scholarly journals Structural and Functional Insights into the Transmembrane Domain Association of Eph Receptors

2021 ◽  
Vol 22 (16) ◽  
pp. 8593
Author(s):  
Amita R. Sahoo ◽  
Matthias Buck
Keyword(s):  
Tyrosine Kinases ◽  
Transmembrane Domain ◽  
Eph Receptors ◽  
Adult Tissue ◽  
Eph Receptor ◽  
Transmembrane Peptides ◽  
Future Studies ◽  
Functional Aspects ◽  
Ephrin Ligands ◽  
Dynamics Simulations

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.

scholarly journals Differential Expression Patterns of Eph Receptors and Ephrin Ligands in Human Cancers

2018 ◽  
Vol 2018 ◽  
pp. 1-23 ◽  
Author(s):  
Chung-Ting Jimmy Kou ◽  
Raj P. Kandpal
Keyword(s):  
Differential Expression ◽  
Tyrosine Kinases ◽  
Neuronal Development ◽  
Transmembrane Domain ◽  
Tissue Injury ◽  
Expression Patterns ◽  
Cancer Therapeutics ◽  
Eph Receptors ◽  
Human Cancers ◽  
Ephrin Ligands

Eph receptors constitute the largest family of receptor tyrosine kinases, which are activated by ephrin ligands that either are anchored to the membrane or contain a transmembrane domain. These molecules play important roles in the development of multicellular organisms, and the physiological functions of these receptor-ligand pairs have been extensively documented in axon guidance, neuronal development, vascular patterning, and inflammation during tissue injury. The recognition that aberrant regulation and expression of these molecules lead to alterations in proliferative, migratory, and invasive potential of a variety of human cancers has made them potential targets for cancer therapeutics. We present here the involvement of Eph receptors and ephrin ligands in lung carcinoma, breast carcinoma, prostate carcinoma, colorectal carcinoma, glioblastoma, and medulloblastoma. The aberrations in their abundances are described in the context of multiple signaling pathways, and differential expression is suggested as the mechanism underlying tumorigenesis.

scholarly journals The Shb scaffold binds the Nck adaptor protein, p120 RasGAP, and Chimaerins and thereby facilitates heterotypic cell segregation by the receptor EphB2

2020 ◽  
Vol 295 (12) ◽  
pp. 3932-3944 ◽  
Author(s):  
Melany J. Wagner ◽  
Marilyn S. Hsiung ◽  
Gerald D. Gish ◽  
Rick D. Bagshaw ◽  
Sasha A. Doodnauth ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Cell Movement ◽  
Adaptor Protein ◽  
Receptor Activation ◽  
Sh2 Domain ◽  
Tumor Formation ◽  
Eph Receptors ◽  
Eph Receptor ◽  
Varied Composition ◽  
Cell Segregation

Eph receptors are a family of receptor tyrosine kinases that control directional cell movement during various biological processes, including embryogenesis, neuronal pathfinding, and tumor formation. The biochemical pathways of Eph receptors are context-dependent in part because of the varied composition of a heterotypic, oligomeric, active Eph receptor complex. Downstream of the Eph receptors, little is known about the essential phosphorylation events that define the context and instruct cell movement. Here, we define a pathway that is required for Eph receptor B2 (EphB2)–mediated cell sorting and is conserved among multiple Eph receptors. Utilizing a HEK293 model of EphB2+/ephrinB1+ cell segregation, we found that the scaffold adaptor protein SH2 domain–containing adaptor protein B (Shb) is essential for EphB2 functionality. Further characterization revealed that Shb interacts with known modulators of cytoskeletal rearrangement and cell mobility, including Nck adaptor protein (Nck), p120-Ras GTPase-activating protein (RasGAP), and the α- and β-Chimaerin Rac GAPs. We noted that phosphorylation of Tyr297, Tyr246, and Tyr336 of Shb is required for EphB2–ephrinB1 boundary formation, as well as binding of Nck, RasGAP, and the chimaerins, respectively. Similar complexes were formed in the context of EphA4, EphA8, EphB2, and EphB4 receptor activation. These results indicate that phosphotyrosine-mediated signaling through Shb is essential in EphB2-mediated heterotypic cell segregation and suggest a conserved function for Shb downstream of multiple Eph receptors.

