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Rüdiger Klein - One of the best experts on this subject based on the ideXlab platform.
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gulp1 controls eph Ephrin trogocytosis and is important for cell rearrangements during development
Journal of Cell Biology, 2019Co-Authors: Jingyi Gong, Thomas N Gaitanos, Yunyun Huang, Louise Gaitanos, Jana Lindner, Rudolf Winklbauer, Rüdiger KleinAbstract:Trogocytosis, in which cells nibble away parts of neighboring cells, is an intercellular cannibalism process conserved from protozoa to mammals. Its underlying molecular mechanisms are not well understood and are likely distinct from phagocytosis, a process that clears entire cells. Bi-directional contact repulsion induced by Eph/Ephrin signaling involves transfer of membrane patches and full-length Eph/Ephrin protein complexes between opposing cells, resembling trogocytosis. Here, we show that the phagocytic adaptor protein Gulp1 regulates EphB/EphrinB trogocytosis to achieve efficient cell rearrangements of cultured cells and during embryonic development. Gulp1 mediates trogocytosis bi-directionally by dynamic engagement with EphB/EphrinB protein clusters in cooperation with the Rac-specific guanine nucleotide exchange factor Tiam2. Ultimately, Gulp1’s presence at the Eph/Ephrin cluster is a prerequisite for recruiting the endocytic GTPase dynamin. These results suggest that EphB/EphrinB trogocytosis, unlike other trogocytosis events, uses a phagocytosis-like mechanism to achieve efficient membrane scission and engulfment.
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exosomes mediate cell contact independent Ephrin eph signaling during axon guidance
Journal of Cell Biology, 2016Co-Authors: Jingyi Gong, Louise Gaitanos, Roman Korner, Rüdiger KleinAbstract:The cellular release of membranous vesicles known as extracellular vesicles (EVs) or exosomes represents a novel mode of intercellular communication. Eph receptor tyrosine kinases and their membrane-tethered Ephrin ligands have very important roles in such biologically diverse processes as neuronal development, plasticity, and pathological diseases. Until now, it was thought that Ephrin-Eph signaling requires direct cell contact. Although the biological functions of Ephrin-Eph signaling are well understood, our mechanistic understanding remains modest. Here we report the release of EVs containing Ephs and Ephrins by different cell types, a process requiring endosomal sorting complex required for transport (ESCRT) activity and regulated by neuronal activity. Treatment of cells with purified EphB2+ EVs induces EphrinB1 reverse signaling and causes neuronal axon repulsion. These results indicate a novel mechanism of Ephrin-Eph signaling independent of direct cell contact and proteolytic cleavage and suggest the participation of EphB2+ EVs in neural development and synapse physiology.
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mechanisms of Ephrin eph signalling in development physiology and disease
Nature Reviews Molecular Cell Biology, 2016Co-Authors: Artur Kania, Rüdiger KleinAbstract:Eph receptor Tyr kinases and their membrane-tethered ligands, the Ephrins, elicit short-distance cell-cell signalling and thus regulate many developmental processes at the interface between pattern formation and morphogenesis, including cell sorting and positioning, and the formation of segmented structures and ordered neural maps. Their roles extend into adulthood, when Ephrin-Eph signalling regulates neuronal plasticity, homeostatic events and disease processes. Recently, new insights have been gained into the mechanisms of Ephrin-Eph signalling in different cell types, and into the physiological importance of Ephrin-Eph in different organs and in disease, raising questions for future research directions.
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Ephrins and Eph Receptors – Synaptogenesis and Synaptic Function
Cellular Migration and Formation of Neuronal Connections, 2013Co-Authors: Alessandro Filosa, Rüdiger KleinAbstract:Ephrin ligands and their cognate Eph receptor tyrosine kinases mediate axon guidance during development and promote synapse formation and neuronal plasticity in the adult brain. Because Ephrins are always associated with the cell surface and possess reverse signaling properties, the Eph–Ephrin system can function in a bidirectional, contact-mediated fashion between two opposing cells. Eph–Ephrin signaling for spine/synapse formation has been shown to be bidirectional and to function in two configurations: axonal Ephrin with dendritic Eph and axonal Eph with dendritic Ephrin. In other cases, Eph receptors can simply act as ligands for signaling competent Ephrins, suggesting unidirectional functions. Ephs and Ephrins also participate in activity-induced long-term changes in synaptic strength and in neuro muscular junction maturation and function.
