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Current Biology : CB Feb 2017Eph receptors comprise the largest family of receptor tyrosine kinases (RTKs), with fourteen receptors divided into two subfamilies - EphAs and EphBs. Yet, despite their...
Eph receptors comprise the largest family of receptor tyrosine kinases (RTKs), with fourteen receptors divided into two subfamilies - EphAs and EphBs. Yet, despite their multitude of functions in almost all tissues of the body, these receptors represent one of the most underappreciated RTK families. What makes Eph receptors unique is that their cognate ligands, the ephrins, are tethered to the cell surface, in contrast to other RTKs whose ligands are generally soluble. This phenomenon means that signalling through Eph receptors is largely dependent on cell-cell contact. In this way, Eph receptors allow cells to sense their immediate surrounding cellular microenvironment and make appropriate behavioural decisions. For example, Eph receptors control whether two contacting cells are repelled by, or attracted to, each other. As such, they play an important role in normal physiological processes, including embryonic tissue boundary formation and directional guidance of developing axons, while in adult tissues they aid in wound healing and the maintenance of intestinal cell populations in particular compartments. Aberrant expression of these receptors, however, has been implicated in many pathologies, including cancer and neurodegenerative diseases. In this Primer we will discuss some of the key aspects of signalling by Ephs and ephrins that make them pivotal players in health and disease.
Topics: Ephrins; Ligands; Neoplasms; Neurodegenerative Diseases; Receptors, Eph Family; Signal Transduction; Wound Healing
PubMed: 28171762
DOI: 10.1016/j.cub.2017.01.003 -
The International Journal of... Apr 2016The ability to efficiently store memories in the brain is a fundamental process and its impairment is associated with multiple human mental disorders. Evidence indicates... (Review)
Review
The ability to efficiently store memories in the brain is a fundamental process and its impairment is associated with multiple human mental disorders. Evidence indicates that long-term memory formation involves alterations of synaptic efficacy produced by modifications in neural transmission and morphology. The Eph receptors and their cognate ephrin ligands have been shown to be involved in these key neuronal processes by regulating events such as presynaptic transmitter release, postsynaptic glutamate receptor conductance and trafficking, synaptic glutamate reuptake, and dendritic spine morphogenesis. Recent findings show that Ephs and ephrins are needed for memory formation in different organisms. These proteins participate in the formation of various types of memories that are subserved by different neurons and brain regions. Ephs and ephrins are involved in brain disorders and diseases with memory impairment symptoms, including Alzheimer's disease and anxiety. Drugs that agonize or antagonize Ephs/ephrins signaling have been developed and could serve as therapeutic agents to treat such diseases. Ephs and ephrins may therefore induce cellular alterations mandatory for memory formation and serve as a target for pharmacological intervention for treatment of memory-related brain diseases.
Topics: Animals; Ephrins; Humans; Memory; Neurons; Receptors, Eph Family
PubMed: 26371183
DOI: 10.1093/ijnp/pyv106 -
International Journal of Molecular... Jun 2021Retinal diseases are the leading cause of irreversible blindness. They affect people of all ages, from newborns in retinopathy of prematurity, through age-independent... (Review)
Review
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.
