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Integrin Signaling and Human Pathologies 2.0
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Integrin Signaling and Human Pathologies 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (28 February 2021) | Viewed by 33249

Special Issue Editors

Dr. Sylvie Monferran

E-Mail Website
Guest Editor
Centre de Recherches en Cancérologie de Toulouse - CRCT UMR1037 Inserm/Université Toulouse III-Paul Sabatier-ERL5294, CNRS 2 avenue Hubert Curien Oncopole entrée C CS 53717, 31037 Toulouse, France
Interests: invasion; RhoGTPases; integrins; stem cells, cancer; resistance to chemotherapy and radiotherapy
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Anthony Lemarié

E-Mail Website
Guest Editor
Research Team: Tumor Radioresistance, from Signalling Pathways to Therapy Department of Experimental Therapeutics Inserm U1037 Toulouse Cancer Research Center (CRCT) & IUCT 2 av. Hubert Curien, 31100 Toulouse, France
Interests: cell death; apoptosis; cellular differentiation; cellular and mitochondrial metabolism; cellular and mitochondrial homoeostasis; oxidative stress; cancer; cancer stem cells; glioma; radiotherapy & radioresistance
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Integrins are adhesion molecules that connect cells to ligands present in the extracellular matrix or to ligands expressed by blood cells. Upon binding to their ligands, integrins activate signaling pathways involved in key cellular processes like migration/invasion, cytoskeleton organization, survival, and angiogenesis. The dysregulation of integrins leads to various human pathologies: inflammatory diseases like atherosclerosis or inflammatory bowel disease; cancers; cardiovascular pathology; and respiratory diseases. This Special Issue of the International Journal of Molecular Sciences entitled “Integrin Signaling and Human Pathologies” will focus on the role of integrins in human pathologies. Authors are invited to submit manuscripts that study or review the role of these adhesion molecules in one of these human pathologies and that underline which integrin could be targeted in order to improve the treatment of these diseases.

Related Closed Special Issues:

Integrins and Human Pathologies

Integrins in Cancer

Dr. Anthony Lemarié
Dr. Sylvie Monferran
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • integrin
  • glanzmann thrombasthenia
  • angiogenesis
  • cardiovascular disease
  • cancer
  • Crohn’s disease
  • ulcerative disease
  • multiple sclerosis
  • inflammatory bowel disease
  • respiratory diseases
  • eosinophilic esophagitis
  • age-related macular degeneration
  • epidermolysis bullosa
  • osteoporosis

Published Papers (7 papers)