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bidirectional modulation of synaptic functions by eph Ephrin signaling
Nature Neuroscience, 2009Co-Authors: Rüdiger KleinAbstract:Ephrin ligands and their cognate Eph receptors guide axons during neural development and regulate synapse formation and neuronal plasticity in the adult. Because Ephrins are tethered to the plasma membrane and possess reverse signaling properties, the Eph-Ephrin system can function in a bidirectional, contact-mediated fashion between two opposing cells. Eph receptors expressed on dendrites are activated by Ephrins (on axons or on astrocytes) and regulate spine and synapse formation. They also participate in activity-induced long-term changes in synaptic strength such as long-term potentiation (LTP). When expressed on axon terminals, Ephrins promote presynaptic differentiation and enhance neurotransmitter release, thereby supporting presynaptic forms of LTP. In some cases, Eph receptors can simply act as ligands for Ephrins without any requirement for Eph receptor signaling, suggesting that the system does not always function bidirectionally.
Alice Davy - One of the best experts on this subject based on the ideXlab platform.
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Regulation and misregulation of Eph/Ephrin expression.
Cell Adhesion & Migration, 2012Co-Authors: Dina N Arvanitis, Alice DavyAbstract:The erythropoietin-producing hepatocellular (Eph) receptors form the largest family of receptor tyrosine kinases. Upon interaction of the Eph receptors with their ligands the Ephrins, signaling cascades are initiated downstream of both receptor and ligand, a feature known as bidirectional signaling. The Eph receptors and Ephrin ligands mediate important roles in embryonic development, particularly in establishing tissue organization by mediating cell adhesion or cell repulsion. In several adult tissues, at least one Eph/Ephrin pair is found to play critical roles in tissue physiology and homeostasis. In recent years numerous members of this family have gained considerable attention since changes in their expression levels are a typical feature in cancer cells. Despite the fact that Eph/Ephrin developmental expression profiles are well documented, little is known on transcriptional and post-transcriptional mechanisms that permits their highly specific, graded, complementary or overlapping expression patterns. Therefore understanding the transcriptional and post-transcriptional mechanisms regulating Eph/Ephrin expression has far-reaching significance in biology. This review provides an overview of the mechanisms regulating Eph/Ephrin expression. We highlight important emerging mechanisms of Eph/Ephrin regulation or misregulation such as epigenetics and miRNAs.
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Ephrin b1 reverse signaling controls a posttranscriptional feedback mechanism via mir 124
Molecular and Cellular Biology, 2010Co-Authors: Dina N Arvanitis, Alice Davy, Thomas Jungas, Annie BeharAbstract:Eph receptors and Ephrins exhibit complex and highly dynamic expression patterns during embryonic development. In addition, changes in their expression levels are often associated with pathological situations in adults. Yet, little is known about the mechanisms regulating their expression. Here we report that the expression of Ephrin-B1 is controlled by a feedback loop involving posttranscriptional regulatory mechanisms. We observed that the EfnB1 3 untranslated region (3-UTR) confers instability to mRNA transcripts, and we identified miR-124 as a posttranscriptional repressor of EfnB1 expression. Furthermore, we showed that miR-124 is itself regulated by Ephrin-B1 reverse signaling, thus revealing the existence of a mutually repressive interaction between Ephrin-B1 and this microRNA (miRNA). Lastly, we demonstrated the relevance of this mutual inhibition for neuronal differentiation. Our results suggest that miRNAs could be important effectors of Eph/Ephrin signaling to refine domains of expression and to regulate function. Ephrins are cell surface proteins involved in cell-cell communication controlling cell and tissue morphogenesis during embryonic development. In the developing embryo, they regulate axon guidance, angiogenesis, tissue patterning, and boundary formation (22, 23). Furthermore, they are involved in a growing number of physiological and pathological processes in the adult, including tumorigenesis, bone homeostasis, neoangiogenesis, synaptic plasticity, and insulin secretion (1, 21). Ephrins were first identified as membrane-bound ligands for Eph receptor tyrosine kinases; however, they have since been categorized as receptors themselves since they are capable of transducing a signaling cascade, despite the fact that they do not possess catalytic activity (10, 13). The signaling cascade activated downstream of Ephrins is called reverse signaling, and it involves a number of signaling effectors, such as cytosolic kinases and small GTPases, that participate in the regulation of cytoskeletal dynamics (21). It has emerged recently that in addition to signaling effectors, transcription factors such as STAT-3 and ZHX2 could lie downstream of Ephrin reverse signaling (2, 33).
