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Signal Transduction: From Molecular Pathways to Translational Research

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 June 2021) | Viewed by 59863

Special Issue Editors

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

Special Issue Information

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.

This second Special Issue invites both original research articles as well as reviews, commentaries, and perspectives that cover all aspects of signal transduction. As the focus theme of this 24th meeting of the Signal Transduction Society (STS) is “target identification and intervention”, we especially welcome manuscripts that address this topic.

Addendum: The Signal Transduction Society (STS) was established in 1998 and is a non-profit organization that provides an interdisciplinary forum for scientists with an interest in signal transduction processes in cells and organisms. The STS annually organizes the “Joint Meeting Signal Transduction—Receptor, Mediators and Genes”. This year, the meeting will take place in Weimar from 2 to 3 November in a shortened form due to the COVID-19 pandemic.

https://www.sigtrans.de/meeting.html

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.

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

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

Published Papers (15 papers)

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Research

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17 pages, 1635 KiB  
Article
Interleukin-9 Facilitates Osteoclastogenesis in Rheumatoid Arthritis
by Santanu Kar, Ranjan Gupta, Rajesh Malhotra, Vijay Sharma, Kamran Farooque, Vijay Kumar, Sushmita Chakraborty and Dipendra Kumar Mitra
Int. J. Mol. Sci. 2021, 22(19), 10397; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910397 - 27 Sep 2021
Cited by 21 | Viewed by 2721
Abstract
In rheumatoid arthritis (RA), inflammatory cytokines play a pivotal role in triggering abnormal osteoclastogenesis leading to articular destruction. Recent studies have demonstrated enhanced levels of interleukin-9 (IL-9) in the serum and synovial fluid of patients with RA. In RA, strong correlation has been [...] Read more.
In rheumatoid arthritis (RA), inflammatory cytokines play a pivotal role in triggering abnormal osteoclastogenesis leading to articular destruction. Recent studies have demonstrated enhanced levels of interleukin-9 (IL-9) in the serum and synovial fluid of patients with RA. In RA, strong correlation has been observed between tissue inflammation and IL-9 expression in synovial tissue. Therefore, we investigated whether IL-9 influences osteoclastogenesis in patients with RA. We conducted the study in active RA patients. For inducing osteoclast differentiation, mononuclear cells were stimulated with soluble receptor activator of NF-kB ligand (sRANKL) and macrophage-colony-stimulating factor (M-CSF) in the presence or absence of recombinant (r) IL-9. IL-9 stimulation significantly enhanced M-CSF/sRANKL-mediated osteoclast formation and function. Transcriptome analysis revealed differential gene expression induced with IL-9 stimulation in the process of osteoclast differentiation. IL-9 mainly modulates the expression of genes, which are involved in the metabolic pathway. Moreover, we observed that IL-9 modulates the expression of matrix metalloproteinases (MMPs), which are critical players in bone degradation. Our results indicate that IL-9 has the potential to influence the structural damage in the RA by promoting osteoclastogenesis and modulating the expression of MMPs. Thus, blocking IL-9 pathways might be an attractive immunotherapeutic target for preventing bone degradation in RA. Full article
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17 pages, 2348 KiB  
Article
A Potential Role of Semaphorin 3A during Orthodontic Tooth Movement
by Sinan Şen, Christopher J. Lux and Ralf Erber
Int. J. Mol. Sci. 2021, 22(15), 8297; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22158297 - 02 Aug 2021
Cited by 7 | Viewed by 2177
Abstract
Background: Induced tooth movement during orthodontic therapy requires mechano-induced bone remodeling. Besides various cytokines and growth-factors, neuronal guidance molecules gained attention for their roles in bone homeostasis and thus, potential roles during tooth movement. Several neuronal guidance molecules have been implicated in the [...] Read more.
