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Fibronectin in Health and Diseases
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Fibronectin in Health and Diseases

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (30 November 2019) | Viewed by 87668

Special Issue Editors

Prof. Dr. Matthew A. Nugent

E-Mail Website
Guest Editor
Jess & Mildred Fisher College of Science and Mathematics, Towson University, 8000 York Road, Towson, MD 21252, USA
Interests: extracellular matrix; cardiovascular disease; cancer; cell biology; growth factors; enzymology; lung disease; COPD
Dr. Michael L. Smith

E-Mail Website
Guest Editor
Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA
Interests: matrix mechanotransduction; extracellular matrix; fibronectin
Dr. Maria Mitsi

E-Mail Website
Guest Editor
Laboratory of Food and Soft Materials, ETH Zurich, 8092 Zurich, Switzerland
Interests: extracellular matrix; fibronectin; growth factors; angiogenesis; structural biology

Special Issue Information

Dear Colleagues,

Fibronectin is a large multimodular protein, which is incorporated in a fibrillar form in the extracellular matrix of almost every cell type. It is a major substrate for cell adhesion and migration and plays important roles in a large number of physiological processes, including wound healing and tissue regeneration, neovascularization, and embryonic development. Thus, fibronectin has been implicated in many diseases where such physiological processes are dysregulated. The ability of fibronectin to carry all these diverse functionalities depends on interactions with a large number of molecules, including adhesive and signaling cell surface receptors, other components of the extracellular matrix, and growth factors and cytokines. The regulation and integration of such a large number of interactions depends on the modular architecture and flexibility of fibronectin, which allows a large number of conformations, exposing or destroying different binding sites. Both biochemical and mechanical factors have the ability to regulate fibronectin conformation and alter fibronectin functionality.

The aim of this Special Issue is to summarize our current knowledge of the role of fibronectin in health and disease and highlight the underlying mechanisms at the cellular and molecular level. Emphasis will be given on the biochemical and mechanical forces that regulate fibronectin conformation, affect its binding partners, and lead to the activation of biochemical pathways that control cell behavior. Furthermore, an overview of the use of fibronectin in various therapeutic approaches will be given, especially the design of fibronectin-based scaffolds for tissue engineering applications. We hope that such a Special Issue will provide valuable information to the scientific community, help to identify open questions, and drive the field forward.

Prof. Matthew A Nugent
Dr. Michael L. Smith
Dr. Maria Mitsi
Guest Editors

Manuscript Submission Information

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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

  • fibronectin
  • conformational flexibility
  • binding sites
  • mechanical forces
  • scaffolds
  • tissue engineering

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Published Papers (15 papers)

