Submit to Cells Review for Cells Propose a Special Issue

Journal Menu

Journal Browser

► Journal Browser

Cell-Cell Interactions and Cell Adhesion Signaling in Disease States

Special Issue Editors
Special Issue Information
Keywords
Benefits of Publishing in a Special Issue
Published Papers

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 55291

Share This Special Issue

Special Issue Editors

Dr. Ann Hopkins

E-Mail Website
Guest Editor

Royal College of Surgeons in Ireland – University of Medicine and Health Sciences, Department of Surgery, Dublin, Ireland
Interests: tight junctions; adhesion; tumorigenesis; Junctional Adhesion Molecule-A (JAM-A); breast cancer; cancer; lipid rafts; cell migration; translational research
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Andrei Ivanov

E-Mail Website
Guest Editor

Department of Inflammation and Immunity, Lerner Research Institute of Cleveland Clinic Foundation, Cleveland, OH, USA
Interests: epithelial barriers; tight junctions; adherens junctions; actin cytoskeleton; myosin motors; cell migration; mucosal inflammation; tumor metastasis

Special Issue Information

Dear Colleagues,

Tissue and organ development is critically regulated by intercellular adhesion proteins which control the assembly of biological barriers; controlling cell polarity and differentiation and aiding orchestrated movement of cell clusters during tissue morphogenesis and repair. These adhesion proteins cluster into elaborate cell–cell adhesion complexes whose dynamic assembly, maintenance and disassembly are controlled by a plethora of exogenous and endogenous signaling factors. In turn, cell–cell adhesion complexes act as versatile environmental sensors and signal transducers that ignite a variety of intracellular molecular and signaling pathways. Collectively, adhesion signaling pathways exert regulatory control at multiple levels, ranging from pre-transcriptional to post-translational; and over downstream functional outcomes as diverse as barrier function, cell polarity, cell differentiation and survival, collective cell migration and immune cell trafficking to/from the vasculature.

In light of an emerging understanding that dysregulated cell–cell adhesion signaling through these (and other) pathways can act as a mechanistic driver of disease, this Special Issue will explore the roles of cell–cell adhesion proteins and signaling ignited at cell–cell interfaces in pathophysiological states. We will cover a variety of cell adhesion complexes, including classical tight junctions, adherens junctions, gap junctions and desmosomes in different cell types. In addition to homotypic cell–cell interactions within epithelial or endothelial barriers, we would be interested in heterotypic adhesion complexes assembled at neuronal interfaces in synapses, at immune cell interfaces during antigen presentation and during immune cell interactions with epithelial and vascular barriers. We will cover molecular and signaling events triggered by cell–cell interactions, ranging from cortical cytoskeletal remodeling to the transcriptional reprogramming of cells. We welcome submissions focused on diverse disease areas including (but not limited to) cancer, inflammatory diseases, autoimmunity, neurodegenerative and neurocognitive conditions, fertility disorders, vascular and cardiovascular disease. Furthermore, since the localization of most adhesion proteins on outer cell membranes makes them attractive receptor targets for a range of infectious agents, submissions focused on the role of cell–cell adhesion proteins in host–pathogen interactions and infection are also welcome. Translational studies that incorporate whole-organism, patient or patient database elements to back up mechanistic cell biological findings will be particularly valuable.

Thank you in advance for considering submitting your original research to this Special Issue. We hope that it will catalyze a greater understanding of the evolving roles of adhesion proteins as biomarkers and potential therapeutic targets in a range of human diseases.

Dr. Ann Hopkins
Prof. Dr. Andrei Ivanov
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. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). 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

Adhesion
Tight junctions
Adherens junctions
Gap junctions
Desmosomes
Neuronal synapse
Immunological synapse
Cell adhesion signaling
Cell adhesion molecules
Collective cell migration
Cancer
Inflammation
Immunopathology
Cardiovascular diseases
Epithelial barriers
Vascular barriers
Cadherins
Immunoglobulin superfamily

Benefits of Publishing in a Special Issue

Ease of navigation: Grouping papers by topic helps scholars navigate broad scope journals more efficiently.
Greater discoverability: Special Issues support the reach and impact of scientific research. Articles in Special Issues are more discoverable and cited more frequently.
Expansion of research network: Special Issues facilitate connections among authors, fostering scientific collaborations.
External promotion: Articles in Special Issues are often promoted through the journal's social media, increasing their visibility.
e-Book format: Special Issues with more than 10 articles can be published as dedicated e-books, ensuring wide and rapid dissemination.