Background: Induced tooth movement during orthodontic therapy requires mechano-induced bone remodeling. Besides various cytokines and growth-factors, neuronal guidance molecules gained attention for their roles in bone homeostasis and thus, potential roles during tooth movement. Several neuronal guidance molecules have been implicated in the regulation of bone remodeling. Amongst them, Semaphorin 3A is particular interesting as it concurrently induces osteoblast differentiation and disturbs osteoclast differentiation. Methods: Mechano-regulation of Sema3A and its receptors PlexinA1 and Neuropilin (RT-qPCR, WB) was evaluated by applying compressive and tension forces to primary human periodontal fibroblasts (hPDLF) and alveolar bone osteoblasts (hOB). The association of the transcription factor Osterix (SP7) and SEMA3A was studied by RT-qPCR. Mechanisms involved in SEMA3A-mediated osteoblast differentiation were assessed by Rac1GTPase pull-downs, β-catenin expression analyses (RT-qPCR) and nuclear translocation assays (IF). Osteogenic markers were analyzed by RT-qPCR. Results: SEMA3A, PLXNA1 and NRP1 were differentially regulated by tension or compressive forces in hPDLF. Osterix (SP7) displayed the same pattern of regulation. Recombinant Sema3A induced the activation of Rac1GTPase, the nuclear translocation of β-catenin and the expression of osteogenic marker genes. Conclusion: Sema3A, its receptors and Osterix are regulated by mechanical forces in hPDLF. SEMA3A upregulation was associated with Osterix (SP7) modulation. Sema3A-enhanced osteogenic marker gene expression in hOB might be dependent on a pathway involving Rac1GTPase and β-catenin. Thus, Semaphorin 3A might contribute to bone remodeling during induced tooth movement. Full article
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16 pages, 2654 KiB  
Article
Genome-Wide Methylation Mapping Using Nanopore Sequencing Technology Identifies Novel Tumor Suppressor Genes in Hepatocellular Carcinoma
by Colin F. Davenport, Tobias Scheithauer, Alessia Dunst, Frauke Sophie Bahr, Marie Dorda, Lutz Wiehlmann and Doan Duy Hai Tran
Int. J. Mol. Sci. 2021, 22(8), 3937; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22083937 - 11 Apr 2021
Cited by 8 | Viewed by 3428
Abstract
Downregulation of multiple tumor suppressor genes (TSGs) plays an important role in cancer formation. Recent evidence has accumulated that cancer progression involves genome-wide alteration of epigenetic modifications, which may cause downregulation of the tumor suppressor gene. Using hepatocellular carcinoma (HCC) as a system, [...] Read more.
Downregulation of multiple tumor suppressor genes (TSGs) plays an important role in cancer formation. Recent evidence has accumulated that cancer progression involves genome-wide alteration of epigenetic modifications, which may cause downregulation of the tumor suppressor gene. Using hepatocellular carcinoma (HCC) as a system, we mapped 5-methylcytosine signal at a genome-wide scale using nanopore sequencing technology to identify novel TSGs. Integration of methylation data with gene transcription profile of regenerated liver and primary HCCs allowed us to identify 10 potential tumor suppressor gene candidates. Subsequent validation led us to focus on functionally characterizing one candidate—glucokinase (GCK). We show here that overexpression of GCK inhibits the proliferation of HCC cells via induction of intracellular lactate accumulation and subsequently causes energy crisis due to NAD+ depletion. This suggests GCK functions as a tumor suppressor gene and may be involved in HCC development. In conclusion, these data provide valuable clues for further investigations of the process of tumorigenesis in human cancer. Full article
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14 pages, 2913 KiB  
Article
NRF2 Enables EGFR Signaling in Melanoma Cells
by Julia Katharina Charlotte Kreß, Christina Jessen, André Marquardt, Anita Hufnagel and Svenja Meierjohann
Int. J. Mol. Sci. 2021, 22(8), 3803; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22083803 - 07 Apr 2021
Cited by 17 | Viewed by 4355
Abstract
Receptor tyrosine kinases (RTK) are rarely mutated in cutaneous melanoma, but the expression and activation of several RTK family members are associated with a proinvasive phenotype and therapy resistance. Epidermal growth factor receptor (EGFR) is a member of the RTK family and is [...] Read more.