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Research

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23 pages, 3461 KiB  
Article
HIV-1 Tat Protein Enters Dysfunctional Endothelial Cells via Integrins and Renders Them Permissive to Virus Replication
by Aurelio Cafaro, Giovanni Barillari, Sonia Moretti, Clelia Palladino, Antonella Tripiciano, Mario Falchi, Orietta Picconi, Maria Rosaria Pavone Cossut, Massimo Campagna, Angela Arancio, Cecilia Sgadari, Claudia Andreini, Lucia Banci, Paolo Monini and Barbara Ensoli
Int. J. Mol. Sci. 2021, 22(1), 317; https://doi.org/10.3390/ijms22010317 - 30 Dec 2020
Cited by 13 | Viewed by 3255
Abstract
Previous work has shown that the Tat protein of Human Immunodeficiency Virus (HIV)-1 is released by acutely infected cells in a biologically active form and enters dendritic cells upon the binding of its arginine-glycine-aspartic acid (RGD) domain to the α5β1, αvβ3, and αvβ5 [...] Read more.
Previous work has shown that the Tat protein of Human Immunodeficiency Virus (HIV)-1 is released by acutely infected cells in a biologically active form and enters dendritic cells upon the binding of its arginine-glycine-aspartic acid (RGD) domain to the α5β1, αvβ3, and αvβ5 integrins. The up-regulation/activation of these integrins occurs in endothelial cells exposed to inflammatory cytokines that are increased in HIV-infected individuals, leading to endothelial cell dysfunction. Here, we show that inflammatory cytokine-activated endothelial cells selectively bind and rapidly take up nano-micromolar concentrations of Tat, as determined by flow cytometry. Protein oxidation and low temperatures reduce Tat entry, suggesting a conformation- and energy-dependent process. Consistently, Tat entry is competed out by RGD-Tat peptides or integrin natural ligands, and it is blocked by anti-α5β1, -αvβ3, and -αvβ5 antibodies. Moreover, modelling–docking calculations identify a low-energy Tat-αvβ3 integrin complex in which Tat makes contacts with both the αv and β3 chains. It is noteworthy that internalized Tat induces HIV replication in inflammatory cytokine-treated, but not untreated, endothelial cells. Thus, endothelial cell dysfunction driven by inflammatory cytokines renders the vascular system a target of Tat, which makes endothelial cells permissive to HIV replication, adding a further layer of complexity to functionally cure and/or eradicate HIV infection. Full article
(This article belongs to the Special Issue Integrin Signaling and Human Pathologies 2.0)
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15 pages, 7558 KiB  
Article
Enhanced Integrin Activation of PLD2-Deficient Platelets Accelerates Inflammation after Myocardial Infarction
by Aglaia Maria Klose, Meike Klier, Simone Gorressen and Margitta Elvers
Int. J. Mol. Sci. 2020, 21(9), 3210; https://doi.org/10.3390/ijms21093210 - 01 May 2020
Cited by 7 | Viewed by 2935
Abstract
Background: Phospholipase (PL)D1 is crucial for integrin αIIbβ3 activation of platelets in arterial thrombosis and TNF-α-mediated inflammation and TGF-β-mediated collagen scar formation after myocardial infarction (MI) in mice. Enzymatic activity of PLD is not responsible for PLD-mediated TNF-α signaling and [...] Read more.
Background: Phospholipase (PL)D1 is crucial for integrin αIIbβ3 activation of platelets in arterial thrombosis and TNF-α-mediated inflammation and TGF-β-mediated collagen scar formation after myocardial infarction (MI) in mice. Enzymatic activity of PLD is not responsible for PLD-mediated TNF-α signaling and myocardial healing. The impact of PLD2 in ischemia reperfusion injury is unknown. Methods: PLD2-deficient mice underwent myocardial ischemia and reperfusion (I/R). Results: Enhanced integrin αIIbβ3 activation of platelets resulted in elevated interleukin (IL)-6 release from endothelial cells in vitro and enhanced IL-6 plasma levels after MI in PLD2-deficient mice. This was accompanied by enhanced migration of inflammatory cells into the infarct border zone and reduced TGF-β plasma levels after 72 h that might account for enhanced inflammation in PLD2-deficient mice. In contrast to PLD1, TNF-α signaling, infarct size and cardiac function 24 h after I/R were not altered when PLD2 was deleted. Furthermore, TGF-β plasma levels, scar formation and heart function were comparable between PLD2-deficient and control mice 21 days post MI. Conclusions: The present study contributes to our understanding about the role of PLD isoforms and altered platelet signaling in the process of myocardial I/R injury. Full article
(This article belongs to the Special Issue Integrin Signaling and Human Pathologies 2.0)
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17 pages, 2406 KiB  
Article
Heterogeneity of Integrin αIIbβ3 Function in Pediatric Immune Thrombocytopenia Revealed by Continuous Flow Cytometry Analysis
by Alexey A. Martyanov, Daria S. Morozova, Maria A. Sorokina, Aleksandra A. Filkova, Daria V. Fedorova, Selima S. Uzueva, Elena V. Suntsova, Galina A. Novichkova, Pavel A. Zharkov, Mikhail A. Panteleev and Anastasia N. Sveshnikova
Int. J. Mol. Sci. 2020, 21(9), 3035; https://doi.org/10.3390/ijms21093035 - 25 Apr 2020
Cited by 15 | Viewed by 4961
Abstract
Immune thrombocytopenia (ITP) is an autoimmune condition primarily induced by the loss of immune tolerance to the platelet glycoproteins. Here we develop a novel flow cytometry approach to analyze integrin αIIbβ3 functioning in ITP in comparison with Glanzmann thrombasthenia (GT) [...] Read more.
Immune thrombocytopenia (ITP) is an autoimmune condition primarily induced by the loss of immune tolerance to the platelet glycoproteins. Here we develop a novel flow cytometry approach to analyze integrin αIIbβ3 functioning in ITP in comparison with Glanzmann thrombasthenia (GT) (negative control) and healthy pediatric donors (positive control). Continuous flow cytometry of Fura-Red-loaded platelets from whole hirudinated blood was used for the characterization of platelet responses to conventional activators. Calcium levels and fibrinogen binding were normalized to ionomycin-induced responses. Ex vivo thrombus formation on collagen was observed in parallel-plate flow chambers. Platelets from all ITP patients had significantly higher cytosolic calcium concentration in the quiescent state compared to healthy donors (15 ± 5 nM vs. 8 ± 5 nM), but calcium increases in response to all activators were normal. Clustering analysis revealed two subpopulations of ITP patients: the subgroup with high fibrinogen binding (HFB), and the subgroup with low fibrinogen binding (LFB) (8% ± 5% for LFB vs. 16% ± 3% for healthy donors in response to ADP). GT platelets had calcium mobilization (81 ± 23 nM), fibrinogen binding (5.1% ± 0.3%) and thrombus growth comparable to the LFB subgroup. Computational modeling suggested phospholipase C-dependent platelet pre-activation for the HFB subgroup and lower levels of functional integrin molecules for the LFB group. Full article
(This article belongs to the Special Issue Integrin Signaling and Human Pathologies 2.0)
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Review