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

Published Papers (13 papers)

Download All Papers

Order results

Result details

Show export options Show export options

Select all

Export citation of selected articles as:

Research

Jump to: Review

15 pages, 2560 KiB

Open AccessArticle

Polyubiquitination and SUMOylation Sites Regulate the Stability of ZO-2 Protein and the Sealing of Tight Junctions

by Misael Cano-Cortina, Lourdes Alarcón, Jael Miranda, Otmar Huber and Lorenza González-Mariscal

Cells 2022, 11(20), 3296; https://doi.org/10.3390/cells11203296 - 19 Oct 2022

Cited by 3 | Viewed by 2153

Abstract

Tight junctions (TJs) regulate the transit of ions and molecules through the paracellular pathway in epithelial cells. Zonula occludens 2 (ZO-2) is a cytoplasmic TJ protein. Here, we studied the ubiquitination of hZO-2 employing mutants of SUMOylation site K730 present in the GuK domain and the putative ubiquitination residues K759 and K992 located at the GuK domain and proline-rich region, respectively. In immunoprecipitation experiments done with MDCK cells transfected with wild-type (WT) hZO-2 or the ubiquitination-site mutants hZO-2-K759R or -K992R, we observed diminished ubiquitination of the mutants, indicating that residues K759 and K992 in hZO-2 are acceptors for ubiquitination. Moreover, using TUBES, we found that residues K759 and K992 of hZO-2 are targets of K48 polyubiquitination, a signal for proteasomal degradation. Accordingly, compared to WT hZO-2, the half-life of hZO-2 mutants K759R and K992R augmented from 19.9 to 37.3 and 23.3 h, respectively. Instead, the ubiquitination of hZO-2 mutant K730R increased, and its half-life diminished to 6.7 h. The lack of these lysine residues in hZO-2 affects TJ sealing as the peak of TER decreased in monolayers of MDCK cells transfected with any of these mutants. These results highlight the importance of ZO-2 ubiquitination and SUMOylation to maintain a healthy and stable pool of ZO-2 molecules at the TJ. Full article

(This article belongs to the Special Issue Cell-Cell Interactions and Cell Adhesion Signaling in Disease States)

► Show Figures

Figure 1

23 pages, 7026 KiB

Open AccessArticle

Therapeutic Validation of GEF-H1 Using a De Novo Designed Inhibitor in Models of Retinal Disease

by Clare Mills, Sandra A. Hemkemeyer, Zerin Alimajstorovic, Chantelle Bowers, Malihe Eskandarpour, John Greenwood, Virginia Calder, A. W. Edith Chan, Paul J. Gane, David L. Selwood, Karl Matter and Maria S. Balda

Cells 2022, 11(11), 1733; https://doi.org/10.3390/cells11111733 - 24 May 2022

Cited by 4 | Viewed by 3126

Abstract

Inflammation and fibrosis are important components of diseases that contribute to the malfunction of epithelia and endothelia. The Rho guanine nucleotide exchange factor (GEF) GEF-H1/ARHGEF-2 is induced in disease and stimulates inflammatory and fibrotic processes, cell migration, and metastasis. Here, we have generated peptide inhibitors to block the function of GEF-H1. Inhibitors were designed using a structural in silico approach or by isolating an inhibitory sequence from the autoregulatory C-terminal domain. Candidate inhibitors were tested for their ability to block RhoA/GEF-H1 binding in vitro, and their potency and specificity in cell-based assays. Successful inhibitors were then evaluated in models of TGFβ-induced fibrosis, LPS-stimulated endothelial cell-cell junction disruption, and cell migration. Finally, the most potent inhibitor was successfully tested in an experimental retinal disease mouse model, in which it inhibited blood vessel leakage and ameliorated retinal inflammation when treatment was initiated after disease diagnosis. Thus, an antagonist that blocks GEF-H1 signaling effectively inhibits disease features in in vitro and in vivo disease models, demonstrating that GEF-H1 is an effective therapeutic target and establishing a new therapeutic approach. Full article