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Research

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19 pages, 5805 KiB  
Article
Overexpression of Extradomain-B Fibronectin is Associated with Invasion of Breast Cancer Cells
by Amita Vaidya, Helen Wang, Victoria Qian, Hannah Gilmore and Zheng-Rong Lu
Cells 2020, 9(8), 1826; https://doi.org/10.3390/cells9081826 - 03 Aug 2020
Cited by 23 | Viewed by 3934
Abstract
Breast tumor heterogeneity is a major impediment to oncotherapy. Cancer cells undergo rapid clonal evolution, thereby acquiring significant growth and invasive advantages. The absence of specific markers of these high-risk populations precludes efficient therapeutic and diagnostic management of the disease. Given the critical [...] Read more.
Breast tumor heterogeneity is a major impediment to oncotherapy. Cancer cells undergo rapid clonal evolution, thereby acquiring significant growth and invasive advantages. The absence of specific markers of these high-risk populations precludes efficient therapeutic and diagnostic management of the disease. Given the critical function of tumor microenvironment in the oncogenic circuitry, we sought to determine the expression profile of the extracellular matrix oncoprotein, extradomain-B fibronectin (EDB-FN) in invasive breast cancer. Analyses of TCGA/GTEx databases and immunostaining of clinical samples found a significant overexpression of EDB-FN in breast tumors, which correlated with poor overall survival. Significant upregulation of EDB-FN was observed in invasive cell populations generated from relatively less invasive MCF7 and MDA-MB-468 cells by long-term TGF-β treatment and acquired chemoresistance. Treatment of the invasive cell populations with an AKT inhibitor (MK2206-HCl) reduced their invasive potential, with a concomitant decrease in their EDB-FN expression, partly through the phosphoAKT-SRp55 pathway. EDB-FN downregulation, with direct RNAi of EDB-FN or indirectly through RNAi of SRp55, also resulted in reduced motility of the invasive cell populations, validating the correlation between EDB-FN expression and invasion of breast cancer cells. These data establish EDB-FN as a promising molecular marker for non-invasive therapeutic surveillance of aggressive breast cancer. Full article
(This article belongs to the Special Issue Fibronectin in Health and Diseases)
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14 pages, 1567 KiB  
Article
Circulating Tumor Cell Migration Requires Fibronectin Acting through Integrin B1 or SLUG
by Jeannette Huaman and Olorunseun O. Ogunwobi
Cells 2020, 9(7), 1594; https://doi.org/10.3390/cells9071594 - 01 Jul 2020
Cited by 10 | Viewed by 3636
Abstract
Fibronectin (FN1) is an extracellular matrix protein gaining increasing attention for its multifaceted roles in cancer progression. Using our recently established circulating tumor cell (CTC) lines, we had demonstrated increased FN1 expression and enhanced migration in CTC lines, in comparison to primary tumor [...] Read more.
Fibronectin (FN1) is an extracellular matrix protein gaining increasing attention for its multifaceted roles in cancer progression. Using our recently established circulating tumor cell (CTC) lines, we had demonstrated increased FN1 expression and enhanced migration in CTC lines, in comparison to primary tumor cell lines. Whether increased FN1 expression is directly required for CTC migration, and the specific role of FN1’s regulation of integrin B1 (ITGB1) and SLUG (SNAI2) in CTC migration remains unclear. Here, for the first time, we report that the knockdown of FN1, ITGB1, or SLUG expression in CTCs leads to a significant decrease in CTC migration. Knocking down two or all three of these proteins simultaneously did not further inhibit migration. We observed a corresponding increase in CTC migration when recombinant FN1 was added to CTCs. This effect was significantly impeded by prior knockdown of ITGB1 or SLUG. Using knock down experiments and western blotting analysis, we confirmed FN1’s regulation of ITGB1 and SLUG to occur via two separate, independent pathways. Consequently, we can conclude that FN1-dependent enhanced migration of CTCs requires downstream signaling through either ITGB1 or SLUG and that FN1 regulation of ITGB1 and SLUG may have important implications for cancer progression and metastasis. Full article
(This article belongs to the Special Issue Fibronectin in Health and Diseases)
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Graphical abstract