Topics: Animals; Ephrins; Humans; Receptors, Eph Family; Retinal Diseases; Retinal Neovascularization
PubMed: 34201393
DOI: 10.3390/ijms22126207 -
Cells Oct 2022Chronic pain is a debilitating condition that influences the social, economic, and psychological aspects of patients' lives. Hence, the need for better treatment is... (Review)
Review
Chronic pain is a debilitating condition that influences the social, economic, and psychological aspects of patients' lives. Hence, the need for better treatment is drawing extensive interest from the research community. Developmental molecules such as Wnt, ephrins, and semaphorins are acknowledged as central players in the proper growth of a biological system. Their receptors and ligands are expressed in a wide variety in both neurons and glial cells, which are implicated in pain development, maintenance, and resolution. Thereby, it is not surprising that the impairment of those pathways affects the activities and functions of the entire cell. Evidence indicates aberrant activation of their pathways in the nervous system in rodent models of chronic pain. In those conditions, Wnt, ephrin, and semaphorin signaling participate in enhancing neuronal excitability, peripheral sensitization, synaptic plasticity, and the production and release of inflammatory cytokines. This review summarizes the current knowledge on three main developmental pathways and their mechanisms linked with the pathogenesis and progression of pain, considering their impacts on neuronal and glial cells in experimental animal models. Elucidations of the downstream pathways may provide a new mechanism for the involvement of Wnt, ephrin, and semaphorin pathways in pain chronicity.
Topics: Animals; Axon Guidance; Chronic Pain; Cytokines; Ephrins; Semaphorins
PubMed: 36231105
DOI: 10.3390/cells11193143 -
Growth Factors (Chur, Switzerland) Dec 2014Eph receptor tyrosine kinases and the corresponding ephrin ligands play a pivotal role in the glioma development and progression. Aberrant protein expression levels of... (Review)
Review
Eph receptor tyrosine kinases and the corresponding ephrin ligands play a pivotal role in the glioma development and progression. Aberrant protein expression levels of the Eph receptors and ephrins are often associated with higher tumor grade and poor prognosis. Their function in tumorigenesis is complex due to the intricate network of possible co-occurring interactions between neighboring tumor cells and tumor microenvironment. Both Ephs and ephrins localize on the surface of tumor cells, tumor vasculature, glioma stem cells, tumor cells infiltrating brain, and immune cells infiltrating tumors. They can both promote and inhibit tumorigenicity depending on the downstream forward and reverse signalling generated. All the above-mentioned features make the Ephs/ephrins system an intriguing candidate for the development of new therapeutic strategies in glioma treatment. This review will give a general overview on the structure and the function of Ephs and ephrins, with a particular emphasis on the state of the knowledge of their role in malignant gliomas.
Topics: Animals; Brain Neoplasms; Cell Proliferation; Ephrins; Glioma; Humans; Protein Binding; Receptors, Eph Family; Signal Transduction
PubMed: 25418012
DOI: 10.3109/08977194.2014.985787 -
Annual Review of Pharmacology and... 2015The erythropoietin-producing hepatocellular carcinoma (Eph) receptor tyrosine kinase family plays important roles in developmental processes, adult tissue homeostasis,... (Review)
Review
The erythropoietin-producing hepatocellular carcinoma (Eph) receptor tyrosine kinase family plays important roles in developmental processes, adult tissue homeostasis, and various diseases. Interaction with Eph receptor-interacting protein (ephrin) ligands on the surface of neighboring cells triggers Eph receptor kinase-dependent signaling. The ephrins can also transmit signals, leading to bidirectional cell contact-dependent communication. Moreover, Eph receptors and ephrins can function independently of each other through interplay with other signaling systems. Given their involvement in many pathological conditions ranging from neurological disorders to cancer and viral infections, Eph receptors and ephrins are increasingly recognized as attractive therapeutic targets, and various strategies are being explored to modulate their expression and function. Eph receptor/ephrin upregulation in cancer cells, the angiogenic vasculature, and injured or diseased tissues also offer opportunities for Eph/ephrin-based targeted drug delivery and imaging. Thus, despite the challenges presented by the complex biology of the Eph receptor/ephrin system, exciting possibilities exist for therapies exploiting these molecules.
Topics: Animals; Antineoplastic Agents; Antiviral Agents; Cardiovascular Agents; Cardiovascular Diseases; Drug Design; Ephrins; Humans; Ligands; Molecular Targeted Therapy; Neoplasms; Nervous System Diseases; Receptors, Eph Family; Signal Transduction; Virus Diseases
PubMed: 25292427
DOI: 10.1146/annurev-pharmtox-011112-140226 -
International Journal of Molecular... Mar 2022The EPH/ephrin system constitutes a bidirectional signaling pathway comprised of a family of tyrosine kinase receptors in tandem with their plasma membrane-bound ligand... (Review)
Review
The EPH/ephrin system constitutes a bidirectional signaling pathway comprised of a family of tyrosine kinase receptors in tandem with their plasma membrane-bound ligand (ephrins). Its significance in a wide variety of physiologic and pathologic processes has been recognized during the past decades. In carcinogenesis, EPH/ephrins coordinate a wide spectrum of pathologic processes, such as angiogenesis, vessel infiltration, and metastasis. Despite the recent advances in colorectal cancer (CRC) diagnosis and treatment, it remains a leading cause of death globally, accounting for 9.2% of all cancer deaths. A growing body of literature has been published lately revitalizing our scientific interest towards the role of EPH/ephrins in pathogenesis and the treatment of CRC. The aim of the present review is to present the recent CRC data which might lead to clinical practice changes in the future.
Topics: Colorectal Neoplasms; Ephrins; Humans; Neovascularization, Pathologic; Receptors, Eph Family; Signal Transduction
PubMed: 35269901
DOI: 10.3390/ijms23052761 -
International Journal of Molecular... Aug 2020Eph receptors and their ephrin ligands are important guidance molecules during neurological and vascular development. In recent years, it has become clear that the Eph... (Review)
Review
Eph receptors and their ephrin ligands are important guidance molecules during neurological and vascular development. In recent years, it has become clear that the Eph protein family remains functional in adult physiology. A subset of Ephs and ephrins is highly expressed by endothelial cells. As endothelial cells form the first barrier between the blood and surrounding tissues, maintenance of a healthy endothelium is crucial for tissue homeostasis. This review gives an overview of the current insights of the role of ephrin ligands and receptors in endothelial function and leukocyte recruitment in the (patho)physiology of adult vascular biology.
Topics: Adult; Endothelial Cells; Ephrins; Hemodynamics; Homeostasis; Humans; Receptors, Eph Family; Signal Transduction
PubMed: 32781521
DOI: 10.3390/ijms21165623 -
Current Rheumatology Reports Apr 2019Fibrosis is a pathological feature of many human diseases that affect multiple organs. The development of anti-fibrotic therapies has been a difficult endeavor due to... (Review)
Review
PURPOSE OF REVIEW
Fibrosis is a pathological feature of many human diseases that affect multiple organs. The development of anti-fibrotic therapies has been a difficult endeavor due to the complexity of signaling pathways associated with fibrogenic processes, complicating the identification and modulation of specific targets. Evidence suggests that ephrin ligands and Eph receptors are crucial signaling molecules that contribute to physiological wound repair and the development of tissue fibrosis. Here, we discuss recent advances in the understanding of ephrin and Eph signaling in tissue repair and fibrosis.
RECENT FINDINGS
Ephrin-B2 is implicated in fibrosis of multiple organs. Intercepting its signaling may help counteract fibrosis. Ephrins and Eph receptors are candidate mediators of fibrosis. Ephrin-B2, in particular, promotes fibrogenic processes in multiple organs. Thus, therapeutic strategies targeting Ephrin-B2 signaling could yield new ways to treat organ fibrosis.
Topics: Animals; Ephrins; Fibrosis; Humans; Receptors, Eph Family; Signal Transduction; Wound Healing
PubMed: 30980212
DOI: 10.1007/s11926-019-0825-x -
International Journal of Molecular... Apr 2021The 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... (Review)
Review
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.
Topics: Animals; Cornea; Corneal Diseases; Corneal Neovascularization; Endothelium, Corneal; Ephrins; Epithelium, Corneal; Humans; Molecular Targeted Therapy; Receptors, Eph Family
PubMed: 33925443
DOI: 10.3390/ijms22094567