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Distinct membrane compartmentalization and signaling of Ephrin-A5 and Ephrin-B1
Biochemical and Biophysical Research Communications, 2008Co-Authors: Tessa N. Campbell, Alice Davy, Mayi Arcellana-panlilio, Stephen M RobbinsAbstract:Abstract Eph receptor tyrosine kinases and their membrane-bound ligand Ephrins form an essential cell communication system. Both Ephrin classes have been shown to localize within cell surface lipid rafts, yet regulate different biological processes. In order to provide insight into this distinct behavior, we examined Ephrin-A5 and B1 localization and signaling in murine fibroblasts and tissues. Results indicated that Ephrin-A5 was constitutively present in detergent-resistant membrane fractions, while Ephrin-B1 displayed translocation to membrane fractions upon stimulation. Ephrin-A5 and B1 were present in detergent-resistant membrane fractions with different buoyancies in vitro and in different raft fractions in vivo . Moreover, Ephrin-A5 and B1 differentially influenced actin reorganization. Finally, microarray analysis revealed unique patterns of gene expression between the two Ephrin classes. We thus demonstrate that distinct localization and compartmentalization provide insight into the subcellular basis for differential signaling observed in Ephrin-A and B classes.
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eph Ephrin signaling networks
Genes & Development, 2008Co-Authors: Dina N Arvanitis, Alice DavyAbstract:Bidirectional signaling has emerged as an important signature by which Ephs and Ephrins control biological functions. Eph/Ephrin signaling participates in a wide spectrum of developmental processes, and cross-regulation with other communication pathways lies at the heart of the complexity underlying their function in vivo. Here, we review in vitro and in vivo data describing molecular, functional, and genetic interactions between Eph/Ephrin and other cell surface signaling pathways. The complexity of Eph/Ephrin function is discussed in terms of the pathways that regulate Eph/Ephrin signaling and also the pathways that are regulated by Eph/Ephrin signaling.
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Eph/Ephrin signaling: networks
Genes & Development, 2008Co-Authors: Dina N Arvanitis, Alice DavyAbstract:Bidirectional signaling has emerged as an important signature by which Ephs and Ephrins control biological functions. Eph/Ephrin signaling participates in a wide spectrum of developmental processes, and cross-regulation with other communication pathways lies at the heart of the complexity underlying their function in vivo. Here, we review in vitro and in vivo data describing molecular, functional, and genetic interactions between Eph/Ephrin and other cell surface signaling pathways. The complexity of Eph/Ephrin function is discussed in terms of the pathways that regulate Eph/Ephrin signaling and also the pathways that are regulated by Eph/Ephrin signaling.
Dimitar B Nikolov - One of the best experts on this subject based on the ideXlab platform.
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structural and functional analyses reveal promiscuous and species specific use of Ephrin receptors by cedar virus
Proceedings of the National Academy of Sciences of the United States of America, 2019Co-Authors: Eric D Laing, Chanakha K Navaratnarajah, Sofia Cheliout Da Silva, Stephanie R Petzing, Yan Xu, Spencer L Sterling, Glenn A Marsh, Linfa Wang, Moushimi Amaya, Dimitar B NikolovAbstract:Cedar virus (CedV) is a bat-borne henipavirus related to Nipah virus (NiV) and Hendra virus (HeV), zoonotic agents of fatal human disease. CedV receptor-binding protein (G) shares only ∼30% sequence identity with those of NiV and HeV, although they can all use Ephrin-B2 as an entry receptor. We demonstrate that CedV also enters cells through additional B- and A-class Ephrins (Ephrin-B1, Ephrin-A2, and Ephrin-A5) and report the crystal structure of the CedV G ectodomain alone and in complex with Ephrin-B1 or Ephrin-B2. The CedV G receptor-binding site is structurally distinct from other henipaviruses, underlying its capability to accommodate additional Ephrin receptors. We also show that CedV can enter cells through mouse Ephrin-A1 but not human Ephrin-A1, which differ by 1 residue in the key contact region. This is evidence of species specific Ephrin receptor usage by a henipavirus, and implicates additional Ephrin receptors in potential zoonotic transmission.