15 pages, 3323 KiB  
Article
Single-Cell Probe Force Studies to Identify Sox2 Overexpression-Promoted Cell Adhesion in MCF7 Breast Cancer Cells
by Jagoba Iturri, Andreas Weber, María d.M. Vivanco and José L. Toca-Herrera
Cells 2020, 9(4), 935; https://doi.org/10.3390/cells9040935 - 10 Apr 2020
Cited by 9 | Viewed by 3588
Abstract
The replacement of the cantilever tip by a living cell in Atomic Force Microscopy (AFM) experiments permits the direct quantification of cell–substrate and cell–cell adhesion forces. This single-cell probe force measurement technique, when complemented by microscopy, allows controlled manipulation of the cell with [...] Read more.
The replacement of the cantilever tip by a living cell in Atomic Force Microscopy (AFM) experiments permits the direct quantification of cell–substrate and cell–cell adhesion forces. This single-cell probe force measurement technique, when complemented by microscopy, allows controlled manipulation of the cell with defined location at the area of interest. In this work, a setup based on two glass half-slides, a non-fouling one with bacterial S-layer protein SbpA from L. sphaericus CMM 2177 and the second with a fibronectin layer, has been employed to measure the adhesion of MCF7 breast cancer cells to fibronectin films (using SbpA as control) and to other cells (symmetric vs. asymmetric systems). The measurements aimed to characterize and compare the adhesion capacities of parental cells and cells overexpressing the embryonic transcription factor Sox2, which have a higher capacity for invasion and are more resistant to endocrine therapy in vivo. Together with the use of fluorescence techniques (epifluorescence, Total Internal Fluorescence Microscopy (TIRF)), the visualization of vinculin and actin distribution in cells in contact with fibronectin surfaces is enabled, facilitating the monitoring and quantification of the formation of adhesion complexes. These findings demonstrate the strength of this combined approach to assess and compare the adhesion properties of cell lines and to illustrate the heterogeneity of adhesive strength found in breast cancer cells. Full article
(This article belongs to the Special Issue Fibronectin in Health and Diseases)
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14 pages, 2880 KiB  
Article
Mechanical Forces between Mycobacterial Antigen 85 Complex and Fibronectin
by Albertus Viljoen, David Alsteens and Yves Dufrêne
Cells 2020, 9(3), 716; https://doi.org/10.3390/cells9030716 - 14 Mar 2020
Cited by 10 | Viewed by 4000
Abstract
Adhesion to extracellular matrix proteins is an important first step in host invasion, employed by many bacterial pathogens. In mycobacteria, the secreted Ag85 complex proteins, involved in the synthesis of the cell envelope, are known to bind to fibronectin (Fn) through molecular forces [...] Read more.
Adhesion to extracellular matrix proteins is an important first step in host invasion, employed by many bacterial pathogens. In mycobacteria, the secreted Ag85 complex proteins, involved in the synthesis of the cell envelope, are known to bind to fibronectin (Fn) through molecular forces that are currently unknown. In this study, single-molecule force spectroscopy is used to study the strength, kinetics and thermodynamics of the Ag85-Fn interaction, focusing on the multidrug-resistant Mycobacterium abscessus species. Single Ag85 proteins bind Fn with a strength of ~75 pN under moderate tensile loading, which compares well with the forces reported for other Fn-binding proteins. The binding specificity is demonstrated by using free Ag85 and Fn peptides with active binding sequences. The Ag85-Fn rupture force increases with mechanical stress (i.e., loading rate) according to the Friddle–Noy–de Yoreo theory. From this model, we extract thermodynamic parameters that are in good agreement with previous affinity determinations by surface plasmon resonance. Strong bonds (up to ~500 pN) are observed under high tensile loading, which may favor strong mycobacterial attachment in the lung where cells are exposed to high shear stress or during hematogenous spread which leads to a disseminated infection. Our results provide new insight into the pleiotropic functions of an important mycobacterial virulence factor that acts as a stress-sensitive adhesin. Full article
(This article belongs to the Special Issue Fibronectin in Health and Diseases)
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17 pages, 3179 KiB  
Article
Stimulation of Fibronectin Matrix Assembly by Lysine Acetylation
by Maria E. Vega, Birgit Kastberger, Bernhard Wehrle-Haller and Jean E. Schwarzbauer
Cells 2020, 9(3), 655; https://doi.org/10.3390/cells9030655 - 08 Mar 2020
