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Eph Receptors and Ephrins
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Eph Receptors and Ephrins

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

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 20460

Special Issue Editors

Dr. Dimitar B. Nikolov

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Guest Editor
Dr. Juha Himanen

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Guest Editor
Memorial Sloan-Kettering Cancer Center, New York, United States

Special Issue Information

Dear Colleagues,

Eph receptor tyrosine kinases and their ephrin ligands mediate unique bidirectional signaling that is a major form of contact-dependent communication between cells. For over 30 years, extensive research has revealed many of the underlying molecular mechanisms in Eph/ephrin signaling and how it directs both developmental processes and adult physiology. Nevertheless, major questions remain, including the details of the Eph/ephrin assembly into large signaling clusters, the precise mechanisms of signaling termination, the molecular mechanisms and biological significance of the cross-talk between different Eph family members, and the context-dependence of the signaling, where the same ligand/receptor interactions can elicit diametrically opposite outcomes. This Special Issue will publish research papers and review articles that cover innovative and multidisciplinary approaches to bring about a better understanding of the cellular and molecular mechanisms of Eph/ephrin signaling in health and disease.

Dr. Dimitar B. Nikolov
Dr. Juha Himanen
Guest Editors

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Published Papers (7 papers)

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Research

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13 pages, 3299 KiB  
Article
The Ephb2 Receptor Uses Homotypic, Head-to-Tail Interactions within Its Ectodomain as an Autoinhibitory Control Mechanism
by Yan Xu, Dorothea Robev, Nayanendu Saha, Bingcheng Wang, Matthew B. Dalva, Kai Xu, Juha P. Himanen and Dimitar B. Nikolov
Int. J. Mol. Sci. 2021, 22(19), 10473; https://doi.org/10.3390/ijms221910473 - 28 Sep 2021
Cited by 4 | Viewed by 2845
Abstract
The Eph receptor tyrosine kinases and their ephrin ligands direct axon pathfinding and neuronal cell migration, as well as mediate many other cell–cell communication events. Their dysfunctional signaling has been shown to lead to various diseases, including cancer. The Ephs and ephrins both [...] Read more.
The Eph receptor tyrosine kinases and their ephrin ligands direct axon pathfinding and neuronal cell migration, as well as mediate many other cell–cell communication events. Their dysfunctional signaling has been shown to lead to various diseases, including cancer. The Ephs and ephrins both localize to the plasma membrane and, upon cell–cell contact, form extensive signaling assemblies at the contact sites. The Ephs and the ephrins are divided into A and B subclasses based on their sequence conservation and affinities for each other. The molecular details of Eph–ephrin recognition have been previously revealed and it has been documented that ephrin binding induces higher-order Eph assemblies, which are essential for full biological activity, via multiple, distinct Eph–Eph interfaces. One Eph–Eph interface type is characterized by a homotypic, head-to-tail interaction between the ligand-binding and the fibronectin domains of two adjacent Eph molecules. While the previous Eph ectodomain structural studies were focused on A class receptors, we now report the crystal structure of the full ectodomain of EphB2, revealing distinct and unique head-to-tail receptor–receptor interactions. The EphB2 structure and structure-based mutagenesis document that EphB2 uses the head-to-tail interactions as a novel autoinhibitory control mechanism for regulating downstream signaling and that these interactions can be modulated by posttranslational modifications. Full article
(This article belongs to the Special Issue Eph Receptors and Ephrins)
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17 pages, 2552 KiB  
Article
Analysis of ADAM12-Mediated Ephrin-A1 Cleavage and Its Biological Functions
by Katsuaki Ieguchi, Takeshi Tomita, Toshifumi Takao, Tsutomu Omori, Taishi Mishima, Isao Shimizu, Massimiliano Tognolini, Alessio Lodola, Takuya Tsunoda, Shinichi Kobayashi, Satoshi Wada and Yoshiro Maru
Int. J. Mol. Sci. 2021, 22(5), 2480; https://doi.org/10.3390/ijms22052480 - 1 Mar 2021
Cited by 12 | Viewed by 2848
Abstract
Accumulating evidence indicates that an elevated ephrin-A1 expression is positively correlated with a worse prognosis in some cancers such as colon and liver cancer. The detailed mechanism of an elevated ephrin-A1 expression in a worse prognosis still remains to be fully elucidated. We [...] Read more.
Accumulating evidence indicates that an elevated ephrin-A1 expression is positively correlated with a worse prognosis in some cancers such as colon and liver cancer. The detailed mechanism of an elevated ephrin-A1 expression in a worse prognosis still remains to be fully elucidated. We previously reported that ADAM12-cleaved ephrin-A1 enhanced lung vascular permeability and thereby induced lung metastasis. However, it is still unclear whether or not cleaved forms of ephrin-A1 are derived from primary tumors and have biological activities. We identified the ADAM12-mediated cleavage site of ephrin-A1 by a Matrix-assisted laser desorption ionization mass spectrometry and checked levels of ephrin-A1 in the serum and the urine derived from the primary tumors by using a mouse model. We found elevated levels of tumor-derived ephrin-A1 in the serum and the urine in the tumor-bearing mice. Moreover, inhibition of ADAM-mediated cleavage of ephrin-A1 or antagonization of the EphA receptors resulted in a significant reduction of lung metastasis. The results suggest that tumor-derived ephrin-A1 is not only a potential biomarker to predict lung metastasis from the primary tumor highly expressing ephrin-A1 but also a therapeutic target of lung metastasis. Full article
(This article belongs to the Special Issue Eph Receptors and Ephrins)
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Review