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insights into eph receptor tyrosine kinase activation from crystal structures of the epha4 ectodomain and its complex with Ephrin a5
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Kai Xu, Yan Xu, Dorothea Tzvetkovarobev, Yehuda Goldgur, Yeepeng Chan, Juha P Himanen, Dimitar B NikolovAbstract:Eph receptor tyrosine kinases and their Ephrin ligands mediate cell signaling during normal and oncogenic development. Eph signaling is initiated in a multistep process leading to the assembly of higher-order Eph/Ephrin clusters that set off bidirectional signaling in interacting cells. Eph and Ephrins are divided in two subclasses based on their abilities to bind and activate each other and on sequence conservation. EphA4 is an exception to the general rule because it can be activated by both A- and B-class Ephrin ligands. Here we present high-resolution structures of the complete EphA4 ectodomain and its complexes with Ephrin-A5. The structures reveal how ligand binding promotes conformational changes in the EphA4 ligand-binding domain allowing the formation of signaling clusters at the sites of cell–cell contact. In addition, the structural data, combined with structure-based mutagenesis, reveal a previously undescribed receptor–receptor interaction between the EphA4 ligand-binding and membrane-proximal fibronectin domains, which is functionally important for efficient receptor activation.
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Ephrin-B2 and Ephrin-B3 as functional henipavirus receptors
Seminars in Cell & Developmental Biology, 2011Co-Authors: Kai Xu, Christopher C. Broder, Dimitar B NikolovAbstract:Abstract Members of the Ephrin cell-surface protein family interact with the Eph receptors, the largest family of receptor tyrosine kinases, mediating bi-directional signaling during tumorogenesis and various developmental events. Surprisingly, Ephrin-B2 and -B3 were recently identified as entry receptors for henipaviruses, emerging zoonotic paramyxoviruses responsible for repeated outbreaks in humans and animals in Australia, Southeast Asia, India and Bangladesh. Nipah virus (NiV) and Hendra virus (HeV) are the only two identified members in the henipavirus genus. While the initial human infection cases came from contact with infected pigs (NiV) or horses (HeV), in the more recent outbreaks of NiV both food-borne and human-to-human transmission were reported. These characteristics, together with high mortality and morbidity rates and lack of effective anti-viral therapies, make the henipaviruses a potential biological-agent threat. Viral entry is an important target for the development of anti-viral drugs. The entry of henipavirus is initiated by the attachment of the viral G envelope glycoprotein to the host cell receptors Ephrin-B2 and/or -B3, followed by activation of the F fusion protein, which triggers fusion between the viral envelop and the host membrane. We review recent progress in the study of henipavirus entry, particularly the identification of Ephrins as their entry receptors, and the structural characterization of the Ephrin/Henipa-G interactions.
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Crystal structure of the human Ephrin-A5 ectodomain.
Protein Science, 2007Co-Authors: Dimitar B Nikolov, Martin Lackmann, Chen Li, Philip D. Jeffrey, Juhapekka HimanenAbstract:The Eph receptors, the largest subfamily of receptor tyrosine kinases, and their Ephrin ligands are important mediators of cell–cell communication regulating cell attachment, pathfinding, and mobility in the nervous and cardiovascular systems. Recent structural studies have revealed unique molecular features that explain many of the biochemical and signaling properties of Ephs and Ephrins. Nevertheless, open questions remain, including understanding the precise molecular mechanism underlining their binding-partner preferences and subclass specificity. In this study, we have determined and present the crystal structure of the extracellular domain of Ephrin-A5—the first structure of an unbound A-class Ephrin. The structure, determined at 2.1 A resolution, is a variation of the Greek key β-barrel folding topology, containing eight β-strands, and stabilized by two disulphide bonds. Overall, Ephrin-A5 is structurally very similar to Ephrin-B1 and Ephrin-B2 but, unlike Ephrin-B2, it does not show dimerization either in solution or in the crystals. Comparing free Ephrin-A5 to the previously published structure of EphB2-bound Ephrin-A5 reveals that significant conformational changes occur only around the G–H Ephrin loop that upon binding bends toward the receptor. Interestingly, the G–H loop undergoes a very similar conformational rearrangement in Ephrin-B2 upon receptor binding. The results of this study further emphasize the importance of the G–H loop for receptor recognition and selectivity, and could serve as a starting point for the development of structure-based Eph antagonists.