Cited by 8 | Viewed by 3919
Abstract
Diabetic nephropathy, a devastating consequence of diabetes mellitus, is characterized by the accumulation of extracellular matrix (ECM) that disrupts the kidney’s filtration apparatus. Elevated glucose levels increase the deposition of a fibronectin (FN) matrix by mesangial cells, the primary matrix-producing cells of the [...] Read more.
Diabetic nephropathy, a devastating consequence of diabetes mellitus, is characterized by the accumulation of extracellular matrix (ECM) that disrupts the kidney’s filtration apparatus. Elevated glucose levels increase the deposition of a fibronectin (FN) matrix by mesangial cells, the primary matrix-producing cells of the kidney, and also increase acetyl-CoA leading to higher levels of lysine acetylation. Here, we investigated the connection between acetylation and the ECM and show that treatment of mesangial cells with deacetylase inhibitors increases both acetylation and FN matrix assembly compared to untreated cells. The matrix effects were linked to lysine 794 (K794) in the β1 integrin cytoplasmic domain based on studies of cells expressing acetylated (K794Q) and non-acetylated (K794R) mimetics. β1(K794Q) cells assembled significantly more FN matrix than wildtype β1 cells, while the non-acetylated β1(K794R) form was inactive. We show that mutation of K794 affects FN assembly by stimulating integrin-FN binding activity and cell contractility. Wildtype and β1(K794Q) cells but not β1(K794R) cells further increased their FN matrix when stimulated with deacetylase inhibitors indicating that increased acetylation on other proteins is required for maximum FN assembly. Thus, lysine acetylation provides a mechanism for glucose-induced fibrosis by up-regulation of FN matrix assembly. Full article
(This article belongs to the Special Issue Fibronectin in Health and Diseases)
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14 pages, 2646 KiB  
Article
Extracellular Matrix Structure and Composition in the Early Four-Chambered Embryonic Heart
by Quentin Jallerat and Adam W. Feinberg
Cells 2020, 9(2), 285; https://doi.org/10.3390/cells9020285 - 24 Jan 2020
Cited by 18 | Viewed by 5836
Abstract
During embryonic development, the heart undergoes complex morphogenesis from a liner tube into the four chambers consisting of ventricles, atria and valves. At the same time, the cardiomyocytes compact into a dense, aligned, and highly vascularized myocardium. The extracellular matrix (ECM) is known [...] Read more.
During embryonic development, the heart undergoes complex morphogenesis from a liner tube into the four chambers consisting of ventricles, atria and valves. At the same time, the cardiomyocytes compact into a dense, aligned, and highly vascularized myocardium. The extracellular matrix (ECM) is known to play an important role in this process but understanding of the expression and organization remains incomplete. Here, we performed 3D confocal imaging of ECM in the left ventricle and whole heart of embryonic chick from stages Hamburger-Hamilton 28–35 (days 5–9) as an accessible model of heart formation. First, we observed the formation of a fibronectin-rich, capillary-like networks in the myocardium between day 5 and day 9 of development. Then, we focused on day 5 prior to vascularization to determine the relative expression of fibronectin, laminin, and collagen type IV. Cardiomyocytes were found to uniaxially align prior to vascularization and, while the epicardium contained all ECM components, laminin was reduced, and collagen type IV was largely absent. Quantification of fibronectin revealed highly aligned fibers with a mean diameter of ~500 nm and interfiber spacing of ~3 µm. These structural parameters (volume, spacing, fiber diameter, length, and orientation) provide a quantitative framework to describe the organization of the embryonic ECM. Full article
(This article belongs to the Special Issue Fibronectin in Health and Diseases)
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26 pages, 9396 KiB  
Article
HSP90 Interacts with the Fibronectin N-terminal Domains and Increases Matrix Formation
by Abir Chakraborty, Natasha Marie-Eraine Boel and Adrienne Lesley Edkins
Cells 2020, 9(2), 272; https://doi.org/10.3390/cells9020272 - 22 Jan 2020
Cited by 21 | Viewed by 4799
Abstract
Heat shock protein 90 (HSP90) is an evolutionarily conserved chaperone protein that controls the function and stability of a wide range of cellular client proteins. Fibronectin (FN) is an extracellular client protein of HSP90, and exogenous HSP90 or inhibitors of HSP90 alter the [...] Read more.