Receptor tyrosine kinases (RTK) are rarely mutated in cutaneous melanoma, but the expression and activation of several RTK family members are associated with a proinvasive phenotype and therapy resistance. Epidermal growth factor receptor (EGFR) is a member of the RTK family and is only expressed in a subgroup of melanomas with poor prognosis. The insight into regulators of EGFR expression and activation is important for the understanding of the development of this malignant melanoma phenotype. Here, we describe that the transcription factor NRF2, the master regulator of the oxidative and electrophilic stress response, mediates the expression and activation of EGFR in melanoma by elevating the levels of EGFR as well as its ligands EGF and TGFα. ChIP sequencing data show that NRF2 directly binds to the promoter of EGF, which contains a canonical antioxidant response element. Accordingly, EGF is induced by oxidative stress and is also increased in lung adenocarcinoma and head and neck carcinoma with mutationally activated NRF2. In contrast, regulation of EGFR and TGFA occurs by an indirect mechanism, which is enabled by the ability of NRF2 to block the activity of the melanocytic lineage factor MITF in melanoma. MITF effectively suppresses EGFR and TGFA expression and therefore serves as link between NRF2 and EGFR. As EGFR was previously described to stimulate NRF2 activity, the mutual activation of NRF2 and EGFR pathways was investigated. The presence of NRF2 was necessary for full EGFR pathway activation, as NRF2-knockout cells showed reduced AKT activation in response to EGF stimulation compared to controls. Conversely, EGF led to the nuclear localization and activation of NRF2, thereby demonstrating that NRF2 and EGFR are connected in a positive feedback loop in melanoma. In summary, our data show that the EGFR-positive melanoma phenotype is strongly supported by NRF2, thus revealing a novel maintenance mechanism for this clinically challenging melanoma subpopulation. Full article
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19 pages, 2328 KiB  
Article
Plumbagin, a Biomolecule with (Anti)Osteoclastic Properties
by Sevinj Sultanli, Soni Ghumnani, Richa Ashma and Katharina F. Kubatzky
Int. J. Mol. Sci. 2021, 22(5), 2779; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052779 - 09 Mar 2021
Cited by 10 | Viewed by 3402
Abstract
Plumbagin is a plant-derived naphthoquinone that is widely used in traditional Asian medicine due to its anti-inflammatory and anti-microbial properties. Additionally, plumbagin is cytotoxic for cancer cells due to its ability to trigger reactive oxygen species (ROS) formation and subsequent apoptosis. Since it [...] Read more.
Plumbagin is a plant-derived naphthoquinone that is widely used in traditional Asian medicine due to its anti-inflammatory and anti-microbial properties. Additionally, plumbagin is cytotoxic for cancer cells due to its ability to trigger reactive oxygen species (ROS) formation and subsequent apoptosis. Since it was reported that plumbagin may inhibit the differentiation of bone resorbing osteoclasts in cancer-related models, we wanted to elucidate whether plumbagin interferes with cytokine-induced osteoclastogenesis. Using C57BL/6 mice, we unexpectedly found that plumbagin treatment enhanced osteoclast formation and that this effect was most pronounced when cells were pre-treated for 24 h with plumbagin before subsequent M-CSF/RANKL stimulation. Plumbagin caused a fast induction of NFATc1 signalling and mTOR-dependent activation of p70S6 kinase which resulted in the initiation of protein translation. In line with this finding, we observed an increase in RANK surface expression after Plumbagin stimulation that enhanced the responsiveness for subsequent RANKL treatment. However, in Balb/c mice and Balb/c-derived RAW264.7 macrophages, these findings could not be corroborated and osteoclastogenesis was inhibited. Our results suggest that the effects of plumbagin depend on the model system used and can therefore either trigger or inhibit osteoclast formation. Full article
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27 pages, 4148 KiB  
Article
The Novel ALG-2 Target Protein CDIP1 Promotes Cell Death by Interacting with ESCRT-I and VAPA/B
by Ryuta Inukai, Kanako Mori, Keiko Kuwata, Chihiro Suzuki, Masatoshi Maki, Terunao Takahara and Hideki Shibata