(This article belongs to the Special Issue Cell-Cell Interactions and Cell Adhesion Signaling in Disease States)

► Show Figures

Figure 1

16 pages, 3079 KiB

Open AccessArticle

MarvelD3 Is Upregulated in Ulcerative Colitis and Has Attenuating Effects during Colitis Indirectly Stabilizing the Intestinal Barrier

by Franziska Weiß, Carolina Czichos, Lukas Knobe, Lena Voges, Christian Bojarski, Geert Michel, Michael Fromm and Susanne M. Krug

Cells 2022, 11(9), 1541; https://doi.org/10.3390/cells11091541 - 4 May 2022

Cited by 3 | Viewed by 2599

Abstract

In inflammatory bowel disease (IBD), the impaired intestinal barrier is mainly characterized by changes in tight junction protein expression. The functional role of the tight junction-associated MARVEL protein MARVELD3 (MD3) in IBD is yet unknown. (i) In colon biopsies from IBD patients we analyzed MD3 expression and (ii) in human colon HT-29/B6 cells we studied the signaling pathways of different IBD-relevant cytokines. (iii) We generated a mouse model with intestinal overexpression of MD3 and investigated functional effects of MD3 upregulation. Colitis, graded by the disease activity index, was induced by dextran sodium sulfate (DSS) and the intestinal barrier was characterized electrophysiologically. MD3 was upregulated in human ulcerative colitis and MD3 expression could be increased in HT-29/B6 cells by IL-13 via the IL13Rα1/STAT pathway. In mice DSS colitis, MD3 overexpression had an ameliorating, protective effect. It was not based on direct enhancement of paracellular barrier properties, but rather on regulatory mechanisms not solved yet in detail. However, as MD3 is involved in regulatory functions such as proliferation and cell survival, we conclude that the protective effects are hardly targeting the intestinal barrier directly but are based on regulatory processes supporting stabilization of the intestinal barrier. Full article

(This article belongs to the Special Issue Cell-Cell Interactions and Cell Adhesion Signaling in Disease States)

► Show Figures

Figure 1

25 pages, 5071 KiB

Open AccessArticle

P-Cadherin Regulates Intestinal Epithelial Cell Migration and Mucosal Repair, but Is Dispensable for Colitis Associated Colon Cancer

by Nayden G. Naydenov, Susana Lechuga, Ajay Zalavadia, Pranab K. Mukherjee, Ilyssa O. Gordon, David Skvasik, Petra Vidovic, Emina Huang, Florian Rieder and Andrei I. Ivanov

Cells 2022, 11(9), 1467; https://doi.org/10.3390/cells11091467 - 27 Apr 2022

Cited by 7 | Viewed by 4601

Abstract

Recurrent chronic mucosal inflammation, a characteristic of inflammatory bowel diseases (IBD), perturbs the intestinal epithelial homeostasis resulting in formation of mucosal wounds and, in most severe cases, leads to colitis-associated colon cancer (CAC). The altered structure of epithelial cell-cell adhesions is a hallmark of intestinal inflammation contributing to epithelial injury, repair, and tumorigenesis. P-cadherin is an important adhesion protein, poorly expressed in normal intestinal epithelial cells (IEC) but upregulated in inflamed and injured mucosa. The goal of this study was to investigate the roles of P-cadherin in regulating intestinal inflammation and CAC. P-cadherin expression was markedly induced in the colonic epithelium of human IBD patients and CAC tissues. The roles of P-cadherin were investigated in P-cadherin null mice using dextran sulfate sodium (DSS)-induced colitis and an azoxymethane (AOM)/DSS induced CAC. Although P-cadherin knockout did not affect the severity of acute DSS colitis, P-cadherin null mice exhibited faster recovery after colitis. No significant differences in the number of colonic tumors were observed in P-cadherin null and control mice. Consistently, the CRISPR/Cas9-mediated knockout of P-cadherin in human IEC accelerated epithelial wound healing without affecting cell proliferation. The accelerated migration of P-cadherin depleted IEC was driven by activation of Src kinases, Rac1 GTPase and myosin II motors and was accompanied by transcriptional reprogramming of the cells. Our findings highlight P-cadherin as a negative regulator of IEC motility in vitro and mucosal repair in vivo. In contrast, this protein is dispensable for IEC proliferation and CAC development. Full article