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13 pages, 1038 KiB  
Review
Role of EphA4 in Mediating Motor Neuron Death in MND
by Jing Zhao, Claire H. Stevens, Andrew W. Boyd, Lezanne Ooi and Perry F. Bartlett
Int. J. Mol. Sci. 2021, 22(17), 9430; https://doi.org/10.3390/ijms22179430 - 30 Aug 2021
Cited by 7 | Viewed by 3124
Abstract
Motor neuron disease (MND) comprises a group of fatal neurodegenerative diseases with no effective cure. As progressive motor neuron cell death is one of pathological characteristics of MND, molecules which protect these cells are attractive therapeutic targets. Accumulating evidence indicates that EphA4 activation [...] Read more.
Motor neuron disease (MND) comprises a group of fatal neurodegenerative diseases with no effective cure. As progressive motor neuron cell death is one of pathological characteristics of MND, molecules which protect these cells are attractive therapeutic targets. Accumulating evidence indicates that EphA4 activation is involved in MND pathogenesis, and inhibition of EphA4 improves functional outcomes. However, the underlying mechanism of EphA4’s function in MND is unclear. In this review, we first present results to demonstrate that EphA4 signalling acts directly on motor neurons to cause cell death. We then review the three most likely mechanisms underlying this effect. Full article
(This article belongs to the Special Issue Eph Receptors and Ephrins)
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13 pages, 12629 KiB  
Review
Structural and Functional Insights into the Transmembrane Domain Association of Eph Receptors
by Amita R. Sahoo and Matthias Buck
Int. J. Mol. Sci. 2021, 22(16), 8593; https://doi.org/10.3390/ijms22168593 - 10 Aug 2021
Cited by 11 | Viewed by 2821
Abstract
Eph receptors are the largest family of receptor tyrosine kinases and by interactions with ephrin ligands mediate a myriad of processes from embryonic development to adult tissue homeostasis. The interaction of Eph receptors, especially at their transmembrane (TM) domains is key to understanding [...] Read more.
Eph receptors are the largest family of receptor tyrosine kinases and by interactions with ephrin ligands mediate a myriad of processes from embryonic development to adult tissue homeostasis. The interaction of Eph receptors, especially at their transmembrane (TM) domains is key to understanding their mechanism of signal transduction across cellular membranes. We review the structural and functional aspects of EphA1/A2 association and the techniques used to investigate their TM domains: NMR, molecular modelling/dynamics simulations and fluorescence. We also introduce transmembrane peptides, which can be used to alter Eph receptor signaling and we provide a perspective for future studies. Full article
(This article belongs to the Special Issue Eph Receptors and Ephrins)
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16 pages, 3471 KiB  
Review
The EphB6 Receptor: Kinase-Dead but Very Much Alive
by Timothy G. Strozen, Jessica C. Sharpe, Evelyn D. Harris, Maruti Uppalapati and Behzad M. Toosi
Int. J. Mol. Sci. 2021, 22(15), 8211; https://doi.org/10.3390/ijms22158211 - 30 Jul 2021
Cited by 9 | Viewed by 2848
Abstract
The Eph receptor tyrosine kinase member EphB6 is a pseudokinase, and similar to other pseudoenzymes has not attracted an equivalent amount of interest as its enzymatically-active counterparts. However, a greater appreciation for the role pseudoenzymes perform in expanding the repertoire of signals generated [...] Read more.
