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Signal Transduction 2.0: From Molecular Pathways to Translational Research

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

Deadline for manuscript submissions: closed (30 January 2023) | Viewed by 27525

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Dr. Katharina Kubatzky

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Guest Editor

Department of Medical Microbiology and Hygiene, Heidelberg University Hospital, 69120 Heidelberg, Germany
Interests: signal transduction; bone; osteoclast; bacterial infection; protein toxin
Special Issues, Collections and Topics in MDPI journals

Dr. Elisabeth Seebach

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Department of Medical Microbiology and Hygiene, Heidelberg University Hospital, Heidelberg, Germany
Interests: Staphylococci; bone infections; biofilm
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

Much progress has been made in the signaling field over the last twenty years; new molecules and mechanisms have been discovered and novel methods and technologies invented. While only a few specialists worked in the field in the 1990s, today, signaling pathways play a prominent role in the research of most life scientists. Nonetheless, signal transduction remains a very dynamic field that covers many aspects from basic to translational research. Our understanding of the molecular signaling pathways has made it possible to specifically design drugs that intervene at dysregulated signaling nodes or to repair missing signaling molecules through gene therapy.

As volume 1 of special issue “Signal Transduction: From Molecular Pathways to Translational Research” is successful we reopen this issue again in the /International Journal of Molecular Sciences/ (https://0-www-mdpi-com.brum.beds.ac.uk/journal/ijms, ISSN 1422-0067, IF 5.923, JCR Category Q1). This second Special Issue invites both original research articles as well as reviews, commentaries, and perspectives that cover all aspects of signal transduction.

https://0-www-mdpi-com.brum.beds.ac.uk/journal/ijms/special_issues/STS_2020

Dr. Katharina Kubatzky
Dr. Elisabeth Seebach
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.

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Keywords

signal transduction
receptor signaling
infection and inflammation
protein interaction
tumor biology
growth factors
cytokines
cell death and differentiation

Published Papers (10 papers)

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Research

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17 pages, 3543 KiB

Open AccessArticle

TGF-β Type I Receptor Signaling in Melanoma Liver Metastases Increases Metastatic Outgrowth

by Dieuwke L. Marvin, Jelmer Dijkstra, Rabia M. Zulfiqar, Michiel Vermeulen, Peter ten Dijke and Laila Ritsma

Int. J. Mol. Sci. 2023, 24(10), 8676; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24108676 - 12 May 2023

Cited by 1 | Viewed by 1816

Abstract

Despite advances in treatment for metastatic melanoma patients, patients with liver metastasis have an unfavorable prognosis. A better understanding of the development of liver metastasis is needed. The multifunctional cytokine Transforming Growth Factor β (TGF-β) plays various roles in melanoma tumors and metastasis, affecting both tumor cells and cells from the surrounding tumor microenvironment. To study the role of TGF-β in melanoma liver metastasis, we created a model to activate or repress the TGF-β receptor pathway in vitro and in vivo in an inducible manner. For this, we engineered B16F10 melanoma cells to have inducible ectopic expression of a constitutively active (ca) or kinase-inactive (ki) TGF-β receptor I, also termed activin receptor-like kinase (ALK5). In vitro, stimulation with TGF-β signaling and ectopic caALK5 expression reduced B16F10 cell proliferation and migration. Contrasting results were found in vivo; sustained caALK5 expression in B16F10 cells in vivo increased the metastatic outgrowth in liver. Blocking microenvironmental TGF-β did not affect metastatic liver outgrowth of both control and caALK5 expressing B16F10 cells. Upon characterizing the tumor microenvironment of control and caALk5 expressing B16F10 tumors, we observed reduced (cytotoxic) T cell presence and infiltration, as well as an increase in bone marrow-derived macrophages in caALK5 expressing B16F10 tumors. This suggests that caALK5 expression in B16F10 cells induces changes in the tumor microenvironment. A comparison of newly synthesized secreted proteins upon caALK5 expression by B16F10 cells revealed increased secretion of matrix remodeling proteins. Our results show that TGF-β receptor activation in B16F10 melanoma cells can increase metastatic outgrowth in liver in vivo, possibly through remodeling of the tumor microenvironment leading to altered infiltration of immune cells. These results provide insights in the role of TGF-β signaling in B16F10 liver metastasis and could have implications regarding the use of TGF-β inhibitors for the treatment of melanoma patients with liver metastasis. Full article