scholarly journals EphB2 and EphB4 receptors forward signaling promotes SDF-1–induced endothelial cell chemotaxis and branching remodeling

Blood ◽  
2006 ◽  
Vol 108 (9) ◽  
pp. 2914-2922 ◽  
Author(s):  
Ombretta Salvucci ◽  
Maria de la Luz Sierra ◽  
Jose A. Martina ◽  
Peter J. McCormick ◽  
Giovanna Tosato
Keyword(s):  
Extracellular Matrix ◽  
Endothelial Cell ◽  
Tyrosine Kinases ◽  
Molecular Mechanisms ◽  
Cell Movement ◽  
Cell Contact ◽  
Eph Receptor ◽  
Cell Clustering ◽  
Chemokine Ligand ◽  
Ephrin Ligands

Abstract The complex molecular mechanisms that drive endothelial cell movement and the formation of new vessels are poorly understood and require further investigation. Eph receptor tyrosine kinases and their membrane-anchored ephrin ligands regulate cell movements mostly by cell–cell contact, whereas the G-protein–coupled receptor CXCR4 and its unique SDF-1 chemokine ligand regulate cell movement mostly through soluble gradients. By using biochemical and functional approaches, we investigated how ephrinB and SDF-1 orchestrate endothelial cell movement and morphogenesis into capillary-like structures. We describe how endogenous EphB2 and EphB4 signaling are required for the formation of extracellular matrix–dependent capillary-like structures in primary human endothelial cells. We further demonstrate that EphB2 and EphB4 activation enhance SDF-1–induced signaling and chemotaxis that are also required for extracellular matrix–dependent endothelial cell clustering. These results support a model in which SDF-1 gradients first promote endothelial cell clustering and then EphB2 and EphB4 critically contribute to subsequent cell movement and alignment into cord-like structures. This study reveals a requirement for endogenous Eph signaling in endothelial cell morphogenic processes, uncovers a novel link between EphB forward signaling and SDF-1–induced signaling, and demonstrates a mechanism for cooperative regulation of endothelial cell movement.

scholarly journals Eph receptor function is modulated by heterooligomerization of A and B type Eph receptors

2011 ◽  
Vol 195 (6) ◽  
pp. 1033-1045 ◽  
Author(s):  
Peter W. Janes ◽  
Bettina Griesshaber ◽  
Lakmali Atapattu ◽  
Eva Nievergall ◽  
Linda L. Hii ◽  
...  
Keyword(s):  
Cellular Responses ◽  
Eph Receptors ◽  
Wild Type ◽  
Eph Receptor ◽  
Receptor Complexes ◽  
Ephb Receptor ◽  
Receptor Profile ◽  
Ephrin Ligands ◽  
The Individual ◽  
Cross Inhibition

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.

scholarly journals Aberrant DNA methylation and epigenetic inactivation of Eph receptor tyrosine kinases and ephrin ligands in acute lymphoblastic leukemia

Blood ◽  
2010 ◽  
Vol 115 (12) ◽  
pp. 2412-2419 ◽  
Author(s):  
Shao-Qing Kuang ◽  
Hao Bai ◽  
Zhi-Hong Fang ◽  
Gonzalo Lopez ◽  
Hui Yang ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Acute Lymphoblastic Leukemia ◽  
Cpg Island ◽  
Lymphoblastic Leukemia ◽  
Methylation Status ◽  
Eph Receptors ◽  
Raji Cells ◽  
Eph Receptor ◽  
Phosphorylated Akt ◽  
Ephrin Ligands