Heat shock protein 90 (HSP90) is an evolutionarily conserved chaperone protein that controls the function and stability of a wide range of cellular client proteins. Fibronectin (FN) is an extracellular client protein of HSP90, and exogenous HSP90 or inhibitors of HSP90 alter the morphology of the extracellular matrix. Here, we further characterized the HSP90 and FN interaction. FN bound to the M domain of HSP90 and interacted with both the open and closed HSP90 conformations; and the interaction was reduced in the presence of sodium molybdate. HSP90 interacted with the N-terminal regions of FN, which are known to be important for matrix assembly. The highest affinity interaction was with the 30-kDa (heparin-binding) FN fragment, which also showed the greatest colocalization in cells and accommodated both HSP90 and heparin in the complex. The strength of interaction with HSP90 was influenced by the inherent stability of the FN fragments, together with the type of motif, where HSP90 preferentially bound the type-I FN repeat over the type-II repeat. Exogenous extracellular HSP90 led to increased incorporation of both full-length and 70-kDa fragments of FN into fibrils. Together, our data suggested that HSP90 may regulate FN matrix assembly through its interaction with N-terminal FN fragments. Full article
(This article belongs to the Special Issue Fibronectin in Health and Diseases)
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13 pages, 1202 KiB  
Article
Role of TLR4 Receptor Complex in the Regulation of the Innate Immune Response by Fibronectin
by Mingzhe Zheng, Anthony Ambesi and Paula J. McKeown-Longo
Cells 2020, 9(1), 216; https://doi.org/10.3390/cells9010216 - 15 Jan 2020
Cited by 21 | Viewed by 3514
Abstract
Chronic inflammation and subsequent tissue fibrosis are associated with a biochemical and mechanical remodeling of the fibronectin matrix. Due to its conformational lability, fibronectin is considerably stretched by the contractile forces of the fibrotic microenvironment, resulting in the unfolding of its Type III [...] Read more.
Chronic inflammation and subsequent tissue fibrosis are associated with a biochemical and mechanical remodeling of the fibronectin matrix. Due to its conformational lability, fibronectin is considerably stretched by the contractile forces of the fibrotic microenvironment, resulting in the unfolding of its Type III domains. In earlier studies, we have shown that a peptide mimetic of a partially unfolded fibronectin Type III domain, FnIII-1c, functions as a Damage Associated Molecular Pattern (DAMP) molecule to induce activation of a toll-like receptor 4 (TLR4)/NF-κB pathway and the subsequent release of fibro-inflammatory cytokines from human dermal fibroblasts. In the current study, we evaluated the requirement of the canonical TLR4/MD2/CD14 receptor complex in the regulation of FnIII-1c induced cytokine release. Using dermal fibroblasts and human embryonic kidney (HEK) cells, we found that all the components of the TLR4/MD2/CD14 complex were required for the release of the fibro-inflammatory cytokine, interleukin 8 (IL-8) in response to both FnIII-1c and the canonical TLR4 ligand, lipopolysaccharide (LPS). However, FnIII-1c mediated IL-8 release was strictly dependent on membrane-associated CD14, while LPS could use soluble CD14. These findings demonstrate that LPS and FnIII-1c share a similar but not identical mechanism of TLR4 activation in human dermal fibroblasts. Full article
(This article belongs to the Special Issue Fibronectin in Health and Diseases)
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21 pages, 12656 KiB  
Article
Fibronectin and Periostin as Prognostic Markers in Ovarian Cancer
by Katarzyna Aleksandra Kujawa, Ewa Zembala-Nożyńska, Alexander Jorge Cortez, Tomasz Kujawa, Jolanta Kupryjańczyk and Katarzyna Marta Lisowska
Cells 2020, 9(1), 149; https://doi.org/10.3390/cells9010149 - 08 Jan 2020
Cited by 33 | Viewed by 4506
Abstract
Previously, based on a DNA microarray experiment, we identified a 96-gene prognostic signature associated with the shorter survival of ovarian cancer patients. We hypothesized that some differentially expressed protein-coding genes from this signature could potentially serve as prognostic markers. The present study was [...] Read more.