(This article belongs to the Special Issue Signal Transduction 2.0: From Molecular Pathways to Translational Research)

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16 pages, 4273 KiB

Open AccessArticle

Butyrate Lowers Cellular Cholesterol through HDAC Inhibition and Impaired SREBP-2 Signalling

by Stephanie Bridgeman, Hon Chiu Woo, Philip Newsholme and Cyril Mamotte

Int. J. Mol. Sci. 2022, 23(24), 15506; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232415506 - 07 Dec 2022

Cited by 5 | Viewed by 2084

Abstract

In animal studies, HDAC inhibitors such as butyrate have been reported to reduce plasma cholesterol, while conferring protection from diabetes, but studies on the underlying mechanisms are lacking. This study compares the influence of butyrate and other HDAC inhibitors to that of statins on cholesterol metabolism in multiple cell lines, but primarily in HepG2 hepatic cells due to the importance of the liver in cholesterol metabolism. Sodium butyrate reduced HepG2 cholesterol content, as did sodium valproate and the potent HDAC inhibitor trichostatin A, suggesting HDAC inhibition as the exacting mechanism. In contrast to statins, which increase SREBP-2 regulated processes, HDAC inhibition downregulated SREBP-2 targets such as HMGCR and the LDL receptor. Moreover, in contrast to statin treatment, butyrate did not increase cholesterol uptake by HepG2 cells, consistent with its failure to increase LDL receptor expression. Sodium butyrate also reduced ABCA1 and SRB1 protein expression in HepG2 cells, but these effects were not consistent across all cell types. Overall, the underlying mechanism of cell cholesterol lowering by sodium butyrate and HDAC inhibition is consistent with impaired SREBP-2 signalling, and calls into question the possible use of butyrate for lowering of serum LDL cholesterol in humans. Full article

(This article belongs to the Special Issue Signal Transduction 2.0: From Molecular Pathways to Translational Research)

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20 pages, 4287 KiB

Open AccessArticle

Slight Variations in the Sequence Downstream of the Polyadenylation Signal Significantly Increase Transgene Expression in HEK293T and CHO Cells

by Evgeniya S. Omelina, Anna E. Letiagina, Lidiya V. Boldyreva, Anna A. Ogienko, Yuliya A. Galimova, Lyubov A. Yarinich, Alexey V. Pindyurin and Evgeniya N. Andreyeva

Int. J. Mol. Sci. 2022, 23(24), 15485; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232415485 - 07 Dec 2022

Cited by 1 | Viewed by 1633

Abstract

Compared to transcription initiation, much less is known about transcription termination. In particular, large-scale mutagenesis studies have, so far, primarily concentrated on promoter and enhancer, but not terminator sequences. Here, we used a massively parallel reporter assay (MPRA) to systematically analyze the influence of short (8 bp) sequence variants (mutations) located downstream of the polyadenylation signal (PAS) on the steady-state mRNA level of the upstream gene, employing an eGFP reporter and human HEK293T cells as a model system. In total, we evaluated 227,755 mutations located at different overlapping positions within +17..+56 bp downstream of the PAS for their ability to regulate the reporter gene expression. We found that the positions +17..+44 bp downstream of the PAS are more essential for gene upregulation than those located more distal to the PAS, and that the mutation sequences ensuring high levels of eGFP mRNA expression are extremely T-rich. Next, we validated the positive effect of a couple of mutations identified in the MPRA screening on the eGFP and luciferase protein expression. The most promising mutation increased the expression of the reporter proteins 13-fold and sevenfold on average in HEK293T and CHO cells, respectively. Overall, these findings might be useful for further improving the efficiency of production of therapeutic products, e.g., recombinant antibodies. Full article

(This article belongs to the Special Issue Signal Transduction 2.0: From Molecular Pathways to Translational Research)

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25 pages, 5085 KiB

Open AccessArticle

Amyloid Aβ_25-35 Aggregates Say ‘NO’ to Long-Term Potentiation in the Hippocampus through Activation of Stress-Induced Phosphatase 1 and Mitochondrial Na⁺/Ca²⁺ Exchanger

by Alexander V. Maltsev, Anna B. Nikiforova, Natalia V. Bal and Pavel M. Balaban

Int. J. Mol. Sci. 2022, 23(19), 11848; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911848 - 06 Oct 2022

