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Molecular Insight into Cell Signalling Proteins

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

Deadline for manuscript submissions: 30 September 2024 | Viewed by 9979

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Special Issue Editor

Dr. Athina-Myrto Chioni

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Guest Editor

School of Life Sciences Pharmacy and Chemistry, Kingston University, Penrhyn Road, Kingston upon Thames KT1 2EE, UK
Interests: developmental biology; cell signalling; cancer; pathobiology; physiological diseases; cellular receptors and ligands

Special Issue Information

Dear Colleagues,

Many proteins are responsible for transmitting signals within cells and facilitating interaction with their neighbouring cells and microenvironment. These intra- and extra-cellular interactions are crucial to regulate their normal functions and homeostasis. For example, cellular differentiation, migration, growth, and survival, as well as morphogenesis and organogenesis, are some examples of how cells can regulate themselves, work together with their evolving environments, and respond to external and internal stimulus. Therefore, a wide range of ligands and receptors are paramount in conveying messages and promoting all dimensions of health.

However, dysregulation of these signalling molecules and cascades can lead to the pathogenesis of many diseases. The nature and mechanisms of the defects in these signalling pathways can vary. Improving our knowledge on (1) the different aspects of the signalling pathways that orchestrate normal biological functions, and (2) underlying key mechanisms that contribute to different stages of disease progression, can advance our understanding of disease manifestation and how to target these pathways for therapeutic purposes.

The scope of this open access Special Issue is to highlight current knowledge and gather novel discoveries in molecular cell signalling in health and disease. What are the triggers and mechanisms of “taking-over” a physiological cell signalling pathway and reversing it into a pathogenic one?

We would like to invite you to submit your original research and/or review articles addressing the role of signalling proteins in health, and, when the signalling pathways are dysregulated, how they can contribute to disease development.

Dr. Athina-Myrto Chioni
Guest Editor

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

molecular signalling pathways
cell signalling
cellular communication
receptor molecules
cell-surface receptors
transmembrane receptors
internal receptors
ion channel linked receptors
G-protein coupled receptors
enzyme linked receptors
ERK signalling
AKT signalling
STAT signalling
downstream signalling
tyrosine kinase receptors
cytokines
chemokines
growth factors
signal transduction
second messenger
chemical signals/ligands
signal transduction
developmental biology
pathobiology
human disease
molecular tumour pathology
tumour microenvironment
angiogenesis
cancer
neuronal diseases
metabolic diseases
developmental diseases
physiological diseases

Published Papers (6 papers)

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Research

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10 pages, 4127 KiB

Open AccessArticle

Pulmonary Adenocarcinoma In Situ and Minimally Invasive Adenocarcinomas in European Patients Have Less KRAS and More EGFR Mutations Compared to Advanced Adenocarcinomas

by Jennie Petterson, Dyar Mustafa, Sashidar Bandaru, Ella Äng Eklund, Andreas Hallqvist, Volkan I. Sayin, Andréanne Gagné, Henrik Fagman and Levent M. Akyürek

Int. J. Mol. Sci. 2024, 25(5), 2959; https://doi.org/10.3390/ijms25052959 - 03 Mar 2024

Viewed by 737

Abstract

Pulmonary adenocarcinoma (ADC) is a very diverse disease, both genetically and histologically, which displays extensive intratumor heterogeneity with numerous acquired mutations. ADC is the most common type of lung cancer and is believed to arise from adenocarcinoma in situ (AIS) which then progresses to minimally invasive adenocarcinoma (MIA). In patients of European ethnicity, we analyzed genetic mutations in AIS (n = 10) and MIA (n = 18) and compared the number of genetic mutations with advanced ADC (n = 2419). Using next-generation sequencing, the number of different mutations detected in both AIS (87.5%) and MIA (94.5%) were higher (p < 0.001) than in advanced ADC (53.7%). In contrast to the high number of mutations in Kirsten rat sarcoma virus gene (KRAS) in advanced ADC (34.6%), there was only one case of AIS with KRAS G12C mutation (3.5%; p < 0.001) and no cases of MIA with KRAS mutation (p < 0.001). In contrast to the modest prevalence of epidermal growth factor receptor (EGFR) mutations in advanced ADC (15.0%), the fraction of EGFR mutant cases was higher in both in AIS (22.2%) and MIA (59.5%; p < 0.001). The EGFR exon 19 deletion mutation was more common in both MIA (50%; n = 6/12) and ADC (41%; n = 149/363), whereas p.L858R was more prevalent in AIS (75%; n = 3/4). In contrast to pulmonary advanced ADC, KRAS driver mutations are less common, whereas mutations in EGFR are more common, in detectable AIS and MIA. Full article