Previously, based on a DNA microarray experiment, we identified a 96-gene prognostic signature associated with the shorter survival of ovarian cancer patients. We hypothesized that some differentially expressed protein-coding genes from this signature could potentially serve as prognostic markers. The present study was aimed to validate two proteins, namely fibronectin (FN1) and periostin (POSTN), in the independent set of ovarian cancer samples. Both proteins are mainly known as extracellular matrix proteins with many important functions in physiology. However, there are also indications that they are implicated in cancer, including ovarian cancer. The expression of these proteins was immunohistochemically analyzed in 108 surgical samples of advanced ovarian cancer (majority: high-grade serous) and additionally on tissue arrays representing different stages of the progression of ovarian and fallopian tube epithelial tumors, from normal epithelia, through benign tumors, to adenocarcinomas of different stages. The correlation with clinical, pathological, and molecular features was evaluated. Kaplan–Meier survival analysis and Cox-proportional hazards models were used to estimate the correlation of the expression levels these proteins with survival. We observed that the higher expression of fibronectin in the tumor stroma was highly associated with shorter overall survival (OS) (Kaplan–Meier analysis, log-rank test p = 0.003). Periostin was also associated with shorter OS (p = 0.04). When we analyzed the combined score, calculated by adding together individual scores for stromal fibronectin and periostin expression, Cox regression demonstrated that this joint FN1&POSTN score was an independent prognostic factor for OS (HR = 2.16; 95% CI: 1.02–4.60; p = 0.044). The expression of fibronectin and periostin was also associated with the source of ovarian tumor sample: metastases showed higher expression of these proteins than primary tumor samples (χ2 test, p = 0.024 and p = 0.032). Elevated expression of fibronectin and periostin was also more common in fallopian cancers than in ovarian cancers. Our results support some previous observations that fibronectin and periostin have a prognostic significance in ovarian cancer. In addition, we propose the joint FN1&POSTN score as an independent prognostic factor for OS. Based on our results, it may also be speculated that these proteins are related to tumor progression and/or may indicate fallopian–epithelial origin of the tumor. Full article
(This article belongs to the Special Issue Fibronectin in Health and Diseases)
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18 pages, 2040 KiB  
Article
A Matricryptic Conformation of the Integrin-Binding Domain of Fibronectin Regulates Platelet-Derived Growth Factor-Induced Intracellular Calcium Release
by Christopher S. Farrar, Geoffrey T. Rouin, Benjamin L. Miller, Carol H. Raeman, Nancie A. Mooney and Denise C. Hocking
Cells 2019, 8(11), 1351; https://doi.org/10.3390/cells8111351 - 30 Oct 2019
Cited by 3 | Viewed by 2627
Abstract
Platelet-derived growth factor (PDGF) signaling is dysregulated in a wide variety of diseases, making PDGF an attractive therapeutic target. However, PDGF also affects numerous signaling cascades essential for tissue homeostasis, limiting the development of PDGF-based therapies that lack adverse side-effects. Recent studies showed [...] Read more.
Platelet-derived growth factor (PDGF) signaling is dysregulated in a wide variety of diseases, making PDGF an attractive therapeutic target. However, PDGF also affects numerous signaling cascades essential for tissue homeostasis, limiting the development of PDGF-based therapies that lack adverse side-effects. Recent studies showed that fibroblast-mediated assembly of extracellular matrix (ECM) fibronectin fibrils attenuates PDGF-induced intracellular calcium release by selectively inhibiting phosphoinositol 3-kinase (PI3K) activation while leaving other PDGF-mediated signaling cascades intact. In the present study, a series of recombinant fibronectin-derived fusion proteins were used to localize the sequences in fibronectin that are responsible for this inhibition. Results demonstrate that attenuation of PDGF-induced intracellular calcium release by the fibronectin matrix mimetic, FNIII1H,8-10 requires α5β1 integrin ligation, but is not dependent upon the matricryptic, heparin-binding site of FNIII1. Intact cell-binding fibronectin fragments were also unable to attenuate PDGF-induced intracellular calcium release. In contrast, a novel integrin-binding fragment that adopts an extended and aligned conformational state, inhibited both PI3K activation and intracellular calcium release in response to PDGF. Taken together, these studies provide evidence that attenuation of PDGF-induced intracellular calcium release by fibronectin is mediated by a novel conformation of the α5β1 integrin-binding, FNIII9-10 modules, that is expressed by fibrillar fibronectin. Full article
(This article belongs to the Special Issue Fibronectin in Health and Diseases)
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Review