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adam meets eph an adam substrate recognition module acts as a molecular switch for Ephrin cleavage in trans
Cell, 2005Co-Authors: Peter W Janes, Nayanendu Saha, William A Barton, Momchil V Kolev, Sabine H Wimmerkleikamp, Eva Nievergall, Carl P Blobel, Juhapekka Himanen, Martin Lackmann, Dimitar B NikolovAbstract:The Eph family of receptor tyrosine kinases and their Ephrin ligands are mediators of cell-cell communication. Cleavage of Ephrin-A2 by the ADAM10 membrane metalloprotease enables contact repulsion between Eph- and Ephrin-expressing cells. How ADAM10 interacts with Ephrins in a regulated manner to cleave only Eph bound Ephrin molecules remains unclear. The structure of ADAM10 disintegrin and cysteine-rich domains and the functional studies presented here define an essential substrate-recognition module for functional interaction of ADAM10 with the Ephrin-A5/EphA3 complex. While ADAM10 constitutively associates with EphA3, the formation of a functional EphA3/Ephrin-A5 complex creates a new molecular recognition motif for the ADAM10 cysteine-rich domain that positions the proteinase domain for effective Ephrin-A5 cleavage. Surprisingly, the cleavage occurs in trans, with ADAM10 and its substrate being on the membranes of opposing cells. Our data suggest a simple mechanism for regulating ADAM10-mediated Ephrin proteolysis, which ensures that only Eph bound Ephrins are recognized and cleaved.
Elena B. Pasquale - One of the best experts on this subject based on the ideXlab platform.
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Eph Receptors, Ephrins, and Synaptic Function
The Neuroscientist, 2020Co-Authors: Keith K. Murai, Elena B. PasqualeAbstract:Compelling new findings have revealed that receptor tyrosine kinases of the Eph family, along with their Ephrin ligands, play an essential role in regulating the properties of developing mature excitatory synapses in the central nervous system. The cell surface localization of both the Eph receptors and the Ephrins enables these proteins to signal bidirectionally at sites of cell-to-cell contact, such as synapses. Eph receptors and Ephrins have indeed been implicated in multiple aspects of synaptic function, including clustering and modulating N-methyl-D-aspartate receptors, modifying the geometry of postsynaptic terminals, and influencing long-term synaptic plasticity and memory. In this review, we discuss how Eph receptors and Ephrins are integrated into the molecular machinery that supports synaptic function.
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Distinctive Structure of the EphA3/Ephrin-A5 Complex Reveals a Dual Mode of Eph Receptor Interaction for Ephrin-A5
PLOS ONE, 2015Co-Authors: Garry Jason Forse, Elena B. Pasquale, Maria Loressa Uson, Fariborz Nasertorabi, Anand Kolatkar, Ilaria Lamberto, Peter KuhnAbstract:The Eph receptor tyrosine kinase/Ephrin ligand system regulates a wide spectrum of physiological processes, while its dysregulation has been implicated in cancer progression. The human EphA3 receptor is widely upregulated in the tumor microenvironment and is highly expressed in some types of cancer cells. Furthermore, EphA3 is among the most highly mutated genes in lung cancer and it is also frequently mutated in other cancers. We report the structure of the ligand-binding domain of the EphA3 receptor in complex with its preferred ligand, Ephrin-A5. The structure of the complex reveals a pronounced tilt of the Ephrin-A5 ligand compared to its orientation when bound to the EphA2 and EphB2 receptors and similar to its orientation when bound to EphA4. This tilt brings an additional area of Ephrin-A5 into contact with regions of EphA3 outside the Ephrin-binding pocket thereby enlarging the size of the interface, which is consistent with the high binding affinity of Ephrin-A5 for EphA3. This large variation in the tilt of Ephrin-A5 bound to different Eph receptors has not been previously observed for other Ephrins.
