• Journal of Gastric Cancer
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• v.6 no.1
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• pp.25-30
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• 2006

Purpose: The EphB2 receptor, a member of the receptor tyrosine kinase family, is a target gene of the Wnt signaling pathway and may achieve a tumor suppressor function through regulation of cell growth and migration. Our aim was to determine whether an altered expression of EphB2 might be associated with gastric cancer development and, if so, to determine to which pathologic parameter it is linked. Materials and Methods: For the construction of the gastric cancer tissue microarray, 83 paraffin-embedded tissues containing gastric cancer areas were cored 3 times and transferred to the recipient master block. The expression patterns of EphB2 were examined on tissue microarray slides by using immunohistochemistry and were compared using pathologic parameters, including histological type, depth of invasion, lymph node metastatsis, and peritoneal dissemination. Results: The EphB2 protein was expressed in the normal gastric mucosal epithelium, especially in the bottom of the mucosa. We found loss of EphB2 expression in 30 (36.1%) of the 83 gastric cancer tissues. Statistically, loss of EphB2 expression was more common in gastric cancer with lymph-node metastasis. There was no significant correlation between EphB2 expression and depth of invasion, histologic type, or peritoneal dissemination. Conclusion: Our findings suggest that loss of EphB2 expression may represent a critical step in gastric carcinogenesis.

• BMB Reports
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• v.49 no.12
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• pp.651-652
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• 2016

EphA2 has been implicated in amplifying ErbB2 tumorigenic signaling. One protein that interacts with EphA2 is the Anks1a PTB adaptor. However, the precise role of Anks1a in EphA2-mediated tumorigenesis is unclear. We demonstrated that Anks1a localizes to the ER upon phosphorylation and that the Ankyrin repeats and PTB of Anks1a bind to EphA2 and Sec23, respectively. Thus, Anks1a facilitates the selective packaging of EphA2 into COPII vesicles. Additionally, Anks1a knockout mice, a phenocopy of EphA2 knockout mice, exhibited markedly reduced ErbB2-induced breast tumorigenesis. Strikingly, ErbB2 did not localize to the cell surface following Anks1a knockdown in primary mammary tumor cells over-expressing ErbB2. Importantly, EphA2 was critical for stabilizing ErbB2 through complex formation, but its interaction with Anks1a also facilitated ErbB2 loading into COPII carriers. These findings suggest a novel role for Anks1a in the molecular pathogenesis of breast tumors and possibly other human diseases.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.3
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• pp.1441-1446
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• 2014

Squamous cell/adenosquamous carcinoma (SC/ASC) of the gallbladder are rare tumors and there are few clinical reports in the literature. Herein we report our clinical experience with 46 patients with SC/ASC and 80 with adenocarcinoma (AC). Expression of EphB1 and Ephrin-B in each tumor was determined using immunohistochemical methods for determination of correlations with prognosis. There was no difference in EphB1 and Ephrin-B expression between SC/ASC and AC tumors (P>0.05), but greater expression in those less than 3 cm in diameter, stage I or II (TNM stage), with no lymph node metastases, with no local invasion and treated with radical resection was apparent. Expression of EphB1 (P<0.05) and Ephrin-B (P<0.01) was higher in well differentiated than in poorly differentiated AC tumors. Kaplan-Meier survival analysis indicated that degree of differentiation, tumor diameter, lymph node metastases, local invasion, surgical approach and expression rate of EphB1 and Ephrin-B were closely related to the survival of SC/ASC (P<0.05) and AC patients (P<0.01). Patients with tumors that positive expressed EphB1 and Ephrin-B, whether it is SC/ASC ($P_{SC/ASC}$ =0.000) or AC ($P_{AC}$ =0.000 or $P_{AC}$ =0.002) had longer survival than those negative expression. Cox multivariate analysis indicated a negative correlation between expression of EphB1 or Ephrin-B and overall survival. Hence, EphB1 and Ephrin-B could be regarded as independent good prognostic factorsand important biological markers for SC/ASC and AC of gallbladder.