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19 pages, 2585 KiB  
Review
Development and Differentiation in Monobodies Based on the Fibronectin Type 3 Domain
by Peter G. Chandler and Ashley M. Buckle
Cells 2020, 9(3), 610; https://doi.org/10.3390/cells9030610 - 04 Mar 2020
Cited by 32 | Viewed by 7736
Abstract
As a non-antibody scaffold, monobodies based on the fibronectin type III (FN3) domain overcome antibody size and complexity while maintaining analogous binding loops. However, antibodies and their derivatives remain the gold standard for the design of new therapeutics. In response, clinical-stage therapeutic proteins [...] Read more.
As a non-antibody scaffold, monobodies based on the fibronectin type III (FN3) domain overcome antibody size and complexity while maintaining analogous binding loops. However, antibodies and their derivatives remain the gold standard for the design of new therapeutics. In response, clinical-stage therapeutic proteins based on the FN3 domain are beginning to use native fibronectin function as a point of differentiation. The small and simple structure of monomeric monobodies confers increased tissue distribution and reduced half-life, whilst the absence of disulphide bonds improves stability in cytosolic environments. Where multi-specificity is challenging with an antibody format that is prone to mis-pairing between chains, multiple FN3 domains in the fibronectin assembly already interact with a large number of molecules. As such, multiple monobodies engineered for interaction with therapeutic targets are being combined in a similar beads-on-a-string assembly which improves both efficacy and pharmacokinetics. Furthermore, full length fibronectin is able to fold into multiple conformations as part of its natural function and a greater understanding of how mechanical forces allow for the transition between states will lead to advanced applications that truly differentiate the FN3 domain as a therapeutic scaffold. Full article
(This article belongs to the Special Issue Fibronectin in Health and Diseases)
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29 pages, 2589 KiB  
Review
Profile of Matrix-Remodeling Proteinases in Osteoarthritis: Impact of Fibronectin
by Selene Pérez-García, Mar Carrión, Irene Gutiérrez-Cañas, Raúl Villanueva-Romero, David Castro, Carmen Martínez, Isidoro González-Álvaro, Francisco J. Blanco, Yasmina Juarranz and Rosa P. Gomariz
Cells 2020, 9(1), 40; https://doi.org/10.3390/cells9010040 - 22 Dec 2019
Cited by 40 | Viewed by 8927
Abstract
The extracellular matrix (ECM) is a complex and specialized three-dimensional macromolecular network, present in nearly all tissues, that also interacts with cell surface receptors on joint resident cells. Changes in the composition and physical properties of the ECM lead to the development of [...] Read more.
The extracellular matrix (ECM) is a complex and specialized three-dimensional macromolecular network, present in nearly all tissues, that also interacts with cell surface receptors on joint resident cells. Changes in the composition and physical properties of the ECM lead to the development of many diseases, including osteoarthritis (OA). OA is a chronic degenerative rheumatic disease characterized by a progressive loss of synovial joint function as a consequence of the degradation of articular cartilage, also associated with alterations in the synovial membrane and subchondral bone. During OA, ECM-degrading enzymes, including urokinase-type plasminogen activator (uPA), matrix metalloproteinases (MMPs), and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs), cleave ECM components, such as fibronectin (Fn), generating fibronectin fragments (Fn-fs) with catabolic properties. In turn, Fn-fs promote activation of these proteinases, establishing a degradative and inflammatory feedback loop. Thus, the aim of this review is to update the contribution of ECM-degrading proteinases to the physiopathology of OA as well as their modulation by Fn-fs. Full article
(This article belongs to the Special Issue Fibronectin in Health and Diseases)
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37 pages, 5497 KiB  
Review
Fibronectin in Cancer: Friend or Foe
by Tsung-Cheng Lin, Cheng-Han Yang, Li-Hsin Cheng, Wen-Tsan Chang, Yuh-Rong Lin and Hung-Chi Cheng
Cells 2020, 9(1), 27; https://doi.org/10.3390/cells9010027 - 20 Dec 2019
Cited by 105 | Viewed by 14097
Abstract
The role of fibronectin (FN) in tumorigenesis and malignant progression has been highly controversial. Cancerous FN plays a tumor-suppressive role, whereas it is pro-metastatic and associated with poor prognosis. Interestingly, FN matrix deposited in the tumor microenvironments (TMEs) promotes tumor progression but is [...] Read more.