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19 pages, 17438 KiB  
Review
Exogenous Integrin αIIbβ3 Inhibitors Revisited: Past, Present and Future Applications
by Danique L. van den Kerkhof, Paola E.J. van der Meijden, Tilman M. Hackeng and Ingrid Dijkgraaf
Int. J. Mol. Sci. 2021, 22(7), 3366; https://doi.org/10.3390/ijms22073366 - 25 Mar 2021
Cited by 14 | Viewed by 4882
Abstract
The integrin αIIbβ3 is the most abundant integrin on platelets. Upon platelet activation, the integrin changes its conformation (inside-out signalling) and outside-in signalling takes place leading to platelet spreading, platelet aggregation and thrombus formation. Bloodsucking parasites such as mosquitoes, leeches and ticks express [...] Read more.
The integrin αIIbβ3 is the most abundant integrin on platelets. Upon platelet activation, the integrin changes its conformation (inside-out signalling) and outside-in signalling takes place leading to platelet spreading, platelet aggregation and thrombus formation. Bloodsucking parasites such as mosquitoes, leeches and ticks express anticoagulant and antiplatelet proteins, which represent major sources of lead compounds for the development of useful therapeutic agents for the treatment of haemostatic disorders or cardiovascular diseases. In addition to hematophagous parasites, snakes also possess anticoagulant and antiplatelet proteins in their salivary glands. Two snake venom proteins have been developed into two antiplatelet drugs that are currently used in the clinic. The group of proteins discussed in this review are disintegrins, low molecular weight integrin-binding cysteine-rich proteins, found in snakes, ticks, leeches, worms and horseflies. Finally, we highlight various oral antagonists, which have been tested in clinical trials but were discontinued due to an increase in mortality. No new αIIbβ3 inhibitors are developed since the approval of current platelet antagonists, and structure-function analysis of exogenous disintegrins could help find platelet antagonists with fewer adverse side effects. Full article
(This article belongs to the Special Issue Integrin Signaling and Human Pathologies 2.0)
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16 pages, 2943 KiB  
Review
FAK Family Kinases in Vascular Diseases
by James M. Murphy, Kyuho Jeong and Ssang-Taek Steve Lim
Int. J. Mol. Sci. 2020, 21(10), 3630; https://doi.org/10.3390/ijms21103630 - 21 May 2020
Cited by 25 | Viewed by 5321
Abstract
In various vascular diseases, extracellular matrix (ECM) and integrin expression are frequently altered, leading to focal adhesion kinase (FAK) or proline-rich tyrosine kinase 2 (Pyk2) activation. In addition to the major roles of FAK and Pyk2 in regulating adhesion dynamics via integrins, recent [...] Read more.
In various vascular diseases, extracellular matrix (ECM) and integrin expression are frequently altered, leading to focal adhesion kinase (FAK) or proline-rich tyrosine kinase 2 (Pyk2) activation. In addition to the major roles of FAK and Pyk2 in regulating adhesion dynamics via integrins, recent studies have shown a new role for nuclear FAK in gene regulation in various vascular cells. In particular, FAK primarily localizes within the nuclei of vascular smooth muscle cells (VSMCs) of healthy arteries. However, vessel injury increased FAK localization back to adhesions and elevated FAK activity, leading to VSMC hyperplasia. The study suggested that abnormal FAK or Pyk2 activation in vascular cells may cause pathology in vascular diseases. Here we will review several studies of FAK and Pyk2 associated with integrin signaling in vascular diseases including restenosis, atherosclerosis, heart failure, pulmonary arterial hypertension, aneurysm, and thrombosis. Despite the importance of FAK family kinases in vascular diseases, comprehensive reviews are scarce. Therefore, we summarized animal models involving FAK family kinases in vascular diseases. Full article
(This article belongs to the Special Issue Integrin Signaling and Human Pathologies 2.0)
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43 pages, 2762 KiB  
Review
β2 Integrins—Multi-Functional Leukocyte Receptors in Health and Disease