The Eph receptor tyrosine kinase member EphB6 is a pseudokinase, and similar to other pseudoenzymes has not attracted an equivalent amount of interest as its enzymatically-active counterparts. However, a greater appreciation for the role pseudoenzymes perform in expanding the repertoire of signals generated by signal transduction systems has fostered more interest in the field. EphB6 acts as a molecular switch that is capable of modulating the signal transduction output of Eph receptor clusters. Although the biological effects of EphB6 activity are well defined, the molecular mechanisms of EphB6 function remain enigmatic. In this review, we use a comparative approach to postulate how EphB6 acts as a scaffold to recruit adaptor proteins to an Eph receptor cluster and how this function is regulated. We suggest that the evolutionary repurposing of EphB6 into a kinase-independent molecular switch in mammals has involved repurposing the kinase activation loop into an SH3 domain-binding site. In addition, we suggest that EphB6 employs the same SAM domain linker and juxtamembrane domain allosteric regulatory mechanisms that are used in kinase-positive Eph receptors to regulate its scaffold function. As a result, although kinase-dead, EphB6 remains a strategically active component of Eph receptor signaling. Full article
(This article belongs to the Special Issue Eph Receptors and Ephrins)
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18 pages, 17617 KiB  
Review
Eph Receptors and Ephrins in Retinal Diseases
by Radoslaw Kaczmarek, Pawel Gajdzis and Malgorzata Gajdzis
Int. J. Mol. Sci. 2021, 22(12), 6207; https://doi.org/10.3390/ijms22126207 - 8 Jun 2021
Cited by 12 | Viewed by 3203
Abstract
Retinal diseases are the leading cause of irreversible blindness. They affect people of all ages, from newborns in retinopathy of prematurity, through age-independent diabetic retinopathy and complications of retinal detachment, to age-related macular degeneration (AMD), which occurs mainly in the elderly. Generally speaking, [...] Read more.
Retinal diseases are the leading cause of irreversible blindness. They affect people of all ages, from newborns in retinopathy of prematurity, through age-independent diabetic retinopathy and complications of retinal detachment, to age-related macular degeneration (AMD), which occurs mainly in the elderly. Generally speaking, the causes of all problems are disturbances in blood supply, hypoxia, the formation of abnormal blood vessels, and fibrosis. Although the detailed mechanisms underlying them are varied, the common point is the involvement of Eph receptors and ephrins in their pathogenesis. In our study, we briefly discussed the pathophysiology of the most common retinal diseases (diabetic retinopathy, retinopathy of prematurity, proliferative vitreoretinopathy, and choroidal neovascularization) and collected available research results on the role of Eph and ephrins. We also discussed the safety aspect of the use of drugs acting on Eph and ephrin for ophthalmic indications. Full article
(This article belongs to the Special Issue Eph Receptors and Ephrins)
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10 pages, 952 KiB  
Review
The Role of Eph Receptors and Ephrins in Corneal Physiology and Diseases
by Radoslaw Kaczmarek, Katarzyna Zimmer, Pawel Gajdzis and Malgorzata Gajdzis
Int. J. Mol. Sci. 2021, 22(9), 4567; https://doi.org/10.3390/ijms22094567 - 27 Apr 2021
Cited by 3 | Viewed by 1899
Abstract
The cornea, while appearing to be simple tissue, is actually an extremely complex structure. In order for it to retain its biomechanical and optical properties, perfect organization of its cells is essential. Proper regeneration is especially important after injuries and in the course [...] Read more.
The cornea, while appearing to be simple tissue, is actually an extremely complex structure. In order for it to retain its biomechanical and optical properties, perfect organization of its cells is essential. Proper regeneration is especially important after injuries and in the course of various diseases. Eph receptors and ephrin are mainly responsible for the proper organization of tissues as well as cell migration and communication. In this review, we present the current state of knowledge on the role of Eph and ephrins in corneal physiology and diseases, in particular, we focused on the functions of the epithelium and endothelium. Since the role of Eph and ephrins in the angiogenesis process has been well established, we also analyzed their influence on conditions with corneal neovascularization. Full article
(This article belongs to the Special Issue Eph Receptors and Ephrins)
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