(This article belongs to the Special Issue Molecular Insight into Cell Signalling Proteins)

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17 pages, 3926 KiB

Open AccessArticle

Phosphorylation-Assisted Luciferase Complementation Assay Designed to Monitor Kinase Activity and Kinase-Domain-Mediated Protein–Protein Binding

by Ádám L. Póti, Laura Dénes, Kinga Papp, Csaba Bató, Zoltán Bánóczi, Attila Reményi and Anita Alexa

Int. J. Mol. Sci. 2023, 24(19), 14854; https://doi.org/10.3390/ijms241914854 - 03 Oct 2023

Viewed by 1086

Abstract

Protein kinases are key regulators of cell signaling and have been important therapeutic targets for three decades. ATP-competitive drugs directly inhibit the activity of kinases but these enzymes work as part of complex protein networks in which protein–protein interactions (often referred to as kinase docking) may govern a more complex activation pattern. Kinase docking is indispensable for many signaling disease-relevant Ser/Thr kinases and it is mediated by a dedicated surface groove on the kinase domain which is distinct from the substrate-binding pocket. Thus, interfering with kinase docking provides an alternative strategy to control kinases. We describe activity sensors developed for p90 ribosomal S6 kinase (RSK) and mitogen-activated protein kinases (MAPKs: ERK, p38, and JNK) whose substrate phosphorylation is known to depend on kinase-docking-groove-mediated protein–protein binding. The in vitro assays were based on fragment complementation of the NanoBit luciferase, which is facilitated upon substrate motif phosphorylation. The new phosphorylation-assisted luciferase complementation (PhALC) sensors are highly selective and the PhALC assay is a useful tool for the quantitative analysis of kinase activity or kinase docking, and even for high-throughput screening of academic compound collections. Full article

(This article belongs to the Special Issue Molecular Insight into Cell Signalling Proteins)

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20 pages, 4250 KiB

Open AccessArticle

KLF13 Regulates the Activity of the GH-Induced JAK/STAT Signaling by Targeting Genes Involved in the Pathway

by José Ávila-Mendoza, Karen Delgado-Rueda, Valeria A. Urban-Sosa, Martha Carranza, Maricela Luna, Carlos G. Martínez-Moreno and Carlos Arámburo

Int. J. Mol. Sci. 2023, 24(13), 11187; https://doi.org/10.3390/ijms241311187 - 07 Jul 2023

Viewed by 1286

Abstract

The Krüppel-like factor 13 (KLF13) has emerged as an important transcription factor involved in essential processes of the central nervous system (CNS). It predominantly functions as a transcriptional repressor, impacting the activity of several signaling pathways with essential roles in the CNS, including the JAK/STAT pathway, which is the canonical mediator of growth hormone (GH) signaling. It is now recognized that GH has important actions as a neurotrophic factor. Therefore, we analyzed the effects of KLF13 on the activity of the JAK/STAT signaling pathway in the hippocampus-derived cell line HT22. Results showed that KLF13 directly regulates the expression of several genes involved in the JAK-STAT pathway, including Jak1, Jak2, Jak3, and Socs1, by associating with their proximal gene promoters. In addition, it was found that in KLF13-deficient HT22 neurons, the expression of Jak1, Stat3, Socs1, Socs3, and Igf1 was dysregulated, exhibiting mRNA levels that went up to 7-fold higher than the control cell line. KLF13 displayed a differential effect on the GH-induced JAK/STAT pathway activity, decreasing the STAT3 branch while enhancing the STAT5 branch. In KLF13-deficient HT22 cells, the activity of the STAT3 branch was enhanced, mediating the GH-dependent augmented expression of the JAK/STAT output genes Socs1, Socs3, Igf1, and Bdnf. Furthermore, GH treatment increased both the nuclear content of KLF13 and Klf13 mRNA levels, suggesting that KLF13 could be part of the mechanisms that maintain the homeostatic state of this pathway. These findings support the notion that KLF13 is a regulator of JAK/STAT activity. Full article

(This article belongs to the Special Issue Molecular Insight into Cell Signalling Proteins)

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14 pages, 2501 KiB

Open AccessArticle

HDAC Inhibition Restores Response to HER2-Targeted Therapy in Breast Cancer via PHLDA1 Induction

by Natasha S. Clayton, Edward P. Carter, Abbie E. Fearon, James A. Heward, Lucía Rodríguez Fernández, Lina Boughetane, Edmund H. Wilkes, Pedro R. Cutillas and Richard P. Grose

Int. J. Mol. Sci. 2023, 24(7), 6228; https://doi.org/10.3390/ijms24076228 - 25 Mar 2023

Viewed by 1565

Abstract

The downregulation of Pleckstrin Homology-Like Domain family A member 1 (PHLDA1) expression mediates resistance to targeted therapies in receptor tyrosine kinase-driven cancers. The restoration and maintenance of PHLDA1 levels in cancer cells thus constitutes a potential strategy to circumvent resistance to inhibitors of receptor tyrosine kinases. Through a pharmacological approach, we identify the inhibition of MAPK signalling as a crucial step in PHLDA1 downregulation. Further ChIP-qPCR analysis revealed that MEK1/2 inhibition produces significant epigenetic changes at the PHLDA1 locus, specifically a decrease in the activatory marks H3Kme3 and H3K27ac. In line with this, we show that treatment with the clinically relevant class I histone deacetylase (HDAC) inhibitor 4SC-202 restores PHLDA1 expression in lapatinib-resistant human epidermal growth factor receptor-2 (HER2)⁺ breast cancer cells. Critically, we show that when given in combination, 4SC-202 and lapatinib exert synergistic effects on 2D cell proliferation and colony formation capacity. We therefore propose that co-treatment with 4SC-202 may prolong the clinical efficacy of lapatinib in HER2⁺ breast cancer patients. Full article

(This article belongs to the Special Issue Molecular Insight into Cell Signalling Proteins)

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Review

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18 pages, 2187 KiB

Open AccessReview

Hypoplastic Left Heart Syndrome: Signaling & Molecular Perspectives, and the Road Ahead

by Sayantap Datta, Wangjia Cao, Mikayla Skillman and Mingfu Wu

Int. J. Mol. Sci. 2023, 24(20), 15249; https://doi.org/10.3390/ijms242015249 - 17 Oct 2023

Viewed by 1338

Abstract

Hypoplastic left heart syndrome (HLHS) is a lethal congenital heart disease (CHD) affecting 8–25 per 100,000 neonates globally. Clinical interventions, primarily surgical, have improved the life expectancy of the affected subjects substantially over the years. However, the etiological basis of HLHS remains fundamentally unclear to this day. Based upon the existing paradigm of studies, HLHS exhibits a multifactorial mode of etiology mediated by a complicated course of genetic and signaling cascade. This review presents a detailed outline of the HLHS phenotype, the prenatal and postnatal risks, and the signaling and molecular mechanisms driving HLHS pathogenesis. The review discusses the potential limitations and future perspectives of studies that can be undertaken to address the existing scientific gap. Mechanistic studies to explain HLHS etiology will potentially elucidate novel druggable targets and empower the development of therapeutic regimens against HLHS in the future. Full article

(This article belongs to the Special Issue Molecular Insight into Cell Signalling Proteins)

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42 pages, 3105 KiB

Open AccessReview

Dysregulated Signalling Pathways Driving Anticancer Drug Resistance

by Nauf Bou Antoun and Athina-Myrto Chioni

Int. J. Mol. Sci. 2023, 24(15), 12222; https://doi.org/10.3390/ijms241512222 - 30 Jul 2023

Cited by 5 | Viewed by 3032

Abstract

One of the leading causes of death worldwide, in both men and women, is cancer. Despite the significant development in therapeutic strategies, the inevitable emergence of drug resistance limits the success and impedes the curative outcome. Intrinsic and acquired resistance are common mechanisms responsible for cancer relapse. Several factors crucially regulate tumourigenesis and resistance, including physical barriers, tumour microenvironment (TME), heterogeneity, genetic and epigenetic alterations, the immune system, tumour burden, growth kinetics and undruggable targets. Moreover, transforming growth factor-beta (TGF-β), Notch, epidermal growth factor receptor (EGFR), integrin-extracellular matrix (ECM), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), phosphoinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR), wingless-related integration site (Wnt/β-catenin), Janus kinase/signal transducers and activators of transcription (JAK/STAT) and RAS/RAF/mitogen-activated protein kinase (MAPK) signalling pathways are some of the key players that have a pivotal role in drug resistance mechanisms. To guide future cancer treatments and improve results, a deeper comprehension of drug resistance pathways is necessary. This review covers both intrinsic and acquired resistance and gives a comprehensive overview of recent research on mechanisms that enable cancer cells to bypass barriers put up by treatments, and, like “satellite navigation”, find alternative routes by which to carry on their “journey” to cancer progression. Full article

(This article belongs to the Special Issue Molecular Insight into Cell Signalling Proteins)

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