• Molecules and Cells
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• v.38 no.1
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• pp.14-19
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• 2015

Eph receptors and their ligands, ephrins, represent the largest group of the receptor tyrosine kinase (RTK) family, and they mediate numerous developmental processes in a variety of organisms. Ephrins are membrane-bound proteins that are mainly divided into two classes: A class ephrins, which are linked to the membrane by a glycosylphosphatidylinositol (GPI) linkage, and B class ephrins, which are transmembrane ligands. Based on their domain structures and affinities for ligand binding, the Eph receptors are also divided into two groups. Trans-dimerization of Eph receptors with their membrane-tethered ligands regulates cell-cell interactions and initiates bidirectional signaling pathways. These pathways are intimately involved in regulating cytoskeleton dynamics, cell migration, and alterations in cellular dynamics and shapes. The EphBs and ephrinBs are specifically localized and modified to promote higher-order clustering and initiate of bidirectional signaling. In this review, we present an in-depth overview of the structure, mechanisms, cell signaling, and functions of EphB/ephrinB in cell adhesion and migration.

• Genomics & Informatics
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• v.21 no.3
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• pp.30.1-30.13
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• 2023

Ephs belong to the largest family of receptor tyrosine kinase and are highly conserved both sequentially and structurally. The structural organization of Eph is similar to other receptor tyrosine kinases; constituting the extracellular ligand binding domain, a fibronectin domain followed by intracellular juxtamembrane kinase, and SAM domain. Eph binds to respective ephrin ligand, through the ligand binding domain and forms a tetrameric complex to activate the kinase domain. Eph-ephrin regulates many downstream pathways that lead to physiological events such as cell migration, proliferation, and growth. Therefore, considering the importance of Eph-ephrin class of protein in tumorigenesis, 7,620 clinically reported missense mutations belonging to the class of variables of unknown significance were retrieved from cBioPortal and evaluated for pathogenicity. Thirty-two mutations predicted to be pathogenic using SIFT, Polyphen-2, PROVEAN, SNPs&GO, PMut, iSTABLE, and PremPS in-silico tools were found located either in critical functional regions or encompassing interactions at the binding interface of Eph-ephrin. However, seven were reported in nonsmall cell lung cancer (NSCLC). Considering the relevance of receptor tyrosine kinases and Eph in NSCLC, these seven mutations were assessed for change in the folding pattern using molecular dynamic simulation. Structural alterations, stability, flexibility, compactness, and solvent-exposed area was observed in EphA3 Trp790Cys, EphA7 Leu749Phe, EphB1 Gly685Cys, EphB4 Val748Ala, and Ephrin A2 Trp112Cys. Hence, it can be concluded that the evaluated mutations have potential to alter the folding pattern and thus can be further validated by in-vitro, structural and in-vivo studies for clinical management.

• The korean journal of orthodontics
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• v.44 no.6
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• pp.320-329
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• 2014

Objective: To investigate the involvement of ephrinB2 in periodontal tissue remodeling in compression areas during orthodontic tooth movement and the effects of compressive force on EphB4 and ephrinB2 expression in osteoblasts and osteoclasts. Methods: A rat model of experimental tooth movement was established to examine the histological changes and the localization of ephrinB2 in compressed periodontal tissues during experimental tooth movement. RAW264.7 cells and ST2 cells, used as precursor cells of osteoclasts and osteoblasts, respectively, were subjected to compressive force in vitro. The gene expression of EphB4 and ephrinB2, as well as bone-associated factors including Runx2, Sp7, NFATc1, and calcitonin receptor, were examined by quantitative real-time polymerase chain reaction (PCR). Results: Histological examination of the compression areas of alveolar bone from experimental rats showed that osteoclastogenic activities were promoted while osteogenic activities were inhibited. Immunohistochemistry revealed that ephrinB2 was strongly expressed in osteoclasts in these areas. Quantitative real-time PCR showed that mRNA levels of NFATc1, calcitonin receptor, and ephrinB2 were increased significantly in compressed RAW264.7 cells, and the expression of ephrinB2, EphB4, Sp7, and Runx2 was decreased significantly in compressed ST2 cells. Conclusions: Our results indicate that compressive force can regulate EphB4 and ephrinB2 expression in osteoblasts and osteoclasts, which might contribute to alveolar bone resorption in compression areas during orthodontic tooth movement.