(This article belongs to the Special Issue Cell-Cell Interactions and Cell Adhesion Signaling in Disease States)

► Show Figures

Figure 1

22 pages, 4825 KiB

Open AccessArticle

A Transcriptional Link between HER2, JAM-A and FOXA1 in Breast Cancer

by Rodrigo G. B. Cruz, Stephen F. Madden, Kieran Brennan and Ann M. Hopkins

Cells 2022, 11(4), 735; https://doi.org/10.3390/cells11040735 - 19 Feb 2022

Cited by 9 | Viewed by 3251

Abstract

Overexpression of the human epidermal growth factor receptor-2 (HER2) is associated with aggressive disease in breast and certain other cancers. At a cellular level, the adhesion protein Junctional Adhesion Molecule-A (JAM-A) has been reported to regulate the expression of HER3 via a transcriptional pathway involving FOXA1. Since FOXA1 is also a suggested transcription factor for HER2, this study set out to determine if JAM-A regulates HER2 expression via a similar mechanism. An integrated tripartite approach was taken, involving cellular expression studies after targeted disruption of individual players in the putative pathway, in silico identification of relevant HER2 promoter regions and, finally, interrogation of cancer patient survival databases to deconstruct functionally important links between HER2, JAM-A and FOXA1 gene expression. The outcome of these investigations revealed a unidirectional pathway in which JAM-A expression transcriptionally regulates that of HER2 by influencing the binding of FOXA1 to a specific site in the HER2 gene promoter. Moreover, a correlation between JAM-A and HER2 gene expression was identified in 75% of a sample of 40 cancer types from The Cancer Genome Atlas, and coincident high mean mRNA expression of JAM-A, HER2 and FOXA1 was associated with poorer survival outcomes in HER2-positive (but not HER2-negative) patients with either breast or gastric tumors. These investigations provide the first evidence of a transcriptional pathway linking JAM-A, HER2 and FOXA1 in cancer settings, and support potential future pharmacological targeting of JAM-A as an upstream regulator of HER2. Full article

(This article belongs to the Special Issue Cell-Cell Interactions and Cell Adhesion Signaling in Disease States)

► Show Figures

Figure 1

13 pages, 3397 KiB

Open AccessArticle

The ACE2 Receptor for Coronavirus Entry Is Localized at Apical Cell—Cell Junctions of Epithelial Cells

by Florian Rouaud, Isabelle Méan and Sandra Citi

Cells 2022, 11(4), 627; https://doi.org/10.3390/cells11040627 - 11 Feb 2022

Cited by 12 | Viewed by 3863

Abstract

Transmembrane proteins of adherens and tight junctions are known targets for viruses and bacterial toxins. The coronavirus receptor ACE2 has been localized at the apical surface of epithelial cells, but it is not clear whether ACE2 is localized at apical Cell—Cell junctions and whether it associates with junctional proteins. Here we explored the expression and localization of ACE2 and its association with transmembrane and tight junction proteins in epithelial tissues and cultured cells by data mining, immunoblotting, immunofluorescence microscopy, and co-immunoprecipitation experiments. ACE2 mRNA is abundant in epithelial tissues, where its expression correlates with the expression of the tight junction proteins cingulin and occludin. In cultured epithelial cells ACE2 mRNA is upregulated upon differentiation and ACE2 protein is widely expressed and co-immunoprecipitates with the transmembrane proteins ADAM17 and CD9. We show by immunofluorescence microscopy that ACE2 colocalizes with ADAM17 and CD9 and the tight junction protein cingulin at apical junctions of intestinal (Caco-2), mammary (Eph4) and kidney (mCCD) epithelial cells. These observations identify ACE2, ADAM17 and CD9 as new epithelial junctional transmembrane proteins and suggest that the cytokine-enhanced endocytic internalization of junction-associated protein complexes comprising ACE2 may promote coronavirus entry. Full article

