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.

scholarly journals The Role of the Eph Receptor Family in Tumorigenesis

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 206
Author(s):  
Meg Anderton ◽  
Emma van der Meulen ◽  
Melissa J. Blumenthal ◽  
Georgia Schäfer
Keyword(s):  
Kaposi's Sarcoma ◽  
Kaposi’S Sarcoma ◽  
Signalling Pathways ◽  
Cancer Therapies ◽  
Eph Receptors ◽  
Eph Receptor ◽  
Ephrin Ligands ◽  
And Migration ◽  
Receptor Family

The Eph receptor tyrosine kinase family, activated by binding to their cognate ephrin ligands, are important components of signalling pathways involved in animal development. More recently, they have received significant interest due to their involvement in oncogenesis. In most cases, their expression is altered, affecting the likes of cell proliferation and migration. Depending on the context, Eph receptors have the potential to act as both tumour promoters and suppressors in a number of cancers, such as breast cancer, colorectal cancer, lung cancer, prostate cancer, brain cancer and Kaposi’s sarcoma (KS), the latter being intrinsically linked to EphA2 as this is the receptor used for endothelial cell entry by the Kaposi’s sarcoma-associated herpesvirus (KSHV). In addition, EphA2 deregulation is associated with KS, indicating that it has a dual role in this case. Associations between EphA2 sequence variation and KSHV infection/KS progression have been detected, but further work is required to formally establish the links between EphA2 signalling and KS oncogenesis. This review consolidates the available literature of the role of the Eph receptor family, and particularly EphA2, in tumorigenesis, with the aim to develop a better understanding of Eph signalling pathways for potential targeting in novel cancer therapies.

scholarly journals Eph receptors: the bridge linking host and virus

2019 ◽  
Vol 77 (12) ◽  
pp. 2355-2365 ◽  
Author(s):  
Jia Wang ◽  
Xiang Zheng ◽  
Qiu Peng ◽  
Xuemei Zhang ◽  
Zailong Qin
Keyword(s):  
Virus Infection ◽  
Cellular Membrane ◽  
Viral Envelope ◽  
Surface Glycoprotein ◽  
Target Cells ◽  
Eph Receptors ◽  
Virus Infections ◽  
Eph Receptor ◽  
Ephrin Ligands ◽  
Receptor Family

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.

scholarly journals The composition of EphB2 clusters determines the strength in the cellular repulsion response

2014 ◽  
Vol 204 (3) ◽  
pp. 409-422 ◽  
Author(s):  
Andreas Schaupp ◽  
Ola Sabet ◽  
Irina Dudanova ◽  
Marion Ponserre ◽  
Philippe Bastiaens ◽  
...  
Keyword(s):  
Fluorescence Anisotropy ◽  
Cluster Size ◽  
Cellular Responses ◽  
Living Cells ◽  
Eph Receptors ◽  
Ephrin Ligands ◽  
Membrane Bound ◽  
Regulatory Effects ◽  
Functional Relevance ◽  
Cell Collapse

Trans interactions of erythropoietin-producing human hepatocellular (Eph) receptors with their membrane-bound ephrin ligands generate higher-order clusters that can form extended signaling arrays. The functional relevance of the cluster size for repulsive signaling is not understood. We used chemical dimerizers and fluorescence anisotropy to generate and visualize specific EphB2 cluster species in living cells. We find that cell collapse responses are induced by small-sized EphB2 clusters, suggesting that extended EphB2 arrays are dispensable and that EphB2 activation follows an ON–OFF switch with EphB2 dimers being inactive and trimers and tetramers being fully functional. Moreover, the strength of the collapse response is determined by the abundance of multimers over dimers within a cluster population: the more dimers are present, the weaker the response. Finally, we show that the C-terminal modules of EphB2 have negative regulatory effects on ephrin-induced clustering. These results shed new light on the mechanism and regulation of EphB2 activation and provide a model on how Eph signaling translates into graded cellular responses.

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 The Value of EphB2 Receptor and Cognate Ephrin Ligands in Prognostic and Predictive Assessments of Human Breast Cancer

2021 ◽  
Vol 22 (15) ◽  
pp. 8098
Author(s):  
Abdul Shukkur Ebrahim ◽  
Zeyad Hailat ◽  
Sudeshna Bandyopadhyay ◽  
Daniel Neill ◽  
Mustapha Kandouz
Keyword(s):  
Breast Cancer ◽  
Distant Metastasis ◽  
Predictive Value ◽  
Intracellular Signaling ◽  
Ductal Carcinoma ◽  
Cancer Development ◽  
Eph Receptors ◽  
Free Survival ◽  
Expression Levels ◽  
Ephrin Ligands