Eph receptors and their ephrin ligands are involved in normal hematopoietic development and tumorigenesis. Using methylated CpG island amplification/DNA promoter microarray, we identified several EPH receptor and EPHRIN genes as potential hypermethylation targets in acute lymphoblastic leukemia (ALL). We subsequently studied the DNA methylation status of the Eph/ephrin family by bisulfite pyrosequencing. Hypermethylation of EPHA2, -A4, -A5, -A6, -A7, -A10, EPHB1, -B2, -B3, -B4, EFNA1, -A3, -A5, and EFNB1 and -B2 genes was detected in leukemia cell lines and primary ALL bone marrow samples. Expression analysis of EPHB4, EFNB2, and EFNA5 genes demonstrated that DNA methylation was associated with gene silencing. We cloned the promoter region of EPHB4 and demonstrated that promoter hypermethylation can result in EPHB4 transcriptional silencing. Restoration of EPHB4 expression by lentiviral transduction resulted in reduced proliferation and apoptotic cell death in Raji cells in which EPHB4 is methylated and silenced. Finally, we demonstrated that phosphorylated Akt is down-regulated in Raji cells transduced with EPHB4. These results suggest that epigenetic silencing by hypermethylation of EPH/EPHRIN family genes contributes to ALL pathogenesis and that EPHB4 can function as a tumor suppressor in ALL.

Dancing with the dead: Eph receptors and their kinase-null partnersThis paper is one of a selection of papers published in a Special Issue entitled CSBMCB 53rd Annual Meeting — Membrane Proteins in Health and Disease, and has undergone the Journal’s usual peer review process.

2011 ◽  
Vol 89 (2) ◽  
pp. 115-129 ◽  
Author(s):  
Luke Truitt ◽  
Andrew Freywald
Keyword(s):  
Membrane Proteins ◽  
Tyrosine Kinases ◽  
Molecular Mechanisms ◽  
Receptor Tyrosine Kinases ◽  
Peer Review Process ◽  
Eph Receptors ◽  
Eph Receptor ◽  
Biological Responses ◽  
Wide Range ◽  
Multicellular Organisms

Eph receptor tyrosine kinases and their ligands, ephrins, are membrane proteins coordinating a wide range of biological functions both in developing embryos and in adult multicellular organisms. Numerous studies have implicated Eph receptors in the induction of opposing responses, including cell adhesion or repulsion, support or inhibition of cell proliferation and cell migration, and progression or suppression of multiple malignancies. Similar to other receptor tyrosine kinases, Eph receptors rely on their ability to catalyze tyrosine phosphorylation for signal transduction. Interestingly, however, Eph receptors also actively utilize three kinase-deficient receptor tyrosine kinases, EphB6, EphA10, and Ryk, in their signaling network. The accumulating evidence suggests that the unusual flexibility of the Eph family, allowing it to initiate antagonistic responses, might be partially explained by the influence of the kinase-dead participants and that the exact outcome of an Eph-mediated action is likely to be defined by the balance between the signaling of catalytically potent and catalytically null receptors. We discuss in this minireview the emerging functions of the kinase-dead EphB6, EphA10, and Ryk receptors both in normal biological responses and in malignancy, and analyze currently available information related to the molecular mechanisms of their action in the context of the Eph family.

Eph receptors and ephrins: effectors of morphogenesis

Development ◽  
1999 ◽  
Vol 126 (10) ◽  
pp. 2033-2044 ◽  
Author(s):  
N. Holder ◽  
R. Klein
Keyword(s):  
Cell Migration ◽  
Pattern Formation ◽  
Axon Guidance ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Eph Receptors ◽  
Structural Domains ◽  
Eph Receptor

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.

Eph Receptor Tyrosine Kinases and Ephrin Ligands Are Epigenetically Inactivated in Acute Lymphoblastic Leukemia and Are Potential New Tumor Suppressor Genes in Human Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2128-2128 ◽  
Author(s):  
Shao-qing Kuang ◽  
Zhi-Hong Fang ◽  
Gonzalo Lopez ◽  
Weigang Tong ◽  
Hui Yang ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cell Lines ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Leukemia Cell ◽  
Human Leukemia ◽  
Eph Receptor ◽  
Leukemia Cell Lines ◽  
Ephrin Ligands ◽  
Aberrant Dna Methylation