Int. J. Mol. Sci. 2021, 22(3), 1175; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031175 - 25 Jan 2021
Cited by 5 | Viewed by 2919
Abstract
Apoptosis-linked gene 2 (ALG-2, also known as PDCD6) is a member of the penta-EF-hand (PEF) family of Ca2+-binding proteins. The murine gene encoding ALG-2 was originally reported to be an essential gene for apoptosis. However, the role of ALG-2 in cell [...] Read more.
Apoptosis-linked gene 2 (ALG-2, also known as PDCD6) is a member of the penta-EF-hand (PEF) family of Ca2+-binding proteins. The murine gene encoding ALG-2 was originally reported to be an essential gene for apoptosis. However, the role of ALG-2 in cell death pathways has remained elusive. In the present study, we found that cell death-inducing p53 target protein 1 (CDIP1), a pro-apoptotic protein, interacts with ALG-2 in a Ca2+-dependent manner. Co-immunoprecipitation analysis of GFP-fused CDIP1 (GFP-CDIP1) revealed that GFP-CDIP1 associates with tumor susceptibility gene 101 (TSG101), a known target of ALG-2 and a subunit of endosomal sorting complex required for transport-I (ESCRT-I). ESCRT-I is a heterotetrameric complex composed of TSG101, VPS28, VPS37 and MVB12/UBAP1. Of diverse ESCRT-I species originating from four VPS37 isoforms (A, B, C, and D), CDIP1 preferentially associates with ESCRT-I containing VPS37B or VPS37C in part through the adaptor function of ALG-2. Overexpression of GFP-CDIP1 in HEK293 cells caused caspase-3/7-mediated cell death. In addition, the cell death was enhanced by co-expression of ALG-2 and ESCRT-I, indicating that ALG-2 likely promotes CDIP1-induced cell death by promoting the association between CDIP1 and ESCRT-I. We also found that CDIP1 binds to vesicle-associated membrane protein-associated protein (VAP)A and VAPB through the two phenylalanines in an acidic tract (FFAT)-like motif in the C-terminal region of CDIP1, mutations of which resulted in reduction of CDIP1-induced cell death. Therefore, our findings suggest that different expression levels of ALG-2, ESCRT-I subunits, VAPA and VAPB may have an impact on sensitivity of anticancer drugs associated with CDIP1 expression. Full article
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17 pages, 1811 KiB  
Article
YB-1 Interferes with TNFα–TNFR Binding and Modulates Progranulin-Mediated Inhibition of TNFα Signaling
by Christopher L. Hessman, Josephine Hildebrandt, Aneri Shah, Sabine Brandt, Antonia Bock, Björn C. Frye, Ute Raffetseder, Robert Geffers, Monika C. Brunner-Weinzierl, Berend Isermann, Peter R. Mertens and Jonathan A. Lindquist
Int. J. Mol. Sci. 2020, 21(19), 7076; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197076 - 25 Sep 2020
Cited by 8 | Viewed by 3385
Abstract
Inflammation and an influx of macrophages are common elements in many diseases. Among pro-inflammatory cytokines, tumor necrosis factor α (TNFα) plays a central role by amplifying the cytokine network. Progranulin (PGRN) is a growth factor that binds to TNF receptors and interferes with [...] Read more.
Inflammation and an influx of macrophages are common elements in many diseases. Among pro-inflammatory cytokines, tumor necrosis factor α (TNFα) plays a central role by amplifying the cytokine network. Progranulin (PGRN) is a growth factor that binds to TNF receptors and interferes with TNFα-mediated signaling. Extracellular PGRN is processed into granulins by proteases released from immune cells. PGRN exerts anti-inflammatory effects, whereas granulins are pro-inflammatory. The factors coordinating these ambivalent functions remain unclear. In our study, we identify Y-box binding protein-1 (YB-1) as a candidate for this immune-modulating activity. Using a yeast-2-hybrid assay with YB-1 protein as bait, clones encoding for progranulin were selected using stringent criteria for strong interaction. We demonstrate that at physiological concentrations, YB-1 interferes with the binding of TNFα to its receptors in a dose-dependent manner using a flow cytometry-based binding assay. We show that YB-1 in combination with progranulin interferes with TNFα-mediated signaling, supporting the functionality with an NF-κB luciferase reporter assay. Together, we show that YB-1 displays immunomodulating functions by affecting the binding of TNFα to its receptors and influencing TNFα-mediated signaling via its interaction with progranulin. Full article
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Review