(This article belongs to the Special Issue Cell-Cell Interactions and Cell Adhesion Signaling in Disease States)

► Show Figures

Figure 1

Review

Jump to: Research

22 pages, 1155 KiB

Open AccessReview

Tight Junction Protein Signaling and Cancer Biology

by Zeina Nehme, Natascha Roehlen, Punita Dhawan and Thomas F. Baumert

Cells 2023, 12(2), 243; https://doi.org/10.3390/cells12020243 - 6 Jan 2023

Cited by 31 | Viewed by 4496

Abstract

Tight junctions (TJs) are intercellular protein complexes that preserve tissue homeostasis and integrity through the control of paracellular permeability and cell polarity. Recent findings have revealed the functional role of TJ proteins outside TJs and beyond their classical cellular functions as selective gatekeepers. This is illustrated by the dysregulation in TJ protein expression levels in response to external and intracellular stimuli, notably during tumorigenesis. A large body of knowledge has uncovered the well-established functional role of TJ proteins in cancer pathogenesis. Mechanistically, TJ proteins act as bidirectional signaling hubs that connect the extracellular compartment to the intracellular compartment. By modulating key signaling pathways, TJ proteins are crucial players in the regulation of cell proliferation, migration, and differentiation, all of which being essential cancer hallmarks crucial for tumor growth and metastasis. TJ proteins also promote the acquisition of stem cell phenotypes in cancer cells. These findings highlight their contribution to carcinogenesis and therapeutic resistance. Moreover, recent preclinical and clinical studies have used TJ proteins as therapeutic targets or prognostic markers. This review summarizes the functional role of TJ proteins in cancer biology and their impact for novel strategies to prevent and treat cancer. Full article

(This article belongs to the Special Issue Cell-Cell Interactions and Cell Adhesion Signaling in Disease States)

► Show Figures

Figure 1

26 pages, 1555 KiB

Open AccessReview

Mechanotransduction in Skin Inflammation

by Maria S. Shutova and Wolf-Henning Boehncke

Cells 2022, 11(13), 2026; https://doi.org/10.3390/cells11132026 - 25 Jun 2022

Cited by 16 | Viewed by 5544

Abstract

In the process of mechanotransduction, the cells in the body perceive and interpret mechanical stimuli to maintain tissue homeostasis and respond to the environmental changes. Increasing evidence points towards dysregulated mechanotransduction as a pathologically relevant factor in human diseases, including inflammatory conditions. Skin is the organ that constantly undergoes considerable mechanical stresses, and the ability of mechanical factors to provoke inflammatory processes in the skin has long been known, with the Koebner phenomenon being an example. However, the molecular mechanisms and key factors linking mechanotransduction and cutaneous inflammation remain understudied. In this review, we outline the key players in the tissue’s mechanical homeostasis, the available data, and the gaps in our current understanding of their aberrant regulation in chronic cutaneous inflammation. We mainly focus on psoriasis as one of the most studied skin inflammatory diseases; we also discuss mechanotransduction in the context of skin fibrosis as a result of chronic inflammation. Even though the role of mechanotransduction in inflammation of the simple epithelia of internal organs is being actively studied, we conclude that the mechanoregulation in the stratified epidermis of the skin requires more attention in future translational research. Full article

(This article belongs to the Special Issue Cell-Cell Interactions and Cell Adhesion Signaling in Disease States)

► Show Figures

Graphical abstract

15 pages, 998 KiB

Open AccessReview

Modulation of Trans-Synaptic Neurexin–Neuroligin Interaction in Pathological Pain