Abstract The Eph (erythroprotein-producing hepatoma amplified sequence) family receptor tyrosine kinases and their ephrin ligands (ephrins) are involved in a variety of functions in normal cell development and cancer. We have identified several members of this family as potential targets of aberrant DNA methylation using Methylated CpG Island Amplification (MCA) / DNA promoter microarray technology. This is of importance as there are no prior reports of potential Eph receptor or Ephrin epigenetic inactivation in human leukemia. To further investigate the role of Eph receptor and ephrin family genes in leukemia, we have analyzed their DNA methylation status in a panel of 23 leukemia cell lines and 65 primary ALL patient samples. Aberrant DNA methylation of 9 of these genes (EPHA4, EPHA5, EPHA6, EPHB2, EPHB3, EPHB4, EphrinA5, Ephrin B2, and EphrinB3) was detected in multiple leukemia cell lines but not in normal samples by bisulfite pyrosequencing. In ALL patient samples, the frequencies of DNA methylation detected in the promoter regions of these genes ranged from 23% to 87% for EPHA4, EPHA5, EPHA6, EPHB2, EPHB3, EPHB4, EphrinA5, Ephrin B2, and EphrinB3. Expression analysis of 3 of these genes (EPHA5, EPHB4 and Ephrin B2) in leukemia cell lines by real-time PCR further confirmed methylation associated gene silencing. Treatment of methylated/silenced cell lines with DNA methyltransferase inhibitor 5′-aza-2′-deoxycytidine resulted in gene re-expression. Forced overexpression of EPHB4 using a lentivirus transduction system in Raji cell lines resulted in decreased cell proliferation and adhesion-independent cell growth, as well as in an increase in staurosporine induction of apoptosis. In addition, EPHB4 overexpression resulted in a significant downregulation of phosphorylated Akt pathway but had no effect on mitogen-activated protein kinase pathway. In summary, we describe for the first time the epigenetic suppression of Ephrin receptors and their ligands in human leukemia, indicating that these genes may be potential tumor suppressors in leukemia. Targeting of these pathways may result in the development of new potential therapies and biomarkers for patients with ALL.

scholarly journals Ubiquitin ligase SPSB4 diminishes cell repulsive responses mediated by EphB2

2017 ◽  
Vol 28 (24) ◽  
pp. 3532-3541 ◽  
Author(s):  
Fumihiko Okumura ◽  
Akiko Joo-Okumura ◽  
Keisuke Obara ◽  
Alexander Petersen ◽  
Akihiko Nishikimi ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Tyrosine Kinases ◽  
Kinase Activity ◽  
Receptor Tyrosine Kinases ◽  
Cancer Development ◽  
Tyrosine Kinase Activity ◽  
Eph Receptor ◽  
Ephrin Ligands ◽  
Dependent Cell ◽  
Socs Box

Eph receptor tyrosine kinases and their ephrin ligands are overexpressed in various human cancers, including colorectal malignancies, suggesting important roles in many aspects of cancer development and progression as well as in cellular repulsive responses. The ectodomain of EphB2 receptor is cleaved by metalloproteinases (MMPs) MMP-2/MMP-9 and released into the extracellular space after stimulation by its ligand. The remaining membrane-associated fragment is further cleaved by the presenilin-dependent γ-secretase and releases an intracellular peptide that has tyrosine kinase activity. Although the cytoplasmic fragment is degraded by the proteasome, the responsible ubiquitin ligase has not been identified. Here, we show that SOCS box-containing protein SPSB4 polyubiquitinates EphB2 cytoplasmic fragment and that SPSB4 knockdown stabilizes the cytoplasmic fragment. Importantly, SPSB4 down-regulation enhances cell repulsive responses mediated by EphB2 stimulation. Altogether, we propose that SPSB4 is a previously unidentified ubiquitin ligase regulating EphB2-dependent cell repulsive responses.

scholarly journals Evaluation of the Anti-Tumor Activity of Small Molecules Targeting Eph/Ephrins in APC min/J Mice

2020 ◽  
Vol 13 (4) ◽  
pp. 69
Author(s):  
Miriam Corrado ◽  
Carmine Giorgio ◽  
Elisabetta Barocelli ◽  
Giuseppe Vittucci Marzetti ◽  
Anna Maria Cantoni ◽  
...  
Keyword(s):  
Small Molecules ◽  
Tyrosine Kinases ◽  
Tumor Development ◽  
Eph Receptors ◽  
Pharmacological Approach ◽  
Ephrin Ligands ◽  
Prevent Tumor Growth ◽  
First Time ◽  
Anti Tumor Activity

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.

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