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Biomolecules
Special Issues
New Insights into Integrins
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New Insights into Integrins

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Biological Factors".

Deadline for manuscript submissions: 30 April 2025 | Viewed by 4420

Special Issue Editor

Prof. Dr. Yoshikazu Takada

E-Mail Website
Guest Editor
Department of Dermatology, School of Medicine, University of California–Davis, 4645 Second Ave., Research III Suite 3300, Sacramento, CA 95817, USA
Interests: integrin-growth factor crosstalk; regulation of integrin activation; identification of new integrin ligands
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Integrins were originally identified as a family of receptors for extracellular molecules (e.g., fibronectin) and cell surface molecules (e.g., ICAM-1) in the 1980s. Since, it has been discovered that integrins also interact with soluble ligands such as growth factors (e.g., FGF-1, IGF-1), and almost a decade ago, that several growth factors bind to integrins and cognate receptors simultaneously and generate an integrin–growth factor–cognate receptor ternary complex (ternary complex model). Moreover, growth factor mutants defective in integrin binding are defective in signaling and act as antagonists. It has been recently shown that the a6b1–FGF2–FGFR ternary complex plays a critical role in stem cell maintenance. Additionally, we identified an allosteric site of integrins (site 2) which is distinct from the classical RGD-binding site. Several integrin ligands (e.g., inflammatory chemokines and inflammatory proteins such as secreted PLA2-IIA) bind and induce integrin activation in an allosteric manner. Site 2 was shown to be a binding site for an inflammatory lipid mediator (25-hydroxycholesterol) and is involved in inflammatory signaling in innate immunity. The integrin–growth factor interaction and allosteric activation through site 2 should pave the path to new therapeutic targets. Thus, this Special Issue is designed to facilitate the progress of newly opened fields of integrin study.

Prof. Dr. Yoshikazu Takada
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. Biomolecules is an international peer-reviewed open access monthly 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

  • integrins
  • growth factors
  • ligands

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Published Papers (4 papers)