• BMB Reports
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• v.36 no.3
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• pp.288-293
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• 2003

Low molecular weight phosphotyrosine protein phosphatase (LMW-PTP) has been implicated in modulating the EphB1-mediated signaling pathway. In this study, we demonstrated that the EphA8 receptor phosphorylates LMW-PTP in vitro. In addition, we discovered that mixing these two proteins leads to EphA8 dephosphorylation in the absence of phosphatase inhibitors. Finally, we demonstrated that LMW-PTP, modified by the EphA8 autokinase activity, possesses enhanced catalytic activity in vitro. These results suggest that LMW-PTP may also participate in a feedback-control mechanism of the EphA8 receptor autokinase activity in vivo.

• Genomics & Informatics
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• v.6 no.4
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• pp.192-201
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• 2008

Erythropoietin-producing human hepatocellular carcinoma receptor B1 (EPHB1) is a member of the Eph family of receptor tyrosine kinases that mediate vascular system development. Eph receptor overexpression has been observed in various cancers and is related to the malignant transformation, metastasis, and differentiation of cancers, including hepatocellular carcinoma (HCC). Eph receptors regulate cell migration and attachment to the extracellular matrix by modulating integrin activity. EphrinB1, the ligand of EPHB1, has been shown to regulate HCC carcinogenesis. Here, we sought to determine whether EPHB1 polymorphisms are associated with hepatitis B virus (HBV)-infected liver diseases, including chronic liver disease (CLD) and HCC. We genotyped 26 EPHB1 single nucleotide polymorphisms (SNPs) in 399 Korean CLD, HCC, and LD (CLD+HCC) cases and seroconverted controls (HBV clearance, CLE) using the GoldenGate assay. Two SNPs (rs6793828 and rs11717042) and 1 haplotype that were composed of these SNPs were associated with an increased risk for CLD, HCC, and LD (CLD+HCC) compared with CLE. Haplotypes that could be associated with HBV-infected liver diseases by affecting downstream signaling were located in the Eph tyrosine kinase domain of EPHB1. Therefore, we suggest that EPHB1 SNPs, haplotypes, and diplotypes may be genetic markers for the progression of HBV-associated acute hepatitis to CLD and HCC.

• Tuberculosis and Respiratory Diseases
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• v.78 no.3
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• pp.218-226
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• 2015

Background: Eph receptors and ephrin ligands have several functions including angiogenesis, cell migration, axon guidance, fluid homeostasis, oncogenesis, inflammation and injury repair. The EphA2 receptor potentially mediates the regulation of vascular permeability and inflammation in response to lung injury. Methods: Mice were divided into 3 experimental groups to study the role of EphA2 signaling in the lipopolysaccharide (LPS)-induced lung injury model i.e., IgG+phosphate-buffered saline (PBS) group (IgG instillation before PBS exposure), IgG+LPS group (IgG instillation before LPS exposure) and EphA2 monoclonal antibody (mAb)+LPS group (EphA2 mAb pretreatment before LPS exposure). Results: EphA2 and ephrinA1 were upregulated in LPS-induced lung injury. The lung injury score of the EphA2 mAb+LPS group was lower than that of the IgG+LPS group ($4.30{\pm}2.93$ vs. $11.45{\pm}1.20$, respectively; p=0.004). Cell counts (EphA2 mAb+LPS: $11.33{\times}10^4{\pm}8.84{\times}10^4$ vs. IgG+LPS: $208.0{\times}10^4{\pm}122.6{\times}10^4$; p=0.018) and total protein concentrations (EphA2 mAb+LPS: $0.52{\pm}0.41mg/mL$ vs. IgG+LPS: $1.38{\pm}1.08mg/mL$; p=0.192) were decreased in EphA2 mAb+LPS group, as compared to the IgG+LPS group. In addition, EphA2 antagonism reduced the expression of phospho-p85, phosphoinositide 3-kinase $110{\gamma}$, phospho-Akt, nuclear factor ${\kappa}B$, and proinflammatory cytokines. Conclusion: This results of the study indicated a role for