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Eph Receptors and Ephrins: Therapeutic Opportunities
Annual Review of Pharmacology and Toxicology, 2014Co-Authors: Antonio Barquilla, Elena B. PasqualeAbstract: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-ba...
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Eph Receptor Signaling and Ephrins
Cold Spring Harbor Perspectives in Biology, 2013Co-Authors: Erika M. Lisabeth, Giulia Falivelli, Elena B. PasqualeAbstract:The Eph receptors have the prototypical RTK topology, with a multidomain extracellular region that includes the Ephrin ligand-binding domain, a single transmembrane segment, and a cytoplasmic region that contains the kinase domain (Fig. 1). There are nine EphA receptors in the human genome, which promiscuously bind five Ephrin-A ligands and five EphB receptors, which promiscuously bind three Ephrin-B ligands (Pasquale 2004, 2005). Additionally, EphA4 and EphB2 can also bind Ephrins of a different class. Two members of the family, EphA10 and EphB6, have modifications in conserved regions of their kinase domains that prevent kinase activity. Furthermore, a variety of alternatively spliced forms identified for many Eph receptors differ from the prototypical structure and have distinctive functions (Zisch and Pasquale 1997; Pasquale 2010). Figure 1. Domain structure of Eph receptors and Ephrins. Both Ephrin classes include a conserved Eph receptor-binding domain, which is connected to the plasma membrane by a linker segment whose length can be affected by alternative splicing (Fig. 1). The Ephrin-As are attached to the cell surface by a glycosylphosphatidylinositol (GPI) anchor, although they can also be released to activate EphA receptors at a distance (Bartley et al. 1994; Wykosky et al. 2008), whereas the Ephrin-Bs contain a transmembrane segment and a short cytoplasmic region. Ephrin-A3 and Ephrin-B3 also bind heparan sulfate proteoglycans through an interaction that involves their extracellular linker region and that, at least in the case of Ephrin-A3, potentiates EphA receptor activation and signaling (Irie et al. 2008; Holen et al. 2011). The Eph receptor family has greatly expanded during evolution, and includes almost one fourth of the 58 human RTKs (Schlessinger and Lemmon 2013). A large number of Eph receptors and Ephrins may be required to achieve and maintain the sophisticated tissue organization of higher organisms. Indeed, many are highly expressed in the most complex organ, the brain, particularly during the establishment of its complex architecture and intricate wiring of neuronal connections (Yamaguchi and Pasquale 2004). Besides the brain, Eph receptors and Ephrins are also present in most—if not all—other tissues, often in a combinatorial manner and with dynamically changing expression patterns (Pasquale 2005). In some regions, Eph receptors and Ephrins are both coexpressed in the same cells, in others they have mutually exclusive expression patterns or they can be expressed in complementary gradients. These situations likely reflect different signaling modalities with different biological outcomes. Eph receptors and Ephrins engage in a multitude of activities. They typically mediate contact-dependent communication between cells of the same or different types to control cell morphology, adhesion, movement, proliferation, survival, and differentiation (Pasquale 2005). Through these activities, during development, the Eph/Ephrin system plays a role in the spatial organization of different cell populations, axon guidance, formation of synaptic connections between neurons, and blood vessel remodeling. In the adult, the Eph/Ephrin system regulates remodeling of synapses, epithelial differentiation and integrity, bone remodeling, immune function, insulin secretion, and stem cell self-renewal (Pasquale 2008; Genander and Frisen 2010). In addition, Eph receptors and Ephrins are often up-regulated in injured tissues, where they inhibit some regenerative processes but promote angiogenesis, as well as in cancer cells, where they seem to be able to both promote and suppress tumorigenicity (Du et al. 2007; Pasquale 2008, 2010). Here we provide an overview of Eph receptor and Ephrin signaling mechanisms and biological effects, with an emphasis on recent findings. More detailed information on specific aspects of Eph receptor/Ephrin biology and downstream signaling networks can be found in other recent reviews (Pasquale 2005, 2008, 2010; Arvanitis and Davy 2008; Lackmann and Boyd 2008; Klein 2009; Genander and Frisen 2010).