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24 pages, 4476 KiB  
Review
Classification and Treatment of Diseases in the Age of Genome Medicine Based on Pathway Pathology
by Iver Petersen
Int. J. Mol. Sci. 2021, 22(17), 9418; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179418 - 30 Aug 2021
Cited by 3 | Viewed by 2719
Abstract
The focus of pathology as a biomedical discipline is the identification of the pathomechanisms of diseases and the integration of this knowledge into routine diagnosis and classification. Standard tools are macroscopic and microscopic analysis complemented by immunohistochemistry and molecular pathology. So far, classification [...] Read more.
The focus of pathology as a biomedical discipline is the identification of the pathomechanisms of diseases and the integration of this knowledge into routine diagnosis and classification. Standard tools are macroscopic and microscopic analysis complemented by immunohistochemistry and molecular pathology. So far, classification has been based on the paradigm of cellular pathology established by Rudolf Virchow and others more than 150 years ago, stating that diseases originate from diseased cells. This dogma is meanwhile challenged by the fact that cells can be fully reprogrammed. Many diseases are nowadays considered to originate from undifferentiated stem cells, induced into a diseased state by genetic or epigenetic alterations. In addition, the completion of the Human Genome Project, with the identification of more than 20.000 genes and a much higher number of gene variants and mutations, led to the concept that diseases are dominated by genetics/epigenetics rather than cells of origin. The axiom of cellular pathology, however, still holds true, as cells are the smallest animate units from which diseases originate. Medical doctors and researchers nowadays have to deal with a tremendous amount of data. The International Classification of Diseases will expand from 14.400 entities/codes in ICD-10 to more than 55.000 in ICD-11. In addition, large datasets generated by “genomics“, e.g., whole-genome sequencing, expression profiling or methylome analysis, are meanwhile not only applied in research but also introduced into clinical settings. It constitutes a major task to incorporate all the data into routine medical work. Pathway pathology may help solve this problem. It is based on the realization that diseases are characterized by three essential components: (i) cells of origin/cellular context and (ii) the alteration of cellular as well as (iii) molecular/signal transduction pathways. The concept is illustrated by elaborating on two key cellular pathways, i.e., the cellular senescence of normal cells and the immortality of cancer cells, and by contrasting single cell/single pathway diseases, such as mycoplasma and coughing pneumonia, with complex diseases such as cancer, with multiple cell types as well as multiple affected cellular and signaling pathways. Importantly, the concept of pathway pathology is not just intended to classify disease, but also to conceive new treatment modalities. This article is dedicated to Dr. Leonard Hayflick, who made basic discoveries in pathway pathology not only by identifying cells causing disease (Mycoplasma pneumoniae) and establishing cell strains for treating disease (WI-38 for viral vaccines), but also by first describing cellular senescence and immortality. Full article
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10 pages, 1626 KiB  
Review
ABC Transporters in T Cell-Mediated Physiological and Pathological Immune Responses
by Christoph Thurm, Burkhart Schraven and Sascha Kahlfuss
Int. J. Mol. Sci. 2021, 22(17), 9186; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179186 - 25 Aug 2021
Cited by 18 | Viewed by 5606
Abstract
ATP-binding cassette (ABC) transporters represent a heterogeneous group of ATP-dependent transport proteins, which facilitate the import and/or export of various substrates, including lipids, sugars, amino acids and peptides, ions, and drugs. ABC transporters are involved in a variety of physiological processes in different [...] Read more.
ATP-binding cassette (ABC) transporters represent a heterogeneous group of ATP-dependent transport proteins, which facilitate the import and/or export of various substrates, including lipids, sugars, amino acids and peptides, ions, and drugs. ABC transporters are involved in a variety of physiological processes in different human tissues. More recent studies have demonstrated that ABC transporters also regulate the development and function of different T cell populations, such as thymocytes, Natural Killer T cells, CD8+ T cells, and CD4+ T helper cells, including regulatory T cells. Here, we review the current knowledge on ABC transporters in these T cell populations by summarizing how ABC transporters regulate the function of the individual cell types and how this affects the immunity to viruses and tumors, and the course of autoimmune diseases. Furthermore, we provide a perspective on how a better understanding of the function of ABC transporters in T cells might provide promising novel avenues for the therapy of autoimmunity and to improve immunity to infection and cancer. Full article
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21 pages, 3642 KiB  
Review
The MEK5/ERK5 Pathway in Health and Disease
by Rupesh Paudel, Lorenza Fusi and Marc Schmidt