Cell–cell communication proteins Eph and ephrin constitute the largest family of receptor tyrosine kinases (RTKs). They are distinguished by the fact that both receptors and ligands are membrane-bound, and both can drive intracellular signaling in their respective cells. Ever since these RTKs have been found to be involved in cancer development, strategies to target them therapeutically have been actively pursued. However, before this goal can be rationally achieved, the contributions of either Eph receptors or their ephrin ligands to cancer development and progression should be scrutinized in depth. To assess the clinical pertinence of this concern, we performed a systematic review and meta-analysis of the prognostic/predictive value of EphB2 and its multiple cognate ephrin ligands in breast cancer. We found that EphB2 has prognostic value, as indicated by the association of higher EphB2 expression levels with lower distant metastasis-free survival (DMFS), and the association of lower EphB2 expression levels with poorer relapse-free survival (RFS). We also found that higher EphB2 expression could be a prognostic factor for distant metastasis, specifically in the luminal subtypes of breast cancer. EFNB2 showed a marked correlation between higher expression levels and shorter DMFS. EFNA5 or EFNB1 overexpression is correlated with longer RFS. Increased EFNB1 expression is correlated with longer OS in lymph node (LN)-negative patients and the luminal B subtype. Higher levels of EFNB2 or EFNA5 are significantly correlated with shorter RFS, regardless of LN status. However, while this correlation with shorter RFS is true for EFNB2 in all subtypes except basal, it is also true for EFNA5 in all subtypes except HER2+. The analysis also points to possible predictive value for EphB2. In systemically treated patients who have undergone either endocrine therapy or chemotherapy, we found that higher expression of EphB2 is correlated with better rates of RFS. Bearing in mind the limitations inherent to any mRNA-based profiling method, we complemented our analysis with an immunohistochemical assessment of expression levels of both the EphB2 receptor and cognate ephrin ligands. We found that the latter are significantly more expressed in cancers than in normal tissues, and even more so in invasive and metastatic samples than in ductal carcinoma in situ (DCIS). Finally, in an in vitro cellular model of breast cancer progression, based on H-Ras-transformation of the MCF10A benign mammary cell line, we observed dramatic increases in the mRNA expression of EphB2 receptor and EFNB1 and EFNB2 ligands in transformed and invasive cells in comparison with their benign counterparts. Taken together, these data show the clinical validity of a model whereby EphB2, along with its cognate ephrin ligands, have dual anti- and pro-tumor progression effects. In so doing, they reinforce the necessity of further biological investigations into Ephs and ephrins, prior to using them in targeted therapies.

scholarly journals Synthesis of Trypsin-Resistant Variants of the Listeria-Active Bacteriocin Salivaricin P

2010 ◽  
Vol 76 (16) ◽  
pp. 5356-5362 ◽  
Author(s):  
Eileen F. O'Shea ◽  
Paula M. O'Connor ◽  
Paul D. Cotter ◽  
R. Paul Ross ◽  
Colin Hill
Keyword(s):  
Antimicrobial Activity ◽  
Gastrointestinal Tract ◽  
Cleavage Sites ◽  
Wild Type ◽  
Enhanced Resistance ◽  
Fold Reduction ◽  
Two Component ◽  
Specific Protease ◽  
The Individual ◽  
Protease Action

ABSTRACT Two-component salivaricin P-like bacteriocins have demonstrated potential as antimicrobials capable of controlling infections in the gastrointestinal tract (GIT). The anti-Listeria activity of salivaricin P is optimal when the individual peptides Sln1 and Sln2 are added in succession at a 1:1 ratio. However, as degradation by digestive proteases may compromise the functionality of these peptides within the GIT, we investigated the potential to create salivaricin variants with enhanced resistance to the intestinal protease trypsin. A total of 11 variants of the salivaricin P components, in which conservative modifications at the trypsin-specific cleavage sites were explored in order to protect the peptides from trypsin degradation while maintaining their potent antimicrobial activity, were generated. Analysis of these variants revealed that eight were resistant to trypsin digestion while retaining antimicrobial activity. Combining the complementary trypsin-resistant variants Sln1-5 and Sln2-3 resulted in a MIC50 of 300 nM against Listeria monocytogenes, a 3.75-fold reduction in activity compared to the level for wild-type salivaricin P. This study demonstrates the potential of engineering bacteriocin variants which are resistant to specific protease action but which retain significant antimicrobial activity.

scholarly journals Differential expression of five tRNA(UAGTrp) amber suppressors in Caenorhabditis elegans.