Cited by 2 | Viewed by 2073

Abstract

The search for strategies for strengthening the synaptic efficiency in Aβ_25-35-treated slices is a challenge for the compensation of amyloidosis-related pathologies. Here, we used the recording of field excitatory postsynaptic potentials (fEPSPs), nitric oxide (NO) imaging, measurements of serine/threonine protein phosphatase (STPP) activity, and the detection of the functional mitochondrial parameters in suspension of brain mitochondria to study the Aβ_25-35-associated signaling in the hippocampus. Aβ_25-35 aggregates shifted the kinase–phosphatase balance during the long-term potentiation (LTP) induction in the enhancement of STPP activity. The PP1/PP2A inhibitor, okadaic acid, but not the PP2B blocker, cyclosporin A, prevented Aβ_25-35-dependent LTP suppression for both simultaneous and delayed enzyme blockade protocols. STPP activity in the Aβ_25-35-treated slices was upregulated, which is reverted relative to the control values in the presence of PP1/PP2A but not in the presence of the PP2B blocker. A selective inhibitor of stress-induced PP1α, sephin1, but not of the PP2A blocker, cantharidin, is crucial for Aβ_25-35-mediated LTP suppression prevention. A mitochondrial Na⁺/Ca²⁺ exchanger (mNCX) blocker, CGP37157, also attenuated the Aβ_25-35-induced LTP decline. Aβ_25-35 aggregates did not change the mitochondrial transmembrane potential or reactive oxygen species (ROS) production but affected the ion transport and Ca²⁺-dependent swelling of organelles. The staining of hippocampal slices with NO-sensitive fluorescence dye, DAF-FM, showed stimulation of the NO production in the Aβ_25-35-pretreated slices at the dendrite-containing regions of CA1 and CA3, in the dentate gyrus (DG), and in the CA1/DG somata. NO scavenger, PTIO, or nNOS blockade by selective inhibitor 3Br-7NI partly restored the Aβ_25-35-induced LTP decline. Thus, hippocampal NO production could be another marker for the impairment of synaptic plasticity in amyloidosis-related states, and kinase–phosphatase balance management could be a promising strategy for the compensation of Aβ_25-35-driven deteriorations. Full article

(This article belongs to the Special Issue Signal Transduction 2.0: From Molecular Pathways to Translational Research)

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20 pages, 5923 KiB

Open AccessArticle

The TRPV1 Receptor Is Up-Regulated by Sphingosine 1-Phosphate and Is Implicated in the Anandamide-Dependent Regulation of Mitochondrial Activity in C2C12 Myoblasts

by Sara Standoli, Sara Pecchioli, Daniel Tortolani, Camilla Di Meo, Federico Fanti, Manuel Sergi, Marina Bacci, Isabelle Seidita, Caterina Bernacchioni, Chiara Donati, Paola Bruni, Mauro Maccarrone, Cinzia Rapino and Francesca Cencetti

Int. J. Mol. Sci. 2022, 23(19), 11103; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911103 - 21 Sep 2022

Cited by 2 | Viewed by 1900

Abstract

The sphingosine 1-phosphate (S1P) and endocannabinoid (ECS) systems comprehend bioactive lipids widely involved in the regulation of similar biological processes. Interactions between S1P and ECS have not been so far investigated in skeletal muscle, where both systems are active. Here, we used murine C2C12 myoblasts to investigate the effects of S1P on ECS elements by qRT-PCR, Western blotting and UHPLC-MS. In addition, the modulation of the mitochondrial membrane potential (ΔΨm), by JC-1 and Mitotracker Red CMX-Ros fluorescent dyes, as well as levels of protein controlling mitochondrial function, along with the oxygen consumption were assessed, by Western blotting and respirometry, respectively, after cell treatment with methanandamide (mAEA) and in the presence of S1P or antagonists to endocannabinoid-binding receptors. S1P induced a significant increase in TRPV1 expression both at mRNA and protein level, while it reduced the protein content of CB2. A dose-dependent effect of mAEA on ΔΨm, mediated by TRPV1, was evidenced; in particular, low doses were responsible for increased ΔΨm, whereas a high dose negatively modulated ΔΨm and cell survival. Moreover, mAEA-induced hyperpolarization was counteracted by S1P. These findings open new dimension to S1P and endocannabinoids cross-talk in skeletal muscle, identifying TRPV1 as a pivotal target. Full article

(This article belongs to the Special Issue Signal Transduction 2.0: From Molecular Pathways to Translational Research)

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Review

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30 pages, 3809 KiB

Open AccessReview

Sigma-1 Receptor Signaling: In Search of New Therapeutic Alternatives for Cardiovascular and Renal Diseases

by Francisco Javier Munguia-Galaviz, Alejandra Guillermina Miranda-Diaz, Miguel Alejandro Cardenas-Sosa and Raquel Echavarria

Int. J. Mol. Sci. 2023, 24(3), 1997; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24031997 - 19 Jan 2023

Cited by 5 | Viewed by 4189

Abstract

Cardiovascular and renal diseases are among the leading causes of death worldwide, and regardless of current efforts, there is a demanding need for therapeutic alternatives to reduce their progression to advanced stages. The stress caused by diseases leads to the activation of protective mechanisms in the cell, including chaperone proteins. The Sigma-1 receptor (Sig-1R) is a ligand-operated chaperone protein that modulates signal transduction during cellular stress processes. Sig-1R interacts with various ligands and proteins to elicit distinct cellular responses, thus, making it a potential target for pharmacological modulation. Furthermore, Sig-1R ligands activate signaling pathways that promote cardioprotection, ameliorate ischemic injury, and drive myofibroblast activation and fibrosis. The role of Sig-1R in diseases has also made it a point of interest in developing clinical trials for pain, neurodegeneration, ischemic stroke, depression in patients with heart failure, and COVID-19. Sig-1R ligands in preclinical models have significantly beneficial effects associated with improved cardiac function, ventricular remodeling, hypertrophy reduction, and, in the kidney, reduced ischemic damage. These basic discoveries could inform clinical trials for heart failure (HF), myocardial hypertrophy, acute kidney injury (AKI), and chronic kidney disease (CKD). Here, we review Sig-1R signaling pathways and the evidence of Sig-1R modulation in preclinical cardiac and renal injury models to support the potential therapeutic use of Sig-1R agonists and antagonists in these diseases. Full article

(This article belongs to the Special Issue Signal Transduction 2.0: From Molecular Pathways to Translational Research)

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49 pages, 4937 KiB

Open AccessReview

Necroptosis: A Pathogenic Negotiator in Human Diseases

by Hitesh Singh Chaouhan, Ch Vinod, Nikita Mahapatra, Shao-Hua Yu, I-Kuan Wang, Kuen-Bao Chen, Tung-Min Yu and Chi-Yuan Li

Int. J. Mol. Sci. 2022, 23(21), 12714; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232112714 - 22 Oct 2022

Cited by 23 | Viewed by 4915

Abstract

Over the past few decades, mechanisms of programmed cell death have attracted the scientific community because they are involved in diverse human diseases. Initially, apoptosis was considered as a crucial mechanistic pathway for programmed cell death; recently, an alternative regulated mode of cell death was identified, mimicking the features of both apoptosis and necrosis. Several lines of evidence have revealed that dysregulation of necroptosis leads to pathological diseases such as cancer, cardiovascular, lung, renal, hepatic, neurodegenerative, and inflammatory diseases. Regulated forms of necrosis are executed by death receptor ligands through the activation of receptor-interacting protein kinase (RIPK)-1/3 and mixed-lineage kinase domain-like (MLKL), resulting in the formation of a necrosome complex. Many papers based on genetic and pharmacological studies have shown that RIPKs and MLKL are the key regulatory effectors during the progression of multiple pathological diseases. This review focused on illuminating the mechanisms underlying necroptosis, the functions of necroptosis-associated proteins, and their influences on disease progression. We also discuss numerous natural and chemical compounds and novel targeted therapies that elicit beneficial roles of necroptotic cell death in malignant cells to bypass apoptosis and drug resistance and to provide suggestions for further research in this field. Full article

(This article belongs to the Special Issue Signal Transduction 2.0: From Molecular Pathways to Translational Research)

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18 pages, 800 KiB

Open AccessReview

Neuronal Guidance Molecules in Bone Remodeling and Orthodontic Tooth Movement

by Sinan Şen and Ralf Erber

Int. J. Mol. Sci. 2022, 23(17), 10077; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231710077 - 03 Sep 2022

Cited by 2 | Viewed by 2007

Abstract

During orthodontic tooth movement, mechanically induced remodeling occurs in the alveolar bone due to the action of orthodontic forces. The number of factors identified to be involved in mechanically induced bone remodeling is growing steadily. With the uncovering of the functions of neuronal guidance molecules (NGMs) for skeletal development as well as for bone homeostasis, NGMs are now also among the potentially significant factors for the regulation of bone remodeling during orthodontic tooth movement. This narrative review attempts to summarize the functions of NGMs in bone homeostasis and provides insight into the currently sparse literature on the functions of these molecules during orthodontic tooth movement. Presently, four families of NGMs are known: Netrins, Slits, Semaphorins, ephrins and Eph receptors. A search of electronic databases revealed roles in bone homeostasis for representatives from all four NGM families. Functions during orthodontic tooth movement, however, were only identified for Semaphorins, ephrins and Eph receptors. For these, crucial prerequisites for participation in the regulation of orthodontically induced bone remodeling, such as expression in cells of the periodontal ligament and in the alveolar bone, as well as mechanical inducibility, were shown, which suggests that the importance of NGMs in orthodontic tooth movement may be underappreciated to date and further research might be warranted. Full article

(This article belongs to the Special Issue Signal Transduction 2.0: From Molecular Pathways to Translational Research)

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18 pages, 5271 KiB

Open AccessReview

CD38–Cyclic ADP-Ribose Signal System in Physiology, Biochemistry, and Pathophysiology

by Shin Takasawa

Int. J. Mol. Sci. 2022, 23(8), 4306; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23084306 - 13 Apr 2022

Cited by 13 | Viewed by 2920

Abstract

Calcium (Ca²⁺) is a ubiquitous and fundamental signaling component that is utilized by cells to regulate a diverse range of cellular functions, such as insulin secretion from pancreatic β-cells of the islets of Langerhans. Cyclic ADP-ribose (cADPR), synthesized from NAD⁺ by ADP-ribosyl cyclase family proteins, such as the mammalian cluster of differentiation 38 (CD38), is important for intracellular Ca²⁺ mobilization for cell functioning. cADPR induces Ca²⁺ release from endoplasmic reticulum via the ryanodine receptor intracellular Ca²⁺ channel complex, in which the FK506-binding protein 12.6 works as a cADPR-binding regulatory protein. Recently, involvements of the CD38-cADPR signal system in several human diseases and animal models have been reported. This review describes the biochemical and molecular biological basis of the CD38-cADPR signal system and the diseases caused by its abnormalities. Full article

(This article belongs to the Special Issue Signal Transduction 2.0: From Molecular Pathways to Translational Research)

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8 pages, 213 KiB

Open AccessConference Report

Report of the 24th Meeting on Signal Transduction 2021

by Bastian Schirmer, Klaudia Giehl and Katharina F. Kubatzky

Int. J. Mol. Sci. 2022, 23(4), 2015; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23042015 - 11 Feb 2022

Viewed by 2648

Abstract

The annual meeting “Signal Transduction—Receptors, Mediators and Genes” of the Signal Transduction Society (STS) is an interdisciplinary conference which is open to all scientists sharing a common interest in the elucidation of the signaling pathways mediating physiological or pathological processes in the health and disease of humans, animals, plants, fungi, prokaryotes, and protists. The 24th meeting on signal transduction was held from 15 to 17 November 2021 in Weimar, Germany. As usual, keynote presentations by invited scientists introduced the respective workshops, and were followed by speakers chosen from the submitted abstracts. A special workshop focused on “Target Identification and Interaction”. Ample time was reserved for the discussion of the presented data during the workshops. Unfortunately, due to restrictions owing to the SARS-CoV-2 pandemic, the poster sessions—and thus intensive scientific discussions at the posters—were not possible. In this report, we provide a concise summary of the various workshops and further aspects of the scientific program. Full article

(This article belongs to the Special Issue Signal Transduction 2.0: From Molecular Pathways to Translational Research)

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