The role of fibronectin (FN) in tumorigenesis and malignant progression has been highly controversial. Cancerous FN plays a tumor-suppressive role, whereas it is pro-metastatic and associated with poor prognosis. Interestingly, FN matrix deposited in the tumor microenvironments (TMEs) promotes tumor progression but is paradoxically related to a better prognosis. Here, we justify how FN impacts tumor transformation and subsequently metastatic progression. Next, we try to reconcile and rationalize the seemingly conflicting roles of FN in cancer and TMEs. Finally, we propose future perspectives for potential FN-based therapeutic strategies. Full article
(This article belongs to the Special Issue Fibronectin in Health and Diseases)
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20 pages, 1375 KiB  
Review
Role of Fibronectin in Primary Open Angle Glaucoma
by Jennifer A. Faralli, Mark S. Filla and Donna M. Peters
Cells 2019, 8(12), 1518; https://doi.org/10.3390/cells8121518 - 26 Nov 2019
Cited by 53 | Viewed by 8500
Abstract
Primary open angle glaucoma (POAG) is the most common form of glaucoma and the 2nd most common cause of irreversible vision loss in the United States. Nearly 67 million people have the disease worldwide including >3 million in the United States. A major [...] Read more.
Primary open angle glaucoma (POAG) is the most common form of glaucoma and the 2nd most common cause of irreversible vision loss in the United States. Nearly 67 million people have the disease worldwide including >3 million in the United States. A major risk factor for POAG is an elevation in intraocular pressure (IOP). The increase in IOP is believed to be caused by an increase in the deposition of extracellular matrix proteins, in particular fibronectin, in a region of the eye known as the trabecular meshwork (TM). How fibronectin contributes to the increase in IOP is not well understood. The increased density of fibronectin fibrils is thought to increase IOP by altering the compliance of the trabecular meshwork. Recent studies, however, also suggest that the composition and organization of fibronectin fibrils would affect IOP by changing the cell-matrix signaling events that control the functional properties of the cells in the trabecular meshwork. In this article, we will discuss how changes in the properties of fibronectin and fibronectin fibrils could contribute to the regulation of IOP. Full article
(This article belongs to the Special Issue Fibronectin in Health and Diseases)
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24 pages, 1181 KiB  
Review
Fibronectin and Its Role in Human Infective Diseases
by Pietro Speziale, Carla Renata Arciola and Giampiero Pietrocola
Cells 2019, 8(12), 1516; https://doi.org/10.3390/cells8121516 - 26 Nov 2019
Cited by 42 | Viewed by 5376
Abstract
Fibronectin is a multidomain glycoprotein ubiquitously detected in extracellular fluids and matrices of a variety of animal and human tissues where it functions as a key link between matrices and cells. Fibronectin has also emerged as the target for a large number of [...] Read more.
Fibronectin is a multidomain glycoprotein ubiquitously detected in extracellular fluids and matrices of a variety of animal and human tissues where it functions as a key link between matrices and cells. Fibronectin has also emerged as the target for a large number of microorganisms, particularly bacteria. There are clear indications that the binding of microorganism’ receptors to fibronectin promotes attachment to and infection of host cells. Each bacterium may use different receptors which recognize specific fibronectin domains, mostly the N-terminal domain and the central cell-binding domain. In many cases, fibronectin receptors have actions over and above that of simple adhesion: In fact, adhesion is often the prerequisite for invasion and internalization of microorganisms in the cells of colonized tissues. This review updates the current understanding of fibronectin receptors of several microorganisms with emphasis on their biochemical and structural properties and the role they can play in the onset and progression of host infection diseases. Furthermore, we describe the antigenic profile and discuss the possibility of designing adhesion inhibitors based on the structure of the fibronectin-binding site in the receptor or the receptor-binding site in fibronectin. Full article
(This article belongs to the Special Issue Fibronectin in Health and Diseases)
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