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Research

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15 pages, 4585 KiB  
Article
Effect of Integrin Blockade on Experimental Spondyloarthritis
by Enoch Yau, Melissa Lim, Zoya Qaiyum, Shaghayegh Foroozan Boroojeni, Michael Tang, Addison Pacheco, Fataneh Tavasolian and Robert D. Inman
Biomolecules 2024, 14(11), 1386; https://doi.org/10.3390/biom14111386 - 31 Oct 2024
Viewed by 955
Abstract
Spondyloarthritis (SpA) describes a group of diseases characterized by chronic inflammation in the spine and peripheral joints. While pathogenesis is still unclear, proinflammatory gut-derived immune cells have been identified in the joints of SpA patients. We previously identified an enriched population of integrin-expressing [...] Read more.
Spondyloarthritis (SpA) describes a group of diseases characterized by chronic inflammation in the spine and peripheral joints. While pathogenesis is still unclear, proinflammatory gut-derived immune cells have been identified in the joints of SpA patients. We previously identified an enriched population of integrin-expressing cells in the joints of SpA patients. Entry of gut-derived cells into joints may be mediated by these integrins. In the current study, we used the SKG murine model of SpA to study the impact of integrin blockade. Mice were injected with antibodies against the integrin α4β7 or the β7 monomer twice a week. Treatment with antibodies against α4β7 reduced disease severity in curdlan-injected SKG mice, with disease scores being comparable between treatment initiation times. Targeting the β7 monomer led to reduced arthritis severity compared to targeting the α4β7 dimer. Treatment with antibodies against α4β7 or β7 decreased expression of these integrins in CD4+ T cells, with the frequency of αE+β7+ T cells in the spleen and lymph nodes correlating with disease severity. In summary, we showed that integrin blockade showed potential for ameliorating disease in a murine model of SpA, lending support for further studies testing integrin blockade in SpA. Full article
(This article belongs to the Special Issue New Insights into Integrins)
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13 pages, 2343 KiB  
Article
Collagen I Increases Palmitate-Induced Lipotoxicity in HepG2 Cells via Integrin-Mediated Death
by Tumisang Edward Maseko, Eva Peterová, Moustafa Elkalaf, Darja Koutová, Jan Melek, Pavla Staňková, Veronika Špalková, Reem Matar, Halka Lotková, Zuzana Červinková and Otto Kučera
Biomolecules 2024, 14(9), 1179; https://doi.org/10.3390/biom14091179 - 20 Sep 2024
Viewed by 1252
Abstract
Various strategies have been employed to improve the reliability of 2D, 3D, and co-culture in vitro models of nonalcoholic fatty liver disease, including using extracellular matrix proteins such as collagen I to promote cell adhesion. While studies have demonstrated the significant benefits of [...] Read more.
Various strategies have been employed to improve the reliability of 2D, 3D, and co-culture in vitro models of nonalcoholic fatty liver disease, including using extracellular matrix proteins such as collagen I to promote cell adhesion. While studies have demonstrated the significant benefits of culturing cells on collagen I, its effects on the HepG2 cell line after exposure to palmitate (PA) have not been investigated. Therefore, this study aimed to assess the effects of PA-induced lipotoxicity in HepG2 cultured in the absence or presence of collagen I. HepG2 cultured in the absence or presence of collagen I was exposed to PA, followed by analyses that assessed cell proliferation, viability, adhesion, cell death, mitochondrial respiration, reactive oxygen species production, gene and protein expression, and triacylglycerol accumulation. Culturing HepG2 on collagen I was associated with increased cell proliferation, adhesion, and expression of integrin receptors, and improved cellular spreading compared to culturing them in the absence of collagen I. However, PA-induced lipotoxicity was greater in collagen I-cultured HepG2 than in those cultured in the absence of collagen I and was associated with increased α2β1 receptors. In summary, the present study demonstrated for the first time that collagen I-cultured HepG2 exhibited exacerbated cell death following exposure to PA through integrin-mediated death. The findings from this study may serve as a caution to those using 2D models or 3D scaffold-based models of HepG2 in the presence of collagen I. Full article
(This article belongs to the Special Issue New Insights into Integrins)
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18 pages, 3609 KiB  
Article
FGF1 Suppresses Allosteric Activation of β3 Integrins by FGF2: A Potential Mechanism of Anti-Inflammatory and Anti-Thrombotic Action of FGF1
by Yoko K. Takada, Xuesong Wu, David Wei, Samuel Hwang and Yoshikazu Takada
Biomolecules 2024, 14(8), 888; https://doi.org/10.3390/biom14080888 - 23 Jul 2024
Viewed by 1007
Abstract
Several inflammatory cytokines bind to the allosteric site (site 2) and allosterically activate integrins. Site 2 is also a binding site for 25-hydroxycholesterol, an inflammatory lipid mediator, and is involved in inflammatory signaling (e.g., TNF and IL-6 secretion) in addition to integrin activation. [...] Read more.
Several inflammatory cytokines bind to the allosteric site (site 2) and allosterically activate integrins. Site 2 is also a binding site for 25-hydroxycholesterol, an inflammatory lipid mediator, and is involved in inflammatory signaling (e.g., TNF and IL-6 secretion) in addition to integrin activation. FGF2 is pro-inflammatory and pro-thrombotic, and FGF1, homologous to FGF2, has anti-inflammatory and anti-thrombotic actions, but the mechanism of these actions is unknown. We hypothesized that FGF2 and FGF1 bind to site 2 of integrins and regulate inflammatory signaling. Here, we describe that FGF2 is bound to site 2 and allosterically activated β3 integrins, suggesting that the pro-inflammatory action of FGF2 is mediated by binding to site 2. In contrast, FGF1 bound to site 2 but did not activate these integrins and instead suppressed integrin activation induced by FGF2, indicating that FGF1 acts as an antagonist of site 2 and that the anti-inflammatory action of FGF1 is mediated by blocking site 2. A non-mitogenic FGF1 mutant (R50E), which is defective in binding to site 1 of αvβ3, suppressed β3 integrin activation by FGF2 as effectively as WT FGF1. Full article
(This article belongs to the Special Issue New Insights into Integrins)
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Review

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24 pages, 1973 KiB  
Review
Integrin and Its Associated Proteins as a Mediator for Mechano-Signal Transduction
by Kazuo Katoh
Biomolecules 2025, 15(2), 166; https://doi.org/10.3390/biom15020166 - 23 Jan 2025
Viewed by 656
Abstract
Mechano-signal transduction is a process in which cells perceive extracellular mechanical signals, convert them into intracellular biochemical signals, and produce a response. Integrins are cell surface receptors that sense the extracellular mechanical cues and bind to the extracellular matrix (ECM). This binding induces [...] Read more.
Mechano-signal transduction is a process in which cells perceive extracellular mechanical signals, convert them into intracellular biochemical signals, and produce a response. Integrins are cell surface receptors that sense the extracellular mechanical cues and bind to the extracellular matrix (ECM). This binding induces integrin clustering and activation. Cytoplasmic tails of activated integrins interact and induce cytoskeleton tensions via several adaptor proteins. Integrins monitor extracellular stiffness via cytoskeleton tensions and modulate ECM stiffness via downstream signaling pathways regulating the expression of genes of ECM components. Integrin-mediated mechano-transduction is very crucial for the cell as it regulates the cell physiology both in normal and diseased conditions according to extracellular mechanical cues. It regulates cell proliferation, survival, and migration. Abnormal mechanical cues such as extreme and prolonged mechanical stress result in pathological conditions including fibrosis, cancers, skin, and autoimmune disorders. This paper aims to explore the role of integrins and their associated proteins in mechano-signal transduction. It highlights the integrins and their associated proteins as targets for therapy development. Furthermore, it also presents the challenges to the targeted drug development, which can be drug resistance and cytotoxicity. It is concluded in this paper that research on integrin-mediated mechano-signal transduction and its relationship with cell physiology and pathologies will be an important step towards the development of effective therapies. Full article
(This article belongs to the Special Issue New Insights into Integrins)
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