Int. J. Mol. Sci. 2021, 22(14), 7594; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147594 - 15 Jul 2021
Cited by 29 | Viewed by 6368
Abstract
The MEK5/ERK5 mitogen-activated protein kinases (MAPK) cascade is a unique signaling module activated by both mitogens and stress stimuli, including cytokines, fluid shear stress, high osmolarity, and oxidative stress. Physiologically, it is mainly known as a mechanoreceptive pathway in the endothelium, where it [...] Read more.
The MEK5/ERK5 mitogen-activated protein kinases (MAPK) cascade is a unique signaling module activated by both mitogens and stress stimuli, including cytokines, fluid shear stress, high osmolarity, and oxidative stress. Physiologically, it is mainly known as a mechanoreceptive pathway in the endothelium, where it transduces the various vasoprotective effects of laminar blood flow. However, it also maintains integrity in other tissues exposed to mechanical stress, including bone, cartilage, and muscle, where it exerts a key function as a survival and differentiation pathway. Beyond its diverse physiological roles, the MEK5/ERK5 pathway has also been implicated in various diseases, including cancer, where it has recently emerged as a major escape route, sustaining tumor cell survival and proliferation under drug stress. In addition, MEK5/ERK5 dysfunction may foster cardiovascular diseases such as atherosclerosis. Here, we highlight the importance of the MEK5/ERK5 pathway in health and disease, focusing on its role as a protective cascade in mechanical stress-exposed healthy tissues and its function as a therapy resistance pathway in cancers. We discuss the perspective of targeting this cascade for cancer treatment and weigh its chances and potential risks when considering its emerging role as a protective stress response pathway. Full article
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37 pages, 2451 KiB  
Review
Ras Isoforms from Lab Benches to Lives—What Are We Missing and How Far Are We?
by Arathi Nair, Katharina F. Kubatzky and Bhaskar Saha
Int. J. Mol. Sci. 2021, 22(12), 6508; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126508 - 17 Jun 2021
Cited by 5 | Viewed by 4935
Abstract
The central protein in the oncogenic circuitry is the Ras GTPase that has been under intense scrutiny for the last four decades. From its discovery as a viral oncogene and its non-oncogenic contribution to crucial cellular functioning, an elaborate genetic, structural, and functional [...] Read more.
The central protein in the oncogenic circuitry is the Ras GTPase that has been under intense scrutiny for the last four decades. From its discovery as a viral oncogene and its non-oncogenic contribution to crucial cellular functioning, an elaborate genetic, structural, and functional map of Ras is being created for its therapeutic targeting. Despite decades of research, there still exist lacunae in our understanding of Ras. The complexity of the Ras functioning is further exemplified by the fact that the three canonical Ras genes encode for four protein isoforms (H-Ras, K-Ras4A, K-Ras4B, and N-Ras). Contrary to the initial assessment that the H-, K-, and N-Ras isoforms are functionally similar, emerging data are uncovering crucial differences between them. These Ras isoforms exhibit not only cell-type and context-dependent functions but also activator and effector specificities on activation by the same receptor. Preferential localization of H-, K-, and N-Ras in different microdomains of the plasma membrane and cellular organelles like Golgi, endoplasmic reticulum, mitochondria, and endosome adds a new dimension to isoform-specific signaling and diverse functions. Herein, we review isoform-specific properties of Ras GTPase and highlight the importance of considering these towards generating effective isoform-specific therapies in the future. Full article
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17 pages, 1587 KiB  
Review
Histamine: A Bacterial Signal Molecule
by Tino Krell, José A. Gavira, Félix Velando, Matilde Fernández, Amalia Roca, Elizabet Monteagudo-Cascales and Miguel A. Matilla
Int. J. Mol. Sci. 2021, 22(12), 6312; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126312 - 12 Jun 2021
Cited by 12 | Viewed by 4367
Abstract
Bacteria have evolved sophisticated signaling mechanisms to coordinate interactions with organisms of other domains, such as plants, animals and human hosts. Several important signal molecules have been identified that are synthesized by members of different domains and that play important roles in inter-domain [...] Read more.
Bacteria have evolved sophisticated signaling mechanisms to coordinate interactions with organisms of other domains, such as plants, animals and human hosts. Several important signal molecules have been identified that are synthesized by members of different domains and that play important roles in inter-domain communication. In this article, we review recent data supporting that histamine is a signal molecule that may play an important role in inter-domain and inter-species communication. Histamine is a key signal molecule in humans, with multiple functions, such as being a neurotransmitter or modulator of immune responses. More recent studies have shown that bacteria have evolved different mechanisms to sense histamine or histamine metabolites. Histamine sensing in the human pathogen Pseudomonas aeruginosa was found to trigger chemoattraction to histamine and to regulate the expression of many virulence-related genes. Further studies have shown that many bacteria are able to synthesize and secrete histamine. The release of histamine by bacteria in the human gut was found to modulate the host immune responses and, at higher doses, to result in host pathologies. The elucidation of the role of histamine as an inter-domain signaling molecule is an emerging field of research and future investigation is required to assess its potential general nature. Full article
