R-βarrestin2 complexes, respectively. Additionally, untargeted phosphoproteomics analysis reveals unique phosphorylation sites by SK609 and PRX in D3R. These results suggest that SK609 induces conformational changes and unique phosphorylation patterns that promote interactions with G-proteins and are not conducive for β-arrestin2 recruitment and signaling. Full article
(This article belongs to the Special Issue Advances in Cell Signaling Pathways and Signal Transduction)
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21 pages, 6082 KiB  
Article
Downregulation of IL-8 and IL-10 by LRRC8A Inhibition through the NOX2–Nrf2–CEBPB Transcriptional Axis in THP-1-Derived M2 Macrophages
by Miki Matsui, Junko Kajikuri, Hiroaki Kito, Elghareeb E. Elboray, Takayoshi Suzuki and Susumu Ohya
Int. J. Mol. Sci. 2024, 25(17), 9612; https://doi.org/10.3390/ijms25179612 - 5 Sep 2024
Viewed by 1573
Abstract
M2-polarized, tumor-associated macrophages (TAMs) produce pro-tumorigenic and angiogenic mediators, such as interleukin-8 (IL-8) and IL-10. Leucine-rich repeat-containing protein 8 members (LRRC8s) form volume-regulated anion channels and play an important role in macrophage functions by regulating cytokine and chemokine production. We herein [...] Read more.
M2-polarized, tumor-associated macrophages (TAMs) produce pro-tumorigenic and angiogenic mediators, such as interleukin-8 (IL-8) and IL-10. Leucine-rich repeat-containing protein 8 members (LRRC8s) form volume-regulated anion channels and play an important role in macrophage functions by regulating cytokine and chemokine production. We herein examined the role of LRRC8A in IL-8 and IL-10 expression in THP-1-differentiated M2-like macrophages (M2-MACs), which are a useful tool for investigating TAMs. In M2-MACs, the pharmacological inhibition of LRRC8A led to hyperpolarizing responses after a transient depolarization phase, followed by a slight elevation in the intracellular concentration of Ca2+. Both the small interfering RNA-mediated and pharmacological inhibition of LRRC8A repressed the transcriptional expression of IL-8 and IL-10, resulting in a significant reduction in their secretion. The inhibition of LRRC8A decreased the nuclear translocation of phosphorylated nuclear factor-erythroid 2-related factor 2 (Nrf2), while the activation of Nrf2 reversed the LRRC8A inhibition-induced transcriptional repression of IL-8 and IL-10 in M2-MACs. We identified the CCAAT/enhancer-binding protein isoform B, CEBPB, as a downstream target of Nrf2 signaling in M2-MACs. Moreover, among several upstream candidates, the inhibition of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) suppressed the Nrf2–CEBPB transcriptional axis in M2-MACs. Collectively, the present results indicate that the inhibition of LRRC8A repressed IL-8 and IL-10 transcription in M2-MACs through the NOX2–Nrf2–CEBPB axis and suggest that LRRC8A inhibitors suppress the IL-10-mediated evasion of tumor immune surveillance and IL-8-mediated metastasis and neovascularization in TAMs. Full article
(This article belongs to the Special Issue Advances in Cell Signaling Pathways and Signal Transduction)
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