by Huili Li, Ruijuan Guo, Yun Guan, Junfa Li and Yun Wang

Cells 2022, 11(12), 1940; https://doi.org/10.3390/cells11121940 - 16 Jun 2022

Cited by 5 | Viewed by 3417

Abstract

Synapses serve as the interface for the transmission of information between neurons in the central nervous system. The structural and functional characteristics of synapses are highly dynamic, exhibiting extensive plasticity that is shaped by neural activity and regulated primarily by trans-synaptic cell-adhesion molecules (CAMs). Prototypical trans-synaptic CAMs, such as neurexins (Nrxs) and neuroligins (Nlgs), directly regulate the assembly of presynaptic and postsynaptic molecules, including synaptic vesicles, active zone proteins, and receptors. Therefore, the trans-synaptic adhesion mechanisms mediated by Nrx–Nlg interaction can contribute to a range of synaptopathies in the context of pathological pain and other neurological disorders. The present review provides an overview of the current understanding of the roles of Nrx–Nlg interaction in the regulation of trans-synaptic connections, with a specific focus on Nrx and Nlg structures, the dynamic shaping of synaptic function, and the dysregulation of Nrx–Nlg in pathological pain. Additionally, we discuss a range of proteins capable of modulating Nrx–Nlg interactions at the synaptic cleft, with the objective of providing a foundation to guide the future development of novel therapeutic agents for managing pathological pain. Full article

(This article belongs to the Special Issue Cell-Cell Interactions and Cell Adhesion Signaling in Disease States)

► Show Figures

Figure 1

23 pages, 2557 KiB

Open AccessEditor’s ChoiceReview

Vitamin D Receptor Influences Intestinal Barriers in Health and Disease

by Jun Sun and Yong-Guo Zhang

Cells 2022, 11(7), 1129; https://doi.org/10.3390/cells11071129 - 27 Mar 2022

Cited by 35 | Viewed by 6692

Abstract

Vitamin D receptor (VDR) executes most of the biological functions of vitamin D. Beyond this, VDR is a transcriptional factor regulating the expression levels of many target genes, such as genes for tight junction proteins claudin-2, -5, -12, and -15. In this review, we discuss the progress of research on VDR that influences intestinal barriers in health and disease. We searched PubMed and Google Scholar using key words vitamin D, VDR, tight junctions, cancer, inflammation, and infection. We summarize the literature and progress reports on VDR regulation of tight junction distribution, cellular functions, and mechanisms (directly or indirectly). We review the impacts of VDR on barriers in various diseases, e.g., colon cancer, infection, inflammatory bowel disease, and chronic inflammatory lung diseases. We also discuss the limits of current studies and future directions. Deeper understanding of the mechanisms by which the VDR signaling regulates intestinal barrier functions allow us to develop efficient and effective therapeutic strategies based on levels of tight junction proteins and vitamin D/VDR statuses for human diseases. Full article

(This article belongs to the Special Issue Cell-Cell Interactions and Cell Adhesion Signaling in Disease States)

► Show Figures

Graphical abstract

24 pages, 1619 KiB

Open AccessReview

Microbial Metabolite Regulation of Epithelial Cell-Cell Interactions and Barrier Function

by Alfredo Ornelas, Alexander S. Dowdell, J. Scott Lee and Sean P. Colgan

Cells 2022, 11(6), 944; https://doi.org/10.3390/cells11060944 - 10 Mar 2022

Cited by 27 | Viewed by 4286

Abstract

Epithelial cells that line tissues such as the intestine serve as the primary barrier to the outside world. Epithelia provide selective permeability in the presence of a large constellation of microbes, termed the microbiota. Recent studies have revealed that the symbiotic relationship between the healthy host and the microbiota includes the regulation of cell–cell interactions at the level of epithelial tight junctions. The most recent findings have identified multiple microbial-derived metabolites that influence intracellular signaling pathways which elicit activities at the epithelial apical junction complex. Here, we review recent findings that place microbiota-derived metabolites as primary regulators of epithelial cell–cell interactions and ultimately mucosal permeability in health and disease. Full article

(This article belongs to the Special Issue Cell-Cell Interactions and Cell Adhesion Signaling in Disease States)