1988 ◽  
Vol 8 (9) ◽  
pp. 3627-3635 ◽  
Author(s):  
K Kondo ◽  
J Hodgkin ◽  
R H Waterston
Keyword(s):  
Nervous System ◽  
Caenorhabditis Elegans ◽  
Gene Family ◽  
Development Stage ◽  
Base Change ◽  
Wild Type ◽  
Specific Manner ◽  
Flanking Sequences ◽  
Single Base Change ◽  
The Individual

Caenorhabditis elegans has 12 tRNA(UGGTrp) genes as defined by Southern analysis. In order to evaluate the function of the individual members of this multigene family, we sought to recover amber (UAG)-suppressing mutations from reversion experiments with animals carrying amber mutations in a nervous system-affecting gene (unc-13) or a sex-determining gene (tra-3). Revertants were analyzed by Southern blot, exploiting the fact that the CCA to CTA change at the anticodon creates a new XbaI site. Five different members of the tRNATrp gene family were identified as suppressors: sup-7 X, sup-5 III, sup-24 IV, sup-28 X, and sup-29 IV. All five suppressor genes were sequenced and found to encode identical tRNA(UAGTrp) molecules with a single base change (CCA to CTA) at the anticodon compared with their wild-type counterparts. The flanking sequences had only limited homology. The relative expression of these five genes was determined by measuring the efficiencies of suppressers against amber mutations in genes affecting the nervous system, hypodermis, muscle, and sex determination. The results of these cross-suppression tests showed that the five members of the tRNA(Trp) gene family were differentially regulated in a tissue- or development stage-specific manner.

scholarly journals Ensovibep, a novel trispecific DARPin candidate that protects against SARS-CoV-2 variants

2021 ◽  
Author(s):  
Michael Stumpp
Keyword(s):  
Single Agent ◽  
Standard Of Care ◽  
Cooperative Binding ◽  
Wild Type ◽  
Inhibitory Potency ◽  
Alpha Variant ◽  
The Individual ◽  
Very High ◽  
Comprehensive Study

Abstract SARS-CoV-2 has infected millions of people globally and continues to undergo evolution. Emerging variants can be partially resistant to vaccine induced and therapeutic antibodies, emphasizing the urgent need for accessible, broad-spectrum therapeutics. Here, we report a comprehensive study of ensovibep, the first trispecific clinical DARPin candidate, that can simultaneously engage all three units of the spike protein trimer to potently inhibit ACE2 interaction, as revealed by structural analyses. The cooperative binding of the individual modules enables ensovibep to retain inhibitory potency against all frequent SARS-CoV-2 variants, including Omicron, as of December 2021. Moreover, viral passaging experiments show that ensovibep, when used as a single agent, can prevent development of escape mutations comparably to a cocktail of monoclonal antibodies (mAb). Finally, we demonstrate that the very high in vitro antiviral potency also translates into significant therapeutic protection and reduction of pathogenesis in Roborovski dwarf hamsters infected with either the SARS-CoV-2 wild-type or the Alpha variant. In this model, ensovibep prevents fatality and provides substantial protection equivalent to the standard of care mAb cocktail. These results support further clinical evaluation and indicate that ensovibep could be a valuable alternative to mAb cocktails and other treatments for COVID-19.

scholarly journals A conserved regulatory module regulates receptor kinase signaling in immunity and development

2021 ◽  
Author(s):  
Thomas A. DeFalco ◽  
Pauline Anne ◽  
Sean R. James ◽  
Andrew Willoughby ◽  
Oliver Johanndrees ◽  
...  
Keyword(s):  
Cell Surface ◽  
Cellular Responses ◽  
Receptor Signaling ◽  
Receptor Kinase ◽  
Surface Receptors ◽  
Receptor Complexes ◽  
Regulatory Circuit ◽  
Regulatory Module ◽  
Molecular Patterns ◽  
Receptor Kinase Signaling

ABSTRACTLigand recognition by cell-surface receptors underlies development and immunity in both animals and plants. Modulating receptor signaling is critical for appropriate cellular responses but the mechanisms ensuring this are poorly understood. Here, we show that signaling by plant receptors for pathogen-associated molecular patterns (PAMPs) in immunity and CLAVATA3/EMBRYO SURROUNDING REGION-RELATED peptides (CLEp) in development employ a similar regulatory module. In the absence of ligand, signaling is dampened through association with specific type-2C protein phosphatases (PP2Cs). Upon activation, PAMP and CLEp receptors phosphorylate divergent cytosolic kinases, which, in turn, phosphorylate the phosphatases, thereby promoting their release from the receptor complexes. Our work reveals a regulatory circuit shared between immune and developmental receptor signaling, which may have broader important implications for plant receptor kinase-mediated signaling in general.

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