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structural characterization of the epha4 Ephrin b2 complex reveals new features enabling eph Ephrin binding promiscuity
Journal of Biological Chemistry, 2010Co-Authors: Roberta Noberini, Elena B. Pasquale, Xuelu Huan, Jianxing SongAbstract:Abstract EphA and EphB receptors preferentially bind Ephrin-A and Ephrin-B ligands, respectively, but EphA4 is exceptional for its ability to bind all Ephrins. Here, we report the crystal structure of the EphA4 ligand-binding domain in complex with Ephrin-B2, which represents the first structure of an EphA-Ephrin-B interclass complex. A loose fit of the Ephrin-B2 G-H loop in the EphA4 ligand-binding channel is consistent with a relatively weak binding affinity. Additional surface contacts also exist between EphA4 residues Gln12 and Glu14 and Ephrin-B2. Mutation of Gln12 and Glu14 does not cause significant structural changes in EphA4 or changes in its affinity for Ephrin-A ligands. However, the EphA4 mutant has ∼10-fold reduced affinity for Ephrin-B ligands, indicating that the surface contacts are critical for interclass but not intraclass Ephrin binding. Thus, EphA4 uses different strategies to bind Ephrin-A or Ephrin-B ligands and achieve binding promiscuity. NMR characterization also suggests that the contacts of Gln12 and Glu14 with Ephrin-B2 induce dynamic changes throughout the whole EphA4 ligand-binding domain. Our findings shed light on the distinctive features that enable the remarkable ligand binding promiscuity of EphA4 and suggest that diverse strategies are needed to effectively disrupt different Eph-Ephrin complexes.
Catherine D Nobes - One of the best experts on this subject based on the ideXlab platform.
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Ephrin b2 regulates endothelial cell morphology and motility independently of eph receptor binding
Journal of Cell Science, 2010Co-Authors: Magdalena L Bochenek, Sarah Dickinson, Jonathan W Astin, Ralf H Adams, Catherine D NobesAbstract:The transmembrane protein Ephrin-B2 regulates angiogenesis, i.e. the formation of new blood vessels through endothelial sprouting, proliferation and remodeling processes. In addition to essential roles in the embryonic vasculature, Ephrin-B2 expression is upregulated in the adult at sites of neovascularization, such as tumors and wounds. Ephrins are known to bind Eph receptor family tyrosine kinases on neighboring cells and trigger bidirectional signal transduction downstream of both interacting molecules. Here we show that Ephrin-B2 dynamically modulates the motility and cellular morphology of isolated endothelial cells. Even in the absence of Eph-receptor binding, Ephrin-B2 stimulates repeated cycling between actomyosin-dependent cell contraction and spreading episodes, which requires the presence of the C-terminal PDZ motif. Our results show that Ephrin-B2 is a potent regulator of endothelial cell behavior, and indicate that the control of cell migration and angiogenesis by Ephrins might involve both receptor-dependent and receptor-independent activities.
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rac dependent trans endocytosis of Ephrinbs regulates eph Ephrin contact repulsion
Nature Cell Biology, 2003Co-Authors: Daniel J Marston, Sarah Dickinson, Catherine D NobesAbstract:Eph receptor-Ephrin signals are important for controlling repulsive and attractive cell movements during tissue patterning in embryonic development. However, the dynamic cellular responses to these signals at cell-cell contact sites are poorly understood. To examine these events we have used cell microinjection to express EphB4 and EphrinB2 in adjacent Swiss 3T3 fibroblasts and have studied the interaction of the injected cells using time-lapse microscopy. We show that Eph receptors are locally activated wherever neighbouring cells make contact. This triggers dynamic, Rac-regulated membrane ruffles at the Eph-Ephrin contact sites. Subsequently, the receptor and ligand cells retract from one another, concomitantly with the endocytosis of the activated Eph receptors and their bound, full-length EphrinB ligands. Both the internalization of the receptor-ligand complexes and the subsequent cell retraction events are dependent on actin polymerization, which in turn is dependent on Rac signalling within the receptor-expressing cells. Similar events occur in primary human endothelial cells. Our findings suggest a novel mechanism for cell repulsion, in which the contact between Eph-expressing and Ephrin-expressing cells is destabilized by the localized phagocytosis of the ligand-expressing cell plasma membrane by the receptor-expressing cell.