► Show Figures

Figure 1

25 pages, 7280 KiB

Open AccessReview

Disruption of Claudin-Made Tight Junction Barriers by Clostridium perfringens Enterotoxin: Insights from Structural Biology

by Chinemerem P. Ogbu, Sourav Roy and Alex J. Vecchio

Cells 2022, 11(5), 903; https://doi.org/10.3390/cells11050903 - 5 Mar 2022

Cited by 12 | Viewed by 5572

Abstract

Claudins are a family of integral membrane proteins that enable epithelial cell/cell interactions by localizing to and driving the formation of tight junctions. Via claudin self-assembly within the membranes of adjoining cells, their extracellular domains interact, forming barriers to the paracellular transport of small molecules and ions. The bacterium Clostridium perfringens causes prevalent gastrointestinal disorders in mammals by employing an enterotoxin (CpE) that targets claudins. CpE binds to claudins at or near tight junctions in the gut and disrupts their barrier function, potentially by disabling their assembly or via cell signaling means—the mechanism(s) remain unclear. CpE ultimately destroys claudin-expressing cells through the formation of a cytotoxic membrane-penetrating β-barrel pore. Structures obtained by X-ray crystallography of CpE, claudins, and claudins in complex with CpE fragments have provided the structural bases of claudin and CpE functions, revealing potential mechanisms for the CpE-mediated disruption of claudin-made tight junctions. This review highlights current progress in this space—what has been discovered and what remains unknown—toward efforts to elucidate the molecular mechanism of CpE disruption of tight junction barriers. It further underscores the key insights obtained through structure that are being applied to develop CpE-based therapeutics that combat claudin-overexpressing cancers or modulate tight junction barriers. Full article

(This article belongs to the Special Issue Cell-Cell Interactions and Cell Adhesion Signaling in Disease States)

► Show Figures

Figure 1

19 pages, 1343 KiB

Open AccessReview

Cell-Cell Interaction-Mediated Signaling in the Testis Induces Reproductive Dysfunction—Lesson from the Toxicant/Pharmaceutical Models

by Lingling Wang, Tiao Bu, Xiaolong Wu, Sheng Gao, Xinyao Li, Angela Bryanne De Jesus, Chris K. C. Wong, Hao Chen, Nancy P. Y. Chung, Fei Sun and C. Yan Cheng

Cells 2022, 11(4), 591; https://doi.org/10.3390/cells11040591 - 9 Feb 2022

Cited by 12 | Viewed by 3584

Abstract

Emerging evidence has shown that cell-cell interactions between testicular cells, in particular at the Sertoli cell-cell and Sertoli-germ cell interface, are crucial to support spermatogenesis. The unique ultrastructures that support cell-cell interactions in the testis are the basal ES (ectoplasmic specialization) and the apical ES. The basal ES is found between adjacent Sertoli cells near the basement membrane that also constitute the blood-testis barrier (BTB). The apical ES is restrictively expressed at the Sertoli-spermatid contact site in the apical (adluminal) compartment of the seminiferous epithelium. These ultrastructures are present in both rodent and human testes, but the majority of studies found in the literature were done in rodent testes. As such, our discussion herein, unless otherwise specified, is focused on studies in testes of adult rats. Studies have shown that the testicular cell-cell interactions crucial to support spermatogenesis are mediated through distinctive signaling proteins and pathways, most notably involving FAK, Akt1/2 and Cdc42 GTPase. Thus, manipulation of some of these signaling proteins, such as FAK, through the use of phosphomimetic mutants for overexpression in Sertoli cell epithelium in vitro or in the testis in vivo, making FAK either constitutively active or inactive, we can modify the outcome of spermatogenesis. For instance, using the toxicant-induced Sertoli cell or testis injury in rats as study models, we can either block or rescue toxicant-induced infertility through overexpression of p-FAK-Y397 or p-FAK-Y407 (and their mutants), including the use of specific activator(s) of the involved signaling proteins against pAkt1/2. These findings thus illustrate that a potential therapeutic approach can be developed to manage toxicant-induced male reproductive dysfunction. In this review, we critically evaluate these recent findings, highlighting the direction for future investigations by bringing the laboratory-based research through a translation path to clinical investigations. Full article

(This article belongs to the Special Issue Cell-Cell Interactions and Cell Adhesion Signaling in Disease States)

► Show Figures

Journal Menu

Journal Browser

Cell-Cell Interactions and Cell Adhesion Signaling in Disease States

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Benefits of Publishing in a Special Issue

Published Papers (13 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI