Journal articles on the topic 'Eph and ephrin interactions'
To see the other types of publications on this topic, follow the link: Eph and ephrin interactions.
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 journal articles for your research on the topic 'Eph and ephrin interactions.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse journal articles on a wide variety of disciplines and organise your bibliography correctly.
1
PRESTOZ, LAETITIA, ELLI CHATZOPOULOU, GREGORY LEMKINE, NATHALIE SPASSKY, BARBARA LEBRAS, TETSUSHI KAGAWA, KATZUHIRO IKENAKA, BERNARD ZALC, and JEAN-LÉON THOMAS. "Control of axonophilic migration of oligodendrocyte precursor cells by Eph–ephrin interaction." Neuron Glia Biology 1, no. 1 (February 2004): 73–83. http://dx.doi.org/10.1017/s1740925x04000109.
Full textAbstract:
The migration of oligodendrocyte precursor cells (OPCs) is modulated by secreted molecules in their environment and by cell–cell and matrix–cell interactions. Here, we ask whether membrane-anchored guidance cues, such as the ephrin ligands and their Eph receptors, participate in the control of OPC migration in the optic nerve. We postulate that EphA and EphB receptors, which are expressed on axons of retinal ganglion cells, interact with ephrins on the surface of OPCs. We show the expression of ephrinA5, ephrinB 2 and ephrinB3 in the migrating OPCs of the optic nerve as well as in the diencephalic sites from where they originate. In addition, we demonstrate that coated EphB2-Fc receptors, which are specific for ephrinB2/B3 ligands, induce dramatic changes in the contact and migratory properties of OPCs, indicating that axonal EphB receptors activate ephrinB signaling in OPCs. Based on these findings, we propose that OPCs are characterized by an ephrin code, and that Eph–ephrin interactions between axons and OPCs control the distribution of OPCs in the optic axonal tracts, and the progress and arrest of their migration.
2
Xu, Yan, Dorothea Robev, Nayanendu Saha, Bingcheng Wang, Matthew B. Dalva, Kai Xu, Juha P. Himanen, and Dimitar B. Nikolov. "The Ephb2 Receptor Uses Homotypic, Head-to-Tail Interactions within Its Ectodomain as an Autoinhibitory Control Mechanism." International Journal of Molecular Sciences 22, no. 19 (September 28, 2021): 10473. http://dx.doi.org/10.3390/ijms221910473.
Full textAbstract:
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.
3
Xu, Qiling, Georg Mellitzer, and David G. Wilkinson. "Roles of Eph receptors and ephrins in segmental patterning." Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 355, no. 1399 (July 29, 2000): 993–1002. http://dx.doi.org/10.1098/rstb.2000.0635.
Full textAbstract:
Eph receptor tyrosine kinases and their membrane–bound ligands, ephrins, have key roles in patterning and morphogenesis. Interactions between these molecules are promiscuous, but largely fall into two groups: EphA receptors bind to glycosylphosphatidyl inositol–anchored ephrin–A ligands, and EphB receptors bind to transmembrane ephrin–B proteins. Ephrin–B proteins transduce signals, such that bidirectional signalling can occur upon interaction with the Eph receptor. In many tissues, there are complementary and overlapping expression domains of interacting Eph receptors and ephrins. An important role of Eph receptors and ephrins is to mediate cell contact–dependent repulsion, and this has been implicated in the pathfinding of axons and neural crest cells, and the restriction of cell intermingling between hindbrain segments. Studies in an in vitro system show that bidirectional activation is required to prevent intermingling between cell populations, whereas unidirectional activation can restrict cell communication via gap junctions. Recent work indicates that Eph receptors can also upregulate cell adhesion, but the biochemical basis of repulsion versus adhesion responses is unclear. Eph receptors and ephrins have thus emerged as key regulators that, in parallel with cell adhesion molecules, underlie the establishment and maintenance of patterns of cellular organization.
4
Holder, N., and R. Klein. "Eph receptors and ephrins: effectors of morphogenesis." Development 126, no. 10 (May 15, 1999): 2033–44. http://dx.doi.org/10.1242/dev.126.10.2033.
Full textAbstract:
Eph receptor tyrosine kinases and their ligands, the ephrins, appear to lie functionally at the interface between pattern formation and morphogenesis. We review the role of Eph and ephrin signalling in the formation of segmented structures, in the control of axon guidance and cell migration and in the development of the vasculature. We address the question of how the specificity of response is achieved and discuss the specificity of ephrin-Eph interactions and the significance of structural domains in Eph receptors.
5
Arcas, Aida, David G. Wilkinson, and M. Ángela Nieto. "The Evolutionary History of Ephs and Ephrins: Toward Multicellular Organisms." Molecular Biology and Evolution 37, no. 2 (October 7, 2019): 379–94. http://dx.doi.org/10.1093/molbev/msz222.
Full textAbstract:
Abstract Eph receptor (Eph) and ephrin signaling regulate fundamental developmental processes through both forward and reverse signaling triggered upon cell–cell contact. In vertebrates, they are both classified into classes A and B, and some representatives have been identified in many metazoan groups, where their expression and functions have been well studied. We have extended previous phylogenetic analyses and examined the presence of Eph and ephrins in the tree of life to determine their origin and evolution. We have found that 1) premetazoan choanoflagellates may already have rudimental Eph/ephrin signaling as they have an Eph-/ephrin-like pair and homologs of downstream-signaling genes; 2) both forward- and reverse-downstream signaling might already occur in Porifera since sponges have most genes involved in these types of signaling; 3) the nonvertebrate metazoan Eph is a type-B receptor that can bind ephrins regardless of their membrane-anchoring structure, glycosylphosphatidylinositol, or transmembrane; 4) Eph/ephrin cross-class binding is specific to Gnathostomata; and 5) kinase-dead Eph receptors can be traced back to Gnathostomata. We conclude that Eph/ephrin signaling is of older origin than previously believed. We also examined the presence of protein domains associated with functional characteristics and the appearance and conservation of downstream-signaling pathways to understand the original and derived functions of Ephs and ephrins. We find that the evolutionary history of these gene families points to an ancestral function in cell–cell interactions that could contribute to the emergence of multicellularity and, in particular, to the required segregation of cell populations.
6
Prévost, Nicolas, Donna S. Woulfe, Massimiliano Tognolini, Takako Tanaka, Wenying Jian, Ryan R. Fortna, Hong Jiang, and Lawrence F. Brass. "Signaling by ephrinB1 and Eph kinases in platelets promotes Rap1 activation, platelet adhesion, and aggregation via effector pathways that do not require phosphorylation of ephrinB1." Blood 103, no. 4 (February 15, 2004): 1348–55. http://dx.doi.org/10.1182/blood-2003-06-1781.
Full textAbstract:
Abstract We have previously shown that platelets express 2 receptor tyrosine kinases, EphA4 and EphB1, and the Eph kinase ligand, ephrinB1, and proposed that transcellular Eph/ephrin interactions made possible by the onset of platelet aggregation promote the further growth and stability of the hemostatic plug. The present study examines how this might occur. The results show that clustering of either ephrinB1 or EphA4 causes platelets to adhere to immobilized fibrinogen via αIIbβ3. Adhesion occurs more slowly than with adenosine diphosphate (ADP) and requires phosphatidylinositol 3 (PI3)–kinase and protein kinase C activity but not ephrinB1 phosphorylation. By itself, Eph and ephrin signaling is insufficient to cause aggregation or the binding of soluble fibrinogen, but it can potentiate aggregation initiated by a Ca++ ionophore or by agonists for thrombin and thromboxane receptors. It also enhances Rap1 activation without requiring ADP secretion, ephrinB1 phosphorylation, or the activation of PI3-kinase and Src. From this we conclude that (1) Eph/ephrin signaling enhances the ability of platelet agonists to cause aggregation provided that those agonists can increase cytosolic Ca++; (2) this is accomplished in part by activating Rap1; and (3) these effects require oligomerization of ephrinB1 but not phosphotyrosine-based interactions with the ephrinB1 cytoplasmic domain.
7
Fujiwara, Hiroshi, Yoshihiro Nishioka, Hisanori Matsumoto, Koh Suginami, Akihito Horie, Hirohiko Tani, Noriomi Matsumura, et al. "Eph-Ephrin A System Regulates Human Choriocarcinoma–Derived JEG-3 Cell Invasion." International Journal of Gynecologic Cancer 23, no. 3 (March 2013): 576–82. http://dx.doi.org/10.1097/igc.0b013e3182849e36.
Full textAbstract:
ObjectivesThe Eph-ephrin system is a unique system that can induce multiple cellular responses such as cell migration, regulation of angiogenesis, and axonal guidance. Previously, the Eph-ephrin system was reported to regulate human extravillous trophoblast invasion. In this study, we examined the possible involvement of the Eph-ephrin system in the invasion of malignant gestational trophoblastic diseases using a human choriocarcinoma–derived cell line, JEG-3.MethodsThe mRNA expression of class A Ephs and ephrins on JEG-3 cells was examined by reverse transcription–polymerase chain reaction. The effects of recombinant human Eph A1 (r-Eph A1) and r-ephrin A4 on the proliferation and invasion of JEG-3 cells were investigated by cell proliferation and Matrigel invasion assays. The alterations of integrin expression on JEG-3 cells in the presence of r-Eph A1 and r-ephrin A4 were investigated by flow cytometry. The induction of phosphorylation of focal adhesion kinase in JEG-3 cells by r-ephrin A4 was examined by Western blot analysis.ResultsBy reverse transcription–polymerase chain reaction, mRNAs of Eph A1, A2, and A4 and ephrin A1, A4, and A5 were detected on JEG-3 cells. In Matrigel invasion assay, both r-Eph A1 and r-ephrin A4 promoted the invasion of JEG-3 cells without affecting cell proliferation. During 24-hour culture with r-Eph A1 and r-ephrin A4, the increase in integrin α 5 expression on JEG-3 cells was observed by flow cytometry. Western blotting analysis showed that r-ephrin A4 induced dephosphorylation of focal adhesion kinase in JEG-3 cells.ConclusionsThese findings suggest that Eph-ephrin interaction plays some role in the regulation of choriocarcinoma invasion in cooperation with integrins.
8
Wimmer-Kleikamp, Sabine H., Peter W. Janes, Anthony Squire, Philippe I. H. Bastiaens, and Martin Lackmann. "Recruitment of Eph receptors into signaling clusters does not require ephrin contact." Journal of Cell Biology 164, no. 5 (March 1, 2004): 661–66. http://dx.doi.org/10.1083/jcb.200312001.
Full textAbstract:
Eph receptors and their cell membrane–bound ephrin ligands regulate cell positioning and thereby establish or stabilize patterns of cellular organization. Although it is recognized that ephrin clustering is essential for Eph function, mechanisms that relay information of ephrin density into cell biological responses are poorly understood. We demonstrate by confocal time-lapse and fluorescence resonance energy transfer microscopy that within minutes of binding ephrin-A5–coated beads, EphA3 receptors assemble into large clusters. While remaining positioned around the site of ephrin contact, Eph clusters exceed the size of the interacting ephrin surface severalfold. EphA3 mutants with compromised ephrin-binding capacity, which alone are incapable of cluster formation or phosphorylation, are recruited effectively and become phosphorylated when coexpressed with a functional receptor. Our findings reveal consecutive initiation of ephrin-facilitated Eph clustering and cluster propagation, the latter of which is independent of ephrin contacts and cytosolic Eph signaling functions but involves direct Eph–Eph interactions.
9
Li, Wenqing, Lai Wen, Bhavisha Rathod, Anne-Claude Gingras, Klaus Ley, and Ho-Sup Lee. "Kindlin2 enables EphB/ephrinB bi-directional signaling to support vascular development." Life Science Alliance 6, no. 3 (December 27, 2022): e202201800. http://dx.doi.org/10.26508/lsa.202201800.
Full textAbstract:
Direct contact between cells expressing either ephrin ligands or Eph receptor tyrosine kinase produces diverse developmental responses. Transmembrane ephrinB ligands play active roles in transducing bi-directional signals downstream of EphB/ephrinB interaction. However, it has not been well understood how ephrinB relays transcellular signals to neighboring cells and what intracellular effectors are involved. Here, we report that kindlin2 can mediate bi-directional ephrinB signaling through binding to a highly conserved NIYY motif in the ephrinB2 cytoplasmic tail. We show this interaction is important for EphB/ephrinB-mediated integrin activation in mammalian cells and for blood vessel morphogenesis during zebrafish development. A mixed two-cell population study revealed that kindlin2 (in ephrinB2-expressing cells) modulates transcellular EphB4 activation by promoting ephrinB2 clustering. This mechanism is also operative for EphB2/ephrinB1, suggesting that kindlin2-mediated regulation is conserved for EphB/ephrinB signaling pathways. Together, these findings show that kindlin2 enables EphB4/ephrinB2 bi-directional signal transmission.
10
Janes, Peter W., Bettina Griesshaber, Lakmali Atapattu, Eva Nievergall, Linda L. Hii, Anneloes Mensinga, Chanly Chheang, et al. "Eph receptor function is modulated by heterooligomerization of A and B type Eph receptors." Journal of Cell Biology 195, no. 6 (December 5, 2011): 1033–45. http://dx.doi.org/10.1083/jcb.201104037.
Full textAbstract:
Eph receptors interact with ephrin ligands on adjacent cells to facilitate tissue patterning during normal and oncogenic development, in which unscheduled expression and somatic mutations contribute to tumor progression. EphA and B subtypes preferentially bind A- and B-type ephrins, respectively, resulting in receptor complexes that propagate via homotypic Eph–Eph interactions. We now show that EphA and B receptors cocluster, such that specific ligation of one receptor promotes recruitment and cross-activation of the other. Remarkably, coexpression of a kinase-inactive mutant EphA3 with wild-type EphB2 can cause either cross-activation or cross-inhibition, depending on relative expression. Our findings indicate that cellular responses to ephrin contact are determined by the EphA/EphB receptor profile on a given cell rather than the individual Eph subclass. Importantly, they imply that in tumor cells coexpressing different Ephs, functional mutations in one subtype may cause phenotypes that are a result of altered signaling from heterotypic rather from homotypic Eph clusters.
11
Riedl, Jurgen A., Dominique T. Brandt, Eduard Batlle, Leo S. Price, Hans Clevers, and Johannes L. Bos. "Down-regulation of Rap1 activity is involved in ephrinB1-induced cell contraction." Biochemical Journal 389, no. 2 (July 5, 2005): 465–69. http://dx.doi.org/10.1042/bj20050048.
Full textAbstract:
Ephrins are cell surface ligands that activate Eph receptor tyrosine kinases. This ligand–receptor interaction plays a central role in the sorting of cells. We have previously shown that the ephrinB–EphB signalling pathway is also involved in the migration of intestinal precursor cells along the crypts. Using the colon cell line DLD1 expressing the EphB2 receptor, we showed that stimulation of these cells with soluble ephrinB1 results in a rapid retraction of cell extensions and a detachment of cells. On ephrinB1 stimulation, the small GTPases Rho and Ras are activated and Rap1 is inactivated. Importantly, when a constitutively active Rap1 mutant was introduced into these cells, ephrinB1-induced retraction was inhibited. From these results, we conclude that down-regulation of Rap1 is a prerequisite for ephrin-induced cell retraction in colon cells.
12
Chong, Lisa D., Eui Kyun Park, Erin Latimer, Robert Friesel, and Ira O. Daar. "Fibroblast Growth Factor Receptor-Mediated Rescue of x-Ephrin B1-Induced Cell Dissociation in XenopusEmbryos." Molecular and Cellular Biology 20, no. 2 (January 15, 2000): 724–34. http://dx.doi.org/10.1128/mcb.20.2.724-734.2000.
Full textAbstract:
ABSTRACT The Eph family of receptor tyrosine kinases and their membrane-bound ligands, the ephrins, have been implicated in regulating cell adhesion and migration during development by mediating cell-to-cell signaling events. Genetic evidence suggests that ephrins may transduce signals and become tyrosine phosphorylated during embryogenesis. However, the induction and functional significance of ephrin phosphorylation is not yet clear. Here, we report that when we used ectopically expressed proteins, we found that an activated fibroblast growth factor (FGF) receptor associated with and induced the phosphorylation of ephrin B1 on tyrosine. Moreover, this phosphorylation reduced the ability of overexpressed ephrin B1 to reduce cell adhesion. In addition, we identified a region in the cytoplasmic tail of ephrin B1 that is critical for interaction with the FGF receptor; we also report FGF-induced phosphorylation of ephrins in a neural tissue. This is the first demonstration of communication between the FGF receptor family and the Eph ligand family and implicates cross talk between these two cell surface molecules in regulating cell adhesion.
13
Noren, Nicole K., Nai-Ying Yang, Morgan Silldorff, Ravi Mutyala, and Elena B. Pasquale. "Ephrin-independent regulation of cell substrate adhesion by the EphB4 receptor." Biochemical Journal 422, no. 3 (August 27, 2009): 433–42. http://dx.doi.org/10.1042/bj20090014.
Full textAbstract:
Receptor tyrosine kinases of the Eph family become tyrosine phosphorylated and initiate signalling events upon binding of their ligands, the ephrins. Eph receptors such as EphA2 and EphB4 are highly expressed but poorly tyrosine phosphorylated in many types of cancer cells, suggesting a limited interaction with ephrin ligands. Nevertheless, decreasing the expression of these receptors affects the malignant properties of cancer cells, suggesting that Eph receptors may influence cancer cells independently of ephrin stimulation. Ligand-independent activities of Eph receptors in cancer, however, have not been demonstrated. By using siRNA (small interfering RNA) to downregulate EphB4 in MCF7 and MDA-MB-435 cancer cells, we found that EphB4 inhibits integrin-mediated cell substrate adhesion, spreading and migration, and reduces β1-integrin protein levels. Low expression of the EphB4 preferred ligand, ephrin-B2, and minimal contact between cells in these assays suggest that cell contact-dependent stimulation of EphB4 by the transmembrane ephrin-B2 ligand does not play a role in these effects. Indeed, inhibitors of ephrin-B2 binding to endogenous EphB4 did not influence cell substrate adhesion. Increasing EphB4 expression by transient transfection inhibited cell substrate adhesion, and this effect was also independent of ephrin stimulation because it was not affected by single amino acid mutations in EphB4 that impair ephrin binding. The overexpressed EphB4 was tyrosine phosphorylated, and we found that EphB4 kinase activity is important for inhibition of integrin-mediated adhesion, although several EphB4 tyrosine phosphorylation sites are dispensable. These findings demonstrate that EphB4 can affect cancer cell behaviour in an ephrin-independent manner.
14
Hadjimichael, Argyris C., Alexandros Pergaris, Angelos Kaspiris, Athanasios F. Foukas, Stefania Kokkali, Gerasimos Tsourouflis, and Stamatios Theocharis. "The EPH/Ephrin System in Bone and Soft Tissue Sarcomas’ Pathogenesis and Therapy: New Advancements and a Literature Review." International Journal of Molecular Sciences 23, no. 9 (May 5, 2022): 5171. http://dx.doi.org/10.3390/ijms23095171.
Full textAbstract:
Musculoskeletal sarcomas represent rare heterogenous malignancies of mesenchymal origin that can be divided in two distinct subtypes, bone and soft tissue sarcomas. Current treatment options combine the surgical excision of local tumors and multidrug chemotherapy to prevent metastatic widespread disease. Due to the grim prognosis that usually accompanies such tumors, researchers have attempted to shed light on the molecular pathways implicated in their pathogenesis in order to develop novel, innovative, personalized therapeutic strategies. Erythropoietin-producing human hepatocellular receptors (EPHs) are tyrosine-kinase transmembrane receptors that, along with their ligands, ephrins, participate in both tumor-suppressive or tumor-promoting signaling pathways in bone and soft tissue sarcomas. The EPH/ephrin axis orchestrates cancerous processes such as cell–cell and cell–substrate adhesion and enhances the remodeling of the intracellular cytoskeleton to stimulate the motility and invasiveness of sarcoma cells. The purpose of our study was to review published PubMed literature to extract results from in vitro, in vivo and clinical trials indicative of the role of EPH/ephrin signaling in bone and soft tissue sarcomas. Based on these reports, significant interactions between the EPH/ephrin signaling pathway and a plethora of normal and abnormal cascades contribute to molecular mechanisms enhancing malignancy during sarcoma progression. In addition, EPHs and ephrins are prospective candidates for diagnostic, monitoring and therapeutic purposes in the clinical setting against bone and soft tissue sarcomas.
15
Santiago, Alicia, and Carol A. Erickson. "Ephrin-B ligands play a dual role in the control of neural crest cell migration." Development 129, no. 15 (August 1, 2002): 3621–32. http://dx.doi.org/10.1242/dev.129.15.3621.
Full textAbstract:
Little is known about the mechanisms that direct neural crest cells to the appropriate migratory pathways. Our aim was to determine how neural crest cells that are specified as neurons and glial cells only migrate ventrally and are prevented from migrating dorsolaterally into the skin, whereas neural crest cells specified as melanoblasts are directed into the dorsolateral pathway. Eph receptors and their ephrin ligands have been shown to be essential for migration of many cell types during embryonic development. Consequently, we asked if ephrin-B proteins participate in the guidance of melanoblasts along the dorsolateral pathway, and prevent early migratory neural crest cells from invading the dorsolateral pathway. Using Fc fusion proteins, we detected the expression of ephrin-B ligands in the dorsolateral pathway at the stage when neural crest cells are migrating ventrally. Furthermore, we show that ephrins block dorsolateral migration of early-migrating neural crest cells because when we disrupt the Eph-ephrin interactions by addition of soluble ephrin-B ligand to trunk explants, early neural crest cells migrate inappropriately into the dorsolateral pathway. Surprisingly, we discovered the ephrin-B ligands continue to be expressed along the dorsolateral pathway during melanoblast migration. RT-PCR analysis, in situ hybridisation, and cell surface-labelling of neural crest cell cultures demonstrate that melanoblasts express several EphB receptors. In adhesion assays, engagement of ephrin-B ligands to EphB receptors increases melanoblast attachment to fibronectin. Cell migration assays demonstrate that ephrin-B ligands stimulate the migration of melanoblasts. Furthermore, when Eph signalling is disrupted in vivo, melanoblasts are prevented from migrating dorsolaterally, suggesting ephrin-B ligands promote the dorsolateral migration of melanoblasts. Thus, transmembrane ephrins act as bifunctional guidance cues: they first repel early migratory neural crest cells from the dorsolateral path, and then later stimulate the migration of melanoblasts into this pathway. The mechanisms by which ephrins regulate repulsion or attraction in neural crest cells are unknown. One possibility is that the cellular response involves signalling to the actin cytoskeleton, potentially involving the activation of Cdc42/Rac family of GTPases. In support of this hypothesis, we show that adhesion of early migratory cells to an ephrin-B-derivatized substratum results in cell rounding and disruption of the actin cytoskeleton, whereas plating of melanoblasts on an ephrin-B substratum induces the formation of microspikes filled with F-actin.
16
Matsuo, Koichi, and Natsuko Otaki. "Bone cell interactions through Eph/ephrin." Cell Adhesion & Migration 6, no. 2 (March 2012): 148–56. http://dx.doi.org/10.4161/cam.20888.
Full text
17
Nievergall, Eva, Peter W. Janes, Carolin Stegmayer, Mary E. Vail, Fawaz G. Haj, Shyh Wei Teng, Benjamin G. Neel, Philippe I. Bastiaens, and Martin Lackmann. "PTP1B regulates Eph receptor function and trafficking." Journal of Cell Biology 191, no. 6 (December 6, 2010): 1189–203. http://dx.doi.org/10.1083/jcb.201005035.
Full textAbstract:
Eph receptors orchestrate cell positioning during normal and oncogenic development. Their function is spatially and temporally controlled by protein tyrosine phosphatases (PTPs), but the underlying mechanisms are unclear and the identity of most regulatory PTPs are unknown. We demonstrate here that PTP1B governs signaling and biological activity of EphA3. Changes in PTP1B expression significantly affect duration and amplitude of EphA3 phosphorylation and biological function, whereas confocal fluorescence lifetime imaging microscopy (FLIM) reveals direct interactions between PTP1B and EphA3 before ligand-stimulated receptor internalization and, subsequently, on endosomes. Moreover, overexpression of wild-type (w/t) PTP1B and the [D-A] substrate–trapping mutant decelerate ephrin-induced EphA3 trafficking in a dose-dependent manner, which reveals its role in controlling EphA3 cell surface concentration. Furthermore, we provide evidence that in areas of Eph/ephrin-mediated cell–cell contacts, the EphA3–PTP1B interaction can occur directly at the plasma membrane. Our studies for the first time provide molecular, mechanistic, and functional insights into the role of PTP1B controlling Eph/ephrin-facilitated cellular interactions.
18
Mohd-Zin, Siti Waheeda, Amelia Cheng Wei Tan, Wahib M. Atroosh, Meow-Keong Thong, Abu Bakar Azizi, Nicholas D. E. Greene, and Noraishah Mydin Abdul-Aziz. "Eph and Ephrin Variants in Malaysian Neural Tube Defect Families." Genes 13, no. 6 (May 26, 2022): 952. http://dx.doi.org/10.3390/genes13060952.
Full textAbstract:
Neural tube defects (NTDs) are common birth defects with a complex genetic etiology. Mouse genetic models have indicated a number of candidate genes, of which functional mutations in some have been found in human NTDs, usually in a heterozygous state. This study focuses on Ephs-ephrins as candidate genes of interest owing to growing evidence of the role of this gene family during neural tube closure in mouse models. Eph-ephrin genes were analyzed in 31 Malaysian individuals comprising seven individuals with sporadic spina bifida, 13 parents, one twin-sibling and 10 unrelated controls. Whole exome sequencing analysis and bioinformatic analysis were performed to identify variants in 22 known Eph-ephrin genes. We reported that three out of seven spina bifida probands and three out of thirteen family members carried a variant in either EPHA2 (rs147977279), EPHB6 (rs780569137) or EFNB1 (rs772228172). Analysis of public databases shows that these variants are rare. In exome datasets of the probands and parents of the probands with Eph-ephrin variants, the genotypes of spina bifida-related genes were compared to investigate the probability of the gene–gene interaction in relation to environmental risk factors. We report the presence of Eph-ephrin gene variants that are prevalent in a small cohort of spina bifida patients in Malaysian families.
19
Corrado, Miriam, Carmine Giorgio, Elisabetta Barocelli, Giuseppe Vittucci Marzetti, Anna Maria Cantoni, Rosanna Di Lecce, Matteo Incerti, Riccardo Castelli, Alessio Lodola, and Massimiliano Tognolini. "Evaluation of the Anti-Tumor Activity of Small Molecules Targeting Eph/Ephrins in APC min/J Mice." Pharmaceuticals 13, no. 4 (April 16, 2020): 69. http://dx.doi.org/10.3390/ph13040069.
Full textAbstract:
The Eph receptors are the largest receptors tyrosine kinases (RTKs) family in humans and together with ephrin ligands constitute a complex cellular communication system often dysregulated in many tumors. The role of the Eph-ephrin system in colorectal cancer (CRC) has been investigated and different expression of Eph receptors have been associated with tumor development and progression. In light of this evidence, we investigated if a pharmacological approach aimed at inhibiting Eph/ephrin interaction through small molecules could prevent tumor growth in APC min/J mice. The 8-week treatment with the Eph-ephrin antagonist UniPR129 significantly reduced the number of adenomas in the ileum and decreased the diameter of adenomas in the same region. Overall our data suggested as UniPR129 could be able to slow down the tumor development in APC min/J mice. These results further confirm literature data about Eph kinases as a new valuable target in the intestinal cancer and for the first time showed the feasibility of the Eph-ephrin inhibition as a useful pharmacological approach against the intestinal tumorigenesis. In conclusion this work paves the way for further studies with Eph-ephrin inhibitors in order to confirm the Eph antagonism as innovative pharmacological approach with preventive benefit in the intestinal tumor development.
20
Arvanitis, Dina N., Thomas Jungas, Annie Behar, and Alice Davy. "Ephrin-B1 Reverse Signaling Controls a Posttranscriptional Feedback Mechanism via miR-124." Molecular and Cellular Biology 30, no. 10 (March 22, 2010): 2508–17. http://dx.doi.org/10.1128/mcb.01620-09.
Full textAbstract:
ABSTRACT 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.
21
Cooke, J., C. Moens, L. Roth, L. Durbin, K. Shiomi, C. Brennan, C. Kimmel, S. Wilson, and N. Holder. "Eph signalling functions downstream of Val to regulate cell sorting and boundary formation in the caudal hindbrain." Development 128, no. 4 (February 15, 2001): 571–80. http://dx.doi.org/10.1242/dev.128.4.571.
Full textAbstract:
Rhombomeres are segmental units of the developing vertebrate hindbrain that underlie the reiterated organisation of cranial neural crest migration and neuronal differentiation. valentino (val), a zebrafish homologue of the mouse bzip transcription factor-encoding gene, kreisler, is required for segment boundary formation caudal to rhombomere 4 (r4). val is normally expressed in r5/6 and is required for cells to contribute to this region. In val(−) mutants, rX, a region one rhombomere in length and of mixed identity, lies between r4 and r7. While a number of genes involved in establishing rhombomeric identity are known, it is still largely unclear how segmental integrity is established and boundaries are formed. Members of the Eph family of receptor tyrosine kinases and their ligands, the ephrins, are candidates for functioning in rhombomere boundary formation. Indeed, expression of the receptor ephB4a coincides with val in r5/6, whilst ephrin-B2a, which encodes a ligand for EphB4a, is expressed in r4 and r7, complementary to the domain of val expression. Here we show that in val(−) embryos, ephB4a expression is downregulated and ephrin-B2a expression is upregulated between r4 and r7, indicating that Val is normally required to establish the mutually exclusive expression domains of these two genes. We show that juxtaposition of ephB4a-expressing cells and ephrin-B2a-expressing cells in the hindbrain leads to boundary formation. Loss of the normal spatial regulation of eph/ephrin expression in val mutants correlates not only with absence of boundaries but also with the inability of mutant cells to contribute to wild-type r5/6. Using a genetic mosaic approach, we show that spatially inappropriate Eph signalling underlies the repulsion of val(−) cells from r5/6. We propose that Val controls eph expression and that interactions between EphB4a and Ephrin-B2a mediate cell sorting and boundary formation in the segmenting caudal hindbrain.
22
de Saint-Vis, Blandine, Caroline Bouchet, Grégory Gautier, Jenny Valladeau, Christophe Caux, and Pierre Garrone. "Human dendritic cells express neuronal Eph receptor tyrosine kinases: role of EphA2 in regulating adhesion to fibronectin." Blood 102, no. 13 (December 15, 2003): 4431–40. http://dx.doi.org/10.1182/blood-2003-02-0500.
Full textAbstract:
AbstractEph receptor tyrosine kinases and their ligands, the ephrins, have been primarily described in the nervous system for their roles in axon guidance, development, and cell intermingling. Here we address whether Eph receptors may also regulate dendritic cell (DC) trafficking. Reverse transcription-polymerase chain reaction (RT-PCR) analysis showed that DCs derived from CD34+ progenitors, but not from monocytes, expressed several receptors, in particular EphA2, EphA4, EphA7, EphB1, and EphB3 mRNA. EphB3 was specifically expressed by Langerhans cells, and EphA2 and EphA7 were expressed by both Langerhans- and interstitial-type DCs. EphA and EphB protein expression on DCs generated in vitro was confirmed by staining with ephrin-A3-Fc and ephrin-B3-Fc fusion proteins that bind to different Eph members, in particular EphA2 and EphB3. Immunostaining with anti-EphA2 antibodies demonstrated the expression of EphA2 by immature DCs and by skin Langerhans cells isolated ex vivo. Interestingly, ephrin expression was detected in epidermal keratinocytes and also in DCs. Adhesion of CD34+-derived DCs to fibronectin, but not to poly-l-lysine, was increased in the presence of ephrin-A3-Fc, a ligand of EphA2, through a β1 integrin activation pathway. As such, EphA2/ephrin-A3 interactions may play a role in the localization and network of Langerhans cells in the epithelium and in the regulation of their trafficking. (Blood. 2003;102:4431-4440)
23
Muñoz, Juan Jose, Teresa Cejalvo, Luis Miguel Alonso-Colmenar, David Alfaro, Javier Garcia-Ceca, and Agustin Zapata. "Eph/Ephrin-Mediated Interactions in the Thymus." Neuroimmunomodulation 18, no. 5 (2011): 271–80. http://dx.doi.org/10.1159/000329490.
Full text
24
Kuijper, Sanne, Christopher J. Turner, and Ralf H. Adams. "Regulation of Angiogenesis by Eph–Ephrin Interactions." Trends in Cardiovascular Medicine 17, no. 5 (July 2007): 145–51. http://dx.doi.org/10.1016/j.tcm.2007.03.003.
Full text
25
Damon, Deborah H., Jaclyn A. teRiele, and Stephen B. Marko. "Eph/ephrin interactions modulate vascular sympathetic innervation." Autonomic Neuroscience 158, no. 1-2 (December 2010): 65–70. http://dx.doi.org/10.1016/j.autneu.2010.06.004.
Full text
26
FINNE, Eivind F., Else MUNTHE, and Hans-Christian AASHEIM. "A new ephrin-A1 isoform (ephrin-A1b) with altered receptor binding properties abrogates the cleavage of ephrin-A1a." Biochemical Journal 379, no. 1 (April 1, 2004): 39–46. http://dx.doi.org/10.1042/bj20031619.
Full textAbstract:
Ephrins are ligands for the Eph receptor tyrosine kinases, which play important roles in patterning nervous and vascular systems. Ephrin-A1 is a glycosylphosphatidylinositol-anchored ligand that binds to the EphA receptor tyrosine kinases. In the present study, we have identified a new ephrin-A1 isoform, denoted ephrin-A1b (ephrin-A1 isoform b). Compared with the originally described ephrin-A1 sequence, ephrin-A1a [Holzman, Marks and Dixit (1990) Mol. Cell. Biol. 10, 5830–5838], ephrin-A1b lacks a segment of 22 amino acids (residues 131–152). At the transcript level, exon 3 is spliced out in the transcript encoding ephrin-A1b. Transfection of HEK-293T cells (human embryonic kidney 293 cells) with an ephrin-A1b-expressing plasmid resulted in a significant expression of the protein on the cell surface. However, soluble EphA2 receptor (EphA2-Fc) bound weakly to ephrin-A1b-expressing transfectants, but bound strongly to ephrin-A1a-expressing transfectants. Ephrins have been shown to undergo regulated cleavage after interaction with their receptors. This process is inhibited by co-expression of ephrin-A1a and ephrin-A1b, indicating that ephrin-A1b influences the cleavage process. Taken together, these findings indicate that this newly described isoform may regulate the function of its ephrin-A1a counterpart.
27
Cramer, Karina S., and Ilona J. Miko. "Eph-ephrin signaling in nervous system development." F1000Research 5 (March 30, 2016): 413. http://dx.doi.org/10.12688/f1000research.7417.1.
Full textAbstract:
Ephrins and Eph receptors enable contact-mediated interactions between cells at every stage of nervous system development. In spite of their broad binding affinities, Eph proteins facilitate specificity in neuronal migration and axon targeting. This review focuses on recent studies that demonstrate how these proteins interact with each other, and with other signaling pathways, to guide specificity in a diverse set of developmental processes.
28
Azab, Abdel Kareem, Feda Azab, Aldo M. Roccaro, Antonio Sacco, Phong Quang, Hai T. Ngo, Molly R. Melhem, Judith M. Runnels, Patricia Maiso, and Irene M. Ghobrial. "Eph-B2 Receptor Tyrosine Kinase Is Overexpressed in Waldenstrom's Macroglubulinemia and Plays a Major Role in Its Interaction with the Bone Marrow Microenvironment." Blood 114, no. 22 (November 20, 2009): 2935. http://dx.doi.org/10.1182/blood.v114.22.2935.2935.
Full textAbstract:
Abstract Abstract 2935 Poster Board II-911 INTRODUCTION: Waldenstrom's macroglobulinemia (WM) is a low-grade lymphoma characterized by the presence of lymphoplasmacytic lymphoma cells in the bone marrow (BM). The BM microenvironment was shown to promote growth and proliferation of WM cells. The Eph receptor family are receptor tyrosine kinases RTKs activated by ephrin which a cell-surface protein, and the interaction between the receptor on one cell and the ligand on other cells promotes the activity of the receptor. Eph receptors are known to control processes such as cell growth, proliferation, migration, and invasion, and their expression level was shown to be elevated in a wide range of solid tumors. However, their role in WM was never explored. METHODS AND RESULTS: Using phosphor-RTK array kit, we have screened the activity of 42 RTKs in CD19+ cells from 4 WM patients, WM cell line BCWM1, IgM secreting cell lines MEC1 and RL, and CD19+ cells from the BM of 4 healthy donors. We found that one of the most significant RTKs which showed high activation in all WM cells from patient sample and cells, compared to all normal cells was Eph-B2 receptor. We have used ephrin-B2, the ligand of the receptor Eph-B2, to test the signaling pathways involved in the activity of this receptor. We found, by immunoblotting, that ephrin-B2 induce phosphorylation of the receptor in a bell-curve manner, with the activity peaking in 100 ng/ml, while the expression of the total form of the receptor was unchanged over arrange of 0-1000 ng/ml of ephrin. A comparable activation was found for several cell-adhesion related proteins including FAK, SRC, paxillin, P130 and cofillin. These finding indicated a major role of the Eph-B2 receptor cell adhesion of WM cell. We have coated plates with increasing concentration of ephrin-B2 and tested the adhesion of BCWM1, MEC1 and RL to ephrin. Again, we found the adhesion peaked at the concentration of 100nM of ephrin. In contrast, ephrin-B2 had no chemotactic effect on WM cells. BM microenvironment components including BM stromal cells (BMSCs) and endothelial cells were shown to enhance the proliferation of WM cells detected by thymidine uptake assay. Ephrin-B2 was shown to be expressed on both endothelial cells and BMSCs. The inhibition of either the ephrin-B2 on endothelial cells and BMSCs, or inhibition of the Eph-B2 receptor on WM cell reduced the adhesion of WM cell to both endothelial cells and BMSCs and decreased the increase of WM cell proliferation induced by endothelial cells and BMSCs. The combination of both inhibition ephrin-B2 and Eph-B2 did not have an additive effect compared to each of them alone. Moreover, the inhibition of either ephrin-B2 or Eph-B2 reduced the activation of cell adhesion-related proteins. CONCLUSION: In conclusion, we showed that the Eph-B2/ephrin-B2 axis was activated in WM cells and that it is important for the adhesion and proliferation of WM cells induced by the BM microenvironment. These findings provide a novel therapeutic target for WM. Disclosures: Ghobrial: Millennium: Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau.
29
Guidetti, Lorenzo, Riccardo Castelli, Laura Scalvini, Francesca Ferlenghi, Miriam Corrado, Carmine Giorgio, Massimiliano Tognolini, and Alessio Lodola. "Protein-Protein Interaction Inhibitors Targeting the Eph-Ephrin System with a Focus on Amino Acid Conjugates of Bile Acids." Pharmaceuticals 15, no. 2 (January 24, 2022): 137. http://dx.doi.org/10.3390/ph15020137.
Full textAbstract:
The role of the Eph-ephrin system in the etiology of pathological conditions has been consolidated throughout the years. In this context, approaches directed against this signaling system, intended to modulate its activity, can be strategic therapeutic opportunities. Currently, the most promising class of compounds able to interfere with the Eph receptor-ephrin protein interaction is composed of synthetic derivatives of bile acids. In the present review, we summarize the progresses achieved, in terms of chemical expansions and structure-activity relationships, both in the steroidal core and the terminal carboxylic acid group, along with the pharmacological characterization for the most promising Eph-ephrin antagonists in in vivo settings.
30
Sahoo, Amita R., and Matthias Buck. "Structural and Functional Insights into the Transmembrane Domain Association of Eph Receptors." International Journal of Molecular Sciences 22, no. 16 (August 10, 2021): 8593. http://dx.doi.org/10.3390/ijms22168593.
Full textAbstract:
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.
31
Miao, Hui, Christian H. Nickel, Lloyd G. Cantley, Leslie A. Bruggeman, Laura N. Bennardo, and Bingcheng Wang. "EphA kinase activation regulates HGF-induced epithelial branching morphogenesis." Journal of Cell Biology 162, no. 7 (September 29, 2003): 1281–92. http://dx.doi.org/10.1083/jcb.200304018.
Full textAbstract:
Eph kinases and their ephrin ligands are widely expressed in epithelial cells in vitro and in vivo. Our results show that activation of endogenous EphA kinases in Madin-Darby canine kidney (MDCK) cells negatively regulates hepatocyte growth factor/scatter factor (HGF)–induced branching morphogenesis in collagen gel. Cotreatment with HGF and ephrin-A1 reduced sprouting of cell protrusions, an early step in branching morphogenesis. Moreover, addition of ephrin-A1 after HGF stimulation resulted in collapse and retraction of preexisting cell protrusions. In a newly developed assay that simulates the localized interactions between Ephs and ephrins in vivo, immobilized ephrin-A1 suppressed HGF-induced MDCK cell scattering. Ephrin-A1 inhibited basal ERK1/2 mitogen-activated protein kinase activity; however, the ephrin-A1 effect on cell protrusion was independent of the mitogen-activated protein kinase pathway. Ephrin-A1 suppressed HGF-induced activation of Rac1 and p21-activated kinase, whereas RhoA activation was retained, leading to the preservation of stress fibers. Moreover, dominant-negative RhoA or inhibitor of Rho-associated kinase (Y27632) substantially negated the inhibitory effects of ephrin-A1. These data suggest that interfering with c-Met signaling to Rho GTPases represents a major mechanism by which EphA kinase activation inhibits HGF-induced MDCK branching morphogenesis.
32
Aasheim, Hans-Christian, Else Munthe, Steinar Funderud, Erlend B. Smeland, Klaus Beiske, and Ton Logtenberg. "A splice variant of human ephrin-A4 encodes a soluble molecule that is secreted by activated human B lymphocytes." Blood 95, no. 1 (January 1, 2000): 221–30. http://dx.doi.org/10.1182/blood.v95.1.221.001k01_221_230.
Full textAbstract:
Ephrin-A4 is a ligand for the erythropoietin-producing hepatocellular (Eph) receptor family of tyrosine kinases. We have identified a secreted form of ephrin-A4, denoted ephrin-A4 (s), which is encoded by an alternatively spliced mRNA and is produced by in vivo activated B cells in tonsils. Blood B cells secrete ephrin-A4 (s) upon stimulation via the B-cell antigen receptor. A subpopulation of tonsil cells in the crypts with a dendritic cell phenotype was shown to express EphA2, an Eph receptor tyrosine kinase that was found to be capable of binding an ephrin-A4 immunoglobulin chimeric protein. We conclude that ephrin-A4 (s) may play a role in the interaction between activated B lymphocytes and dendritic cells in human tonsils. (Blood. 2000;95:221-230)
33
Aasheim, Hans-Christian, Else Munthe, Steinar Funderud, Erlend B. Smeland, Klaus Beiske, and Ton Logtenberg. "A splice variant of human ephrin-A4 encodes a soluble molecule that is secreted by activated human B lymphocytes." Blood 95, no. 1 (January 1, 2000): 221–30. http://dx.doi.org/10.1182/blood.v95.1.221.
Full textAbstract:
Abstract Ephrin-A4 is a ligand for the erythropoietin-producing hepatocellular (Eph) receptor family of tyrosine kinases. We have identified a secreted form of ephrin-A4, denoted ephrin-A4 (s), which is encoded by an alternatively spliced mRNA and is produced by in vivo activated B cells in tonsils. Blood B cells secrete ephrin-A4 (s) upon stimulation via the B-cell antigen receptor. A subpopulation of tonsil cells in the crypts with a dendritic cell phenotype was shown to express EphA2, an Eph receptor tyrosine kinase that was found to be capable of binding an ephrin-A4 immunoglobulin chimeric protein. We conclude that ephrin-A4 (s) may play a role in the interaction between activated B lymphocytes and dendritic cells in human tonsils. (Blood. 2000;95:221-230)
34
Mohd-Zin, Siti W., Nor-Linda Abdullah, Aminah Abdullah, Nicholas D. E. Greene, Pike-See Cheah, King-Hwa Ling, Hadri Yusof, et al. "Identification of the genomic mutation in Epha4rb-2J/rb-2J mice." Genome 59, no. 7 (July 2016): 439–48. http://dx.doi.org/10.1139/gen-2015-0142.
Full textAbstract:
The EphA4 receptor tyrosine kinase is involved in numerous cell-signalling activities during embryonic development. EphA4 has the ability to bind to both types of ephrin ligands, the ephrinAs and ephrinBs. The C57BL/6J-Epha4rb-2J/GrsrJ strain, denoted Epha4rb-2J/rb-2J, is a spontaneous mouse mutant that arose at The Jackson Laboratory. These mutants exhibited a synchronous hind limb locomotion defect or “hopping gait” phenotype, which is also characteristic of EphA4 null mice. Genetic complementation experiments suggested that Epha4rb-2J corresponds to an allele of EphA4, but details of the genomic defect in this mouse mutant are currently unavailable. We found a single base-pair deletion in exon 9 resulting in a frame shift mutation that subsequently resulted in a premature stop codon. Analysis of the predicted structure of the truncated protein suggests that both the kinase and sterile α motif (SAM) domains are absent. Definitive determination of genotype is needed for experimental studies of mice carrying the Epha4rb-2J allele, and we have also developed a method to ease detection of the mutation through RFLP. Eph-ephrin family members are reportedly expressed as numerous isoforms. Hence, delineation of the specific mutation in EphA4 in this strain is important for further functional studies, such as protein–protein interactions, immunostaining and gene compensatory studies, investigating the mechanism underlying the effects of altered function of Eph family of receptor tyrosine kinases on phenotype.
35
Kohara, Sho, and Kazushige Ogawa. "Eph/Ephrin Promotes the Adhesion of Liver Tissue-Resident Macrophages to a Mimicked Surface of Liver Sinusoidal Endothelial Cells." Biomedicines 10, no. 12 (December 12, 2022): 3234. http://dx.doi.org/10.3390/biomedicines10123234.
Full textAbstract:
Kupffer cells are maintained via self-renewal in specific microenvironmental niches, primarily the liver sinusoidal endothelial cells (LSECs). In this study, we propagated tissue-resident macrophages (Mø) from mouse liver using mixed culture with hepatic fibroblastic cells. Propagated liver Mø express Id3, Lxra and Spic transcription factors, which are required for Kupffer cell characterization. Thus, Kupffer cell properties are likely to be maintained in liver Mø propagated using mixed culture with fibroblastic cells. We revealed (i) gene expression of certain Eph receptors and ephrin ligands including EphA2, ephrin-A1, EphB4, and ephrin-B1 in propagated liver Mø and primary LSECs, (ii) immunohistochemical localization of these Eph/ephrin member molecules indicating common expression in Kupffer cells and LSECs, and (iii) surface expression of several integrin α and β subunits, including α4β1, αLβ2, αMβ2, and αXβ2 integrin in propagated liver Mø and that of the corresponding ligands ICAM-1 and VCAM-1 in primary LSECs. Moreover, EphA/ephrin-A and EphB/ephrin-B interactions promoted liver Mø adhesion to the ICAM-1-adsorbed surface, which mimicked that of LSECs and may be implicated in the residence of Kupffer cells in the liver sinusoid. Further studies on regulating the residence and regeneration of Kupffer cells in related hepatic disorders are required to validate our findings.
36
Takahashi, Takamune, Keiko Takahashi, Sebastian Gerety, Hai Wang, David J. Anderson, and Thomas O. Daniel. "Temporally Compartmentalized Expression of Ephrin-B2 during Renal Glomerular Development." Journal of the American Society of Nephrology 12, no. 12 (December 2001): 2673–82. http://dx.doi.org/10.1681/asn.v12122673.
Full textAbstract:
ABSTRACT. Glomerular development proceeds through the spatially ordered and sequential recruitment, proliferation, assembly, and differentiation of endothelial, mesangial, and epithelial progenitors. The molecular determinants of cell-cell recognition and targeting in this process have yet to be defined. The Eph/ephrin family of membrane receptors and counter-receptors are critical participants of developmental vascular assembly in extrarenal sites. Renal expression patterns of ephrin-B2 and EphB4 were investigated using mice expressing β-galactosidase under control of ephrin-B2 or EphB4 promoters. The earliest glomerular expression of ephrin-B2 was identified in a subset of differentiating comma-stage glomerular epithelial cells (podocyte progenitors) adjacent to the vascular cleft where endothelial progenitors are subsequently recruited. Epithelial ephrin-B2 expression was accompanied by expression in endothelial and mesangial cells as capillary assembly progressed. At or near completion of glomerular maturation, epithelial ephrin-B2 expression was extinguished, with persistence in glomerular endothelial cells. Throughout development, one of several ephrin-B2 receptors, EphB4, was persistently and exclusively expressed in endothelial cells of venous structures. The findings show sequential ephrin-B2 expression across glomerular lineages, first in a distinct subset of podocyte progenitors and subsequently in endothelial cells of the developing glomerulus. Given targeting functions for Eph/ephrin family proteins, the findings suggest that ephrin-B2 expression marks podocyte progenitors at the site of vascular cleft formation, where expression may establish an “address” to which endothelial and mesangial progenitors are recruited. Thus, the present results suggest that ephrin-B2 and EphB interactions play an important role in glomerular microvascular assembly.
37
Azab, Feda, Abdel Kareem A. Azab, Patricia Maiso, Phong Quang, Aldo M. Roccaro, Antonio Sacco, Hai T. Ngo, et al. "Eph-B2/Ephrin-B2 Interaction Plays a Major Role In the Adhesion and Survival of WM Cells In the Context of the Bone Marrow Microenvironment." Blood 116, no. 21 (November 19, 2010): 142. http://dx.doi.org/10.1182/blood.v116.21.142.142.
Full textAbstract:
Abstract Abstract 142 Introduction: Receptor tyrosine kinases (RTKs) are key regulators of the development and progression of many types of cancer. The Eph receptors represent the largest family of RTKs, which are used extensively throughout embryogenesis and development but detected in adult normal tissues. Elevated levels of expression of Eph receptors was found in a wide range of cancers and correlated with aggressive disease and metastasis. This is, triggered by a wide array of cellular responses, including cell boundary formation, motility, adhesion, and repulsion. Waldenstrom macroglobulinemia (WM) is characterized by widespread involvement of the bone marrow, indicating homing and adhesion of the malignant cells to specific niches in the bone marrow, which provides a protective environment for the survival and proliferation of these cells. Direct adhesion to endothelial cells and several growth factors and cytokines secreted by endothelial cells in the BM were shown to regulate tumor proliferation. In this study we aimed to characterize the role of RTKs, specifically Eph-B2 receptor, in the interaction of WM cells with the BM microenvironment including cell adhesion, proliferation, and cell-cycle. Methods and Results: We first examined the expression and activation (phosphorylation) of different RTKs in primary WM samples and cell lines using an antibody-based RTK-array. Eph-B2 receptor was activated in all patient samples compared to control, with a 5-fold increase in CD19+ WM cells, and we further confirmed that Eph-B2 was phosphorylated in WM cell lines, BCWM.1, and in IgM secreting cell lines RL, MEC-1. We next examined the activity of Ephrin-B2/Eph-B2 on adhesion and migration of WM cells. Treating starved WM cells with recombinant ephrin-B2 (the ligand of Eph-B2) activated cell-adhesion signaling, including focal adhesion kinase (FAK), Src, p130, paxilin and cofilin, but had no effect on WM cell chemotaxis. Moreover, we found that ephrin-B2 was highly expressed on endothelial cells isolated from the BM of WM patients and on HUVEC cells. Inhibition of ephrin-B2 on the endothelial cells or Eph-B2 on the WM cells with blocking antibodies inhibited the adhesion of the WM cells to endothelial cells, as well as the cytoskeletal signaling in WM cells induced by co-culture with endothelial cells. Consequently, inhibition of the ephrin-B2/Eph-B2 interaction reversed the proliferative and cell cycle effect in WM cell which was induced by co-culture with endothelial cells. This was confirmed using BrdU proliferation assay, flow cytometry for cell cycle, and by immuno-blotting to confirm the effect on proliferative signaling pathways including PI3K kinase and cell cycle related proteins including Cyclin-D, Cyclin-E and p-Rb. Conclusion: This study examines the interaction of Eph-B2 receptor in WM and shows that ephrin- B2/Eph-B2 axis regulates adhesion, activation of downstream signaling of integrin-related molecules, survival and cell cycle progression through the interaction of tumor cells with endothelial cells. This provides the basis for further studies to explore Eph-B2 as a novel therapeutic target in WM. Disclosures: Ghobrial: Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.
38
Stark, Danny A., Nathan J. Coffey, Hannah R. Pancoast, Laura L. Arnold, J. Peyton D. Walker, Joanne Vallée, Richard Robitaille, Michael L. Garcia, and DDW Cornelison. "Ephrin-A3 promotes and maintains slow muscle fiber identity during postnatal development and reinnervation." Journal of Cell Biology 211, no. 5 (December 7, 2015): 1077–91. http://dx.doi.org/10.1083/jcb.201502036.
Full textAbstract:
Each adult mammalian skeletal muscle has a unique complement of fast and slow myofibers, reflecting patterns established during development and reinforced via their innervation by fast and slow motor neurons. Existing data support a model of postnatal "matching" whereby predetermined myofiber type identity promotes pruning of inappropriate motor axons, but no molecular mechanism has yet been identified. We present evidence that fiber type–specific repulsive interactions inhibit innervation of slow myofibers by fast motor axons during both postnatal maturation of the neuromuscular junction and myofiber reinnervation after injury. The repulsive guidance ligand ephrin-A3 is expressed only on slow myofibers, whereas its candidate receptor, EphA8, localizes exclusively to fast motor endplates. Adult mice lacking ephrin-A3 have dramatically fewer slow myofibers in fast and mixed muscles, and misexpression of ephrin-A3 on fast myofibers followed by denervation/reinnervation promotes their respecification to a slow phenotype. We therefore conclude that Eph/ephrin interactions guide the fiber type specificity of neuromuscular interactions during development and adult life.
39
Imondi, R., C. Wideman, and Z. Kaprielian. "Complementary expression of transmembrane ephrins and their receptors in the mouse spinal cord: a possible role in constraining the orientation of longitudinally projecting axons." Development 127, no. 7 (April 1, 2000): 1397–410. http://dx.doi.org/10.1242/dev.127.7.1397.
Full textAbstract:
In the developing spinal cord, axons project in both the transverse plane, perpendicular to the floor plate, and in the longitudinal plane, parallel to the floor plate. For many axons, the floor plate is a source of long- and short-range guidance cues that govern growth along both dimensions. We show here that B-class transmembrane ephrins and their receptors are reciprocally expressed on floor plate cells and longitudinally projecting axons in the mouse spinal cord. During the period of commissural axon pathfinding, B-class ephrin protein is expressed at the lateral floor plate boundaries, at the interface between the floor plate and the ventral funiculus. In contrast, B-class Eph receptors are expressed on decussated commissural axon segments projecting within the ventral funiculus, and on ipsilaterally projecting axons constituting the lateral funiculus. Soluble forms of all three B-class ephrins bind to, and induce the collapse of, commissural growth cones in vitro. The collapse-inducing activity associated with B-class ephrins is likely to be mediated by EphB1. Taken together, these data support a possible role for repulsive B-class Eph receptor/ligand interactions in constraining the orientation of longitudinal axon projections at the ventral midline.
40
Swartz, Mary E., Johann Eberhart, Elena B. Pasquale, and Catherine E. Krull. "EphA4/ephrin-A5 interactions in muscle precursor cell migration in the avian forelimb." Development 128, no. 23 (December 1, 2001): 4669–80. http://dx.doi.org/10.1242/dev.128.23.4669.
Full textAbstract:
Limb muscles derive from muscle precursor cells that lie initially in the lateral portion of the somitic dermomyotome and subsequently migrate to their target limb regions, where muscle-specific gene transcription is initiated. Although several molecules that control the generation and delamination of muscle precursor cells have been identified, little is known about the mechanisms that guide muscle precursor cell migration in the limb. We have examined the distribution of members of the Eph family during muscle precursor cell development. The EphA4 receptor tyrosine kinase and its ligand, ephrin-A5, are expressed by muscle precursor cells and forelimb mesoderm in unique spatiotemporal patterns during the period when muscle precursors delaminate from the dermomyotome and migrate into the limb. To test the function of EphA4/ephrin-A5 interactions in muscle precursor migration, we used targeted in ovo electroporation to express ephrin-A5 ectopically specifically in the presumptive limb mesoderm. In the presence of ectopic ephrin-A5, Pax7-positive muscle precursor cells are significantly reduced in number in the proximal limb, compared with controls, and congregate abnormally near the lateral dermomyotome. In stripe assays, isolated muscle precursor cells avoid substrate-bound ephrin-A5 and this avoidance is abolished by addition of soluble ephrin-A5. These data suggest that ephrin-A5 normally restricts migrating, EphA4-positive muscle precursor cells to their appropriate territories in the forelimb, disallowing entry into abnormal embryonic regions.
41
Kakarla, Mamatha, Sathyavathi ChallaSivaKanaka, Mary F. Dufficy, Victoria Gil, Yana Filipovich, Renee Vickman, Susan E. Crawford, Simon W. Hayward, and Omar E. Franco. "Ephrin B Activate Src Family Kinases in Fibroblasts Inducing Stromal Remodeling in Prostate Cancer." Cancers 14, no. 9 (May 9, 2022): 2336. http://dx.doi.org/10.3390/cancers14092336.
Full textAbstract:
Through stromal-epithelial interactions, carcinoma associated fibroblasts (CAF) play a critical role in tumor growth and progression. Activation of erythrophoyetin-producing human hepatocellular (Eph) receptors has been implicated in cancer. Eph receptor interactions with Ephrin ligands lead to bidirectional signals in the recipient and effector cells. The consequences of continuous reverse Ephrin signaling activation in fibroblasts on prostate cancer (PCa) is unknown. When compared to benign prostate fibroblast, CAF displayed higher expression of Ephrin B1, B2, and B3 ligands (EFNB1, EFNB2, and EFNB3). In this study, we found that continuous activation of EFNB1 and EFNB3 in a benign human prostate stromal cell line (BHPrS1) increased the expression of CAF markers and induced a CAF phenotype. BHPrS1EFNB1 and BHPrS1EFNB3 displayed a pro-tumorigenic secretome with multiple effects on neovascularization, collagen deposition, and cancer cell proliferation, overall increasing tumorigenicity of a premalignant prostate epithelial cell line BPH1 and PCa cell line LNCaP, both in vitro and in vivo. Inhibition of Src family kinases (SFK) in BHPrS1EFNB1 and BHPrS1EFNB3 suppressed EFNB-induced ɑ-SMA (Alpha-smooth muscle actin) and TN-C (Tenascin-C) in vitro. Our study suggests that acquisition of CAF characteristics via SFK activation in response to increased EFNB ligands could promote carcinogenesis via modulation of TME in PCa.
42
Ivanov, Andrei, and Andrej Romanovsky. "Putative dual role of ephrin-Eph receptor interactions in inflammation." IUBMB Life (International Union of Biochemistry and Molecular Biology: Life) 58, no. 7 (July 1, 2006): 389–94. http://dx.doi.org/10.1080/15216540600756004.
Full text
43
Stark, D. A., R. M. Karvas, A. L. Siegel, and D. D. W. Cornelison. "Eph/ephrin interactions modulate muscle satellite cell motility and patterning." Development 138, no. 24 (November 9, 2011): 5279–89. http://dx.doi.org/10.1242/dev.068411.
Full text
44
Nguyen, Thao M., Agnieszka Arthur, and Stan Gronthos. "The role of Eph/ephrin molecules in stromal–hematopoietic interactions." International Journal of Hematology 103, no. 2 (October 16, 2015): 145–54. http://dx.doi.org/10.1007/s12185-015-1886-x.
Full text
45
Zhou, Xuan, Liu Xiaoli, Na Xu, Yajuan Xiao, Jinfang Zhang, Bintao Huang, and Qingfeng Du. "Activation Of EphrinB2/EphB4 Influences Myeloid Leukemia Cell Migration and Invasion." Blood 122, no. 21 (November 15, 2013): 1360. http://dx.doi.org/10.1182/blood.v122.21.1360.1360.
Full textAbstract:
Abstract Eph receptors and ephrin ligands are cell-surface molecules capable of bidirectional signaling that control cell-cell interactions, migration and invasion. However, their role and regulation in myeloid leukemia cells remain to be defined. To address the hypothesis that Ephrin/EphB is an important regulator of myeloid leukemia cell migration and invasion, we first screened the mRNA levels of 23 eph and ligand ephrin RTK family members in myeloid leukemia cells (K562, HL-60, THP-1) and mononuclear cells from healthy donors, then found that EphB4, EphA5, EfnA1 highly expressed in most myeloid leukemia cells compared to healthy donors(P<0.05). Both the mRNA and protein levels of EphB4 and EphA5 were detected in 13 primary myeloid leukemia cells (5 from patients with extramedullary leukemia among 13 cases) and 10 mononuclear cells from healthy donors by real-time RT-PCR and Immunoblot analysis. The results showed that both the mRNA and protein levels of EphB4 and EphA5 were higher in 13 primary myeloid leukemia cells relative to the 10 healthy donors (P=0.046). Moreover, the EphB4 were highly expressed in 5 patients with extramedullary leukemia compared with 8 patients without extramedullary leukemia. These findings indicated that EphB4 and EphA5 expression were correlated with the development of myeloid leukemia cells, moreover, EphB4 may be closely related with myeloid leukemia cell migration or invasion. To further clarified the question, migration were determined in leukemia cell lines (K562 cells) which were treated with clustered ephrinA1–Fc proteins, ephrinB2–Fc proteins and Fc proteins by transwell migration assay. Invasion were also determined by matrigel invasion assay. The results showed that, after ephrinB2–Fc stimulation, the numbers of K562 cells migrating through transwell chamber were significantly enhanced compared to Fc proteins stimulation (1.8 to 2.5-fold, P<0.05), meanwhile, the numbers of K562 cells invading the matrigel also enhanced (1.2 to 1.8-fold, P<0.05). However, after ephrinA1–Fc stimulation, the numbers of K562 cells migrating through transwell chamber didn’t significantly increase compared to Fc proteins stimulation (P>0.05), and the numbers of K562 cells invading the matrigel also didn’t enhanced (P>0.05). These findings indicated that ephrinB2–Fc could activate EphB4, leading to the change of myeloid leukemia cell migration and invasion. Further study may help to assess a promising potential of this protein to be used as a prognostic marker or as a target for a molecular therapy. Disclosures: No relevant conflicts of interest to declare.
46
Harrington, Robert J., Michael J. Gutch, Michael O. Hengartner, Nicholas K. Tonks, and Andrew D. Chisholm. "TheC. elegansLAR-like receptor tyrosine phosphatase PTP-3 and the VAB-1 Eph receptor tyrosine kinase have partly redundant functions in morphogenesis." Development 129, no. 9 (May 1, 2002): 2141–53. http://dx.doi.org/10.1242/dev.129.9.2141.
Full textAbstract:
Receptor-like protein-tyrosine phosphatases (RPTPs) form a diverse family of cell surface molecules whose functions remain poorly understood. The LAR subfamily of RPTPs has been implicated in axon guidance and neural development. Here we report the molecular and genetic analysis of the C. elegans LAR subfamily member PTP-3. PTP-3 isoforms are expressed in many tissues in early embryogenesis, and later become localized to neuronal processes and to epithelial adherens junctions. Loss of function in ptp-3 causes low-penetrance defects in gastrulation and epidermal development similar to those of VAB-1 Eph receptor tyrosine kinase mutants. Loss of function in ptp-3 synergistically enhances phenotypes of mutations in the C. elegans Eph receptor VAB-1 and a subset of its ephrin ligands, but does not show specific interactions with several other RTKs or morphogenetic mutants. The genetic interaction of vab-1 and ptp-3 suggests that LAR-like RPTPs and Eph receptors have related and partly redundant functions in C. elegans morphogenesis.
47
Lindsey, Richard C., Charles H. Rundle, and Subburaman Mohan. "40 YEARS OF IGF1: Role of IGF1 and EFN–EPH signaling in skeletal metabolism." Journal of Molecular Endocrinology 61, no. 1 (July 2018): T87—T102. http://dx.doi.org/10.1530/jme-17-0284.
Full textAbstract:
Insulin-like growth factor 1(IGF1) and ephrin ligand (EFN)–receptor (EPH) signaling are both crucial for bone cell function and skeletal development and maintenance. IGF1 signaling is the major mediator of growth hormone-induced bone growth, but a host of different signals and factors regulate IGF1 signaling at the systemic and local levels. Disruption of the Igf1 gene results in reduced peak bone mass in both experimental animal models and humans. Additionally, EFN–EPH signaling is a complex system which, particularly through cell–cell interactions, contributes to the development and differentiation of many bone cell types. Recent evidence has demonstrated several ways in which the IGF1 and EFN–EPH signaling pathways interact with and depend upon each other to regulate bone cell function. While much remains to be elucidated, the interaction between these two signaling pathways opens a vast array of new opportunities for investigation into the mechanisms of and potential therapies for skeletal conditions such as osteoporosis and fracture repair.
48
Slape, Christopher I. "EphA3 Is Expressed on Leukemia Stem Cells, and Eph/Ephrin Signalling Features in the Remodelling of the Leukemia Stem Cell Niche." Blood 124, no. 21 (December 6, 2014): 4783. http://dx.doi.org/10.1182/blood.v124.21.4783.4783.
Full textAbstract:
Abstract EphA3 is a member of the Eph receptor tyrosine kinase family, the largest such family in the human genome. The bi-directional signalling of Eph receptors and their ligands (the ephrins) is responsible for correct migration and positioning of cells during development, as well as adult processes such as angiogenesis and neurogenesis. EphA3 was first discovered as a receptor expressed on the surface of LK63, a B-cell leukemia cell line. It is not expressed on normal human hematopoietic cells, but expression has been noted on the cell surface of leukemic blasts from a high percentage of patients with hematopoietic neoplasia of all lineages. It is particularly commonly expressed in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), where it is present in approximately 50% of patients. A therapeutic antibody against EphA3 has been developed and is in Phase II clinical trials for MDS and AML. Consistent with data from human MDS patients, the NUP98-HOXD13 (NHD13) mouse model of MDS spontaneously expresses EphA3 on a percentage of cells from all populations throughout the hematopoietic compartment. The proportion of positive cells varies from mouse to mouse, but the proportion positively correlates with disease severity, indicating a possible causative relationship. Studies crossing the NHD13 transgene onto an EphA3 knockout background are ongoing and will definitively answer this question. Recent studies have demonstrated the alteration (or “remodelling”) of the hematopoietic stem cell (HSC) micro-environment (or “niche”) by malignant hematopoietic cells, and the role that this plays in maintaining the leukemia stem cell (LSC) population. This self-reinforcing niche remodelling is critical to the maintenance of hematopoietic disease, particularly during a course of chemotherapy. These niche changes have also been shown to be sufficient to drive malignancy, and are therefore an attractive target for the design of disruptive therapeutics. EphA3 and other Eph/ephrin family members are expressed on normal mesenchymal stem/stromal cells (MSCs) and other stromal component cells of the HSC niche. EfnA5 (EphrinA5) is the high-affinity ligand for EphA3, and we observed an increased expression of EfnA5 on stromal cells in the NHD13 mice, indicating that the EphA3-EfnA5 interaction in these mice may facilitate LSC maintenance in the LSC niche. More broadly, it appears that Eph/Ephrin signalling may be a component of the remodelling of the niche to favour LSCs over normal HSCs. Possible indirect means by which this remodelling may occur include production of the cytokines CCL3 (decreased in NHD13 mice) or CXCL12 (variably decreased in NHD13 mice, and its receptor CXCR4 is increased on the cell surface of NHD13 HSCs). Imaging studies confirm preferential homing of EphA3-positive LSCs to niche locations, including co-localisation with CXCL12. It is therefore likely that the remodelled stem cell niche maintains stemness and leukemogenicity of the LSCs via interaction of the Eph/ephrin family members abnormally expressed on the LSCs and stromal cells, respectively. Disclosures No relevant conflicts of interest to declare.
49
Wang, Jia, Xiang Zheng, Qiu Peng, Xuemei Zhang, and Zailong Qin. "Eph receptors: the bridge linking host and virus." Cellular and Molecular Life Sciences 77, no. 12 (December 31, 2019): 2355–65. http://dx.doi.org/10.1007/s00018-019-03409-6.
Full textAbstract:
AbstractEph (erythropoietin-producing hepatoma) receptors and Ephrin ligands constitute the largest subfamily of receptor tyrosine kinase (RTK), which were first discovered in tumors. Heretofore, Eph protein has been shown to be involved in various tumor biological behaviors including proliferation and progression. The occurrence of specific types of tumor is closely related to the virus infection. Virus entry is a complex process characterized by a series of events. The entry into target cells is an essential step for virus to cause diseases, which requires the fusion of the viral envelope and host cellular membrane mediated by viral glycoproteins and cellular receptors. Integrin molecules are well known as entry receptors for most herpes viruses. However, in recent years, Eph receptors and their Ephrin ligands have been reported to be involved in virus infections. The main mechanism may be the interaction between Eph receptors and conserved viral surface glycoprotein, such as the gH/gL or gB protein of the herpesviridae. This review focuses on the relationship between Eph receptor family and virus infection that summarize the processes of viruses such as EBV, KSHV, HCV, RRV, etc., infecting target cells through Eph receptors and activating its downstream signaling pathways resulting in malignancies. Finally, we discussed the perspectives to block virus infection, prevention, and treatment of viral-related tumors via Eph receptor family.
50
Baldwin, Cindy, Zhongchuan Will Chen, Arda Bedirian, Naoko Yokota, Samih H. Nasr, Hamid Rabb, and Serge Lemay. "Upregulation of EphA2 during in vivo and in vitro renal ischemia-reperfusion injury: role of Src kinases." American Journal of Physiology-Renal Physiology 291, no. 5 (November 2006): F960—F971. http://dx.doi.org/10.1152/ajprenal.00020.2006.
Full textAbstract:
Ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury in both native kidneys and renal allografts. Disruption of the actin cytoskeleton is a key event with multiple repercussions on cell adhesion and function during IRI. However, receptors involved in regulating cytoskeletal repair following injury have not been identified. In an in vivo model of renal IRI, we used multiprobe RNase protection assay to examine the expression of Eph receptor tyrosine kinases, key regulators of actin dynamics in embryonic development. We found that one receptor in particular, EphA2, was strongly upregulated in the kidney following IRI. Ephrins, the cell-bound ligands of Eph receptors, were also strongly expressed. In cultured renal tubular cells, diverse injurious stimuli mimicking IRI also resulted in upregulation of EphA2 protein expression. Upregulation of EphA2 was inhibited by the Src kinase inhibitor PP2. Conversely, overexpression of Src kinases strongly enhanced the expression of endogenous EphA2 as well as the activity of a human EphA2 promoter construct. Activation of the Erk pathway was necessary, but not sufficient for full induction of EphA2 upreglation by Src kinases. Stimulation of renal tubular epithelial cells with the EphA2 ligand ephrin-A1 caused tyrosine phosphorylation of endogenous EphA2, paxillin, and an unidentified ∼65-kDa protein and resulted in increased cortical F-actin staining. In summary, under in vitro conditions mimicking IRI, EphA2 expression is strongly upregulated through a Src kinase-dependent pathway. Interactions between upregulated EphA2 and its ephrin ligands may provide critical cell contact-dependent, bidirectional cues for cytoskeletal repair in renal IRI.