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13 pages, 862 KiB  
Review
Current Advances on the Important Roles of Enhancer RNAs in Molecular Pathways of Cancer
by Rui Wang and Qianzi Tang
Int. J. Mol. Sci. 2021, 22(11), 5640; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115640 - 26 May 2021
Cited by 5 | Viewed by 3122
Abstract
Enhancers are critical genomic elements that can cooperate with promoters to regulate gene transcription in both normal and cancer cells. Recent studies reveal that enhancer regions are transcribed to produce a class of noncoding RNAs referred to as enhancer RNAs (eRNAs). Emerging evidence [...] Read more.
Enhancers are critical genomic elements that can cooperate with promoters to regulate gene transcription in both normal and cancer cells. Recent studies reveal that enhancer regions are transcribed to produce a class of noncoding RNAs referred to as enhancer RNAs (eRNAs). Emerging evidence shows that eRNAs play important roles in enhancer activation and enhancer-driven gene regulation, and the expression of eRNAs may be a critical factor in tumorigenesis. The important roles of eRNAs in cancer signaling pathways are also gradually unveiled, providing a new insight into cancer therapy. Here, we review the roles of eRNAs in regulating cancer signaling pathways and discuss the potential of eRNA-targeted therapy for human cancers. Full article
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16 pages, 1827 KiB  
Review
Altered Signal Transduction in the Immune Response to Influenza Virus and S. pneumoniae or S. aureus Co-Infections
by Janine J. Wilden, Jasmin C. Jacob, Christina Ehrhardt, Stephan Ludwig and Yvonne Boergeling
Int. J. Mol. Sci. 2021, 22(11), 5486; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115486 - 22 May 2021
Cited by 10 | Viewed by 3044
Abstract
Influenza virus is a well-known respiratory pathogen, which still leads to many severe pulmonary infections in the human population every year. Morbidity and mortality rates are further increased if virus infection coincides with co-infections or superinfections caused by bacteria such as Streptococcus pneumoniae [...] Read more.
Influenza virus is a well-known respiratory pathogen, which still leads to many severe pulmonary infections in the human population every year. Morbidity and mortality rates are further increased if virus infection coincides with co-infections or superinfections caused by bacteria such as Streptococcus pneumoniae (S. pneumoniae) and Staphylococcus aureus (S. aureus). This enhanced pathogenicity is due to complex interactions between the different pathogens and the host and its immune system and is mainly governed by altered intracellular signaling processes. In this review, we summarize the recent findings regarding the innate and adaptive immune responses during co-infection with influenza virus and S. pneumoniae or S. aureus, describing the signaling pathways involved and how these interactions influence disease outcomes. Full article
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22 pages, 2397 KiB  
Review
Optogenetic Approaches for the Spatiotemporal Control of Signal Transduction Pathways
by Markus M. Kramer, Levin Lataster, Wilfried Weber and Gerald Radziwill
Int. J. Mol. Sci. 2021, 22(10), 5300; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22105300 - 18 May 2021
Cited by 14 | Viewed by 4788
Abstract
Biological signals are sensed by their respective receptors and are transduced and processed by a sophisticated intracellular signaling network leading to a signal-specific cellular response. Thereby, the response to the signal depends on the strength, the frequency, and the duration of the stimulus [...] Read more.
Biological signals are sensed by their respective receptors and are transduced and processed by a sophisticated intracellular signaling network leading to a signal-specific cellular response. Thereby, the response to the signal depends on the strength, the frequency, and the duration of the stimulus as well as on the subcellular signal progression. Optogenetic tools are based on genetically encoded light-sensing proteins facilitating the precise spatiotemporal control of signal transduction pathways and cell fate decisions in the absence of natural ligands. In this review, we provide an overview of optogenetic approaches connecting light-regulated protein-protein interaction or caging/uncaging events with steering the function of signaling proteins. We briefly discuss the most common optogenetic switches and their mode of action. The main part deals with the engineering and application of optogenetic tools for the control of transmembrane receptors including receptor tyrosine kinases, the T cell receptor and integrins, and their effector proteins. We also address the hallmarks of optogenetics, the spatial and temporal control of signaling events. Full article
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