by Monika Bednarczyk, Henner Stege, Stephan Grabbe and Matthias Bros
Int. J. Mol. Sci. 2020, 21(4), 1402; https://doi.org/10.3390/ijms21041402 - 19 Feb 2020
Cited by 65 | Viewed by 7159
Abstract
β2 integrins are heterodimeric surface receptors composed of a variable α (CD11a-CD11d) and a constant β (CD18) subunit and are specifically expressed by leukocytes. The α subunit defines the individual functional properties of the corresponding β2 integrin, but all β2 integrins show functional [...] Read more.
β2 integrins are heterodimeric surface receptors composed of a variable α (CD11a-CD11d) and a constant β (CD18) subunit and are specifically expressed by leukocytes. The α subunit defines the individual functional properties of the corresponding β2 integrin, but all β2 integrins show functional overlap. They mediate adhesion to other cells and to components of the extracellular matrix (ECM), orchestrate uptake of extracellular material like complement-opsonized pathogens, control cytoskeletal organization, and modulate cell signaling. This review aims to delineate the tremendous role of β2 integrins for immune functions as exemplified by the phenotype of LAD-I (leukocyte adhesion deficiency 1) patients that suffer from strong recurrent infections. These immune defects have been largely attributed to impaired migratory and phagocytic properties of polymorphonuclear granulocytes. The molecular base for this inherited disease is a functional impairment of β2 integrins due to mutations within the CD18 gene. LAD-I patients are also predisposed for autoimmune diseases. In agreement, polymorphisms within the CD11b gene have been associated with autoimmunity. Consequently, β2 integrins have received growing interest as targets in the treatment of autoimmune diseases. Moreover, β2 integrin activity on leukocytes has been implicated in tumor development. Full article
(This article belongs to the Special Issue Integrin Signaling and Human Pathologies 2.0)
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18 pages, 3361 KiB  
Review
The RND1 Small GTPase: Main Functions and Emerging Role in Oncogenesis
by Laetitia Mouly, Julia Gilhodes, Anthony Lemarié, Elizabeth Cohen-Jonathan Moyal, Christine Toulas, Gilles Favre, Olivier Sordet and Sylvie Monferran
Int. J. Mol. Sci. 2019, 20(15), 3612; https://doi.org/10.3390/ijms20153612 - 24 Jul 2019
Cited by 10 | Viewed by 3389
Abstract
The Rho GTPase family can be classified into classic and atypical members. Classic members cycle between an inactive Guanosine DiPhosphate -bound state and an active Guanosine TriPhosphate-bound state. Atypical Rho GTPases, such as RND1, are predominantly in an active GTP-bound conformation. The role [...] Read more.
The Rho GTPase family can be classified into classic and atypical members. Classic members cycle between an inactive Guanosine DiPhosphate -bound state and an active Guanosine TriPhosphate-bound state. Atypical Rho GTPases, such as RND1, are predominantly in an active GTP-bound conformation. The role of classic members in oncogenesis has been the subject of numerous studies, while that of atypical members has been less explored. Besides the roles of RND1 in healthy tissues, recent data suggest that RND1 is involved in oncogenesis and response to cancer therapeutics. Here, we present the current knowledge on RND1 expression, subcellular localization, and functions in healthy tissues. Then, we review data showing that RND1 expression is dysregulated in tumors, the molecular mechanisms involved in this deregulation, and the role of RND1 in oncogenesis. For several aggressive tumors, RND1 presents the features of a tumor suppressor gene. In these tumors, low expression of RND1 is associated with a bad prognosis for the patients. Finally, we highlight that RND1 expression is induced by anticancer agents and modulates their response. Of note, RND1 mRNA levels in tumors could be used as a predictive marker of both patient prognosis and response to anticancer agents. Full article
(This article belongs to the Special Issue Integrin Signaling and Human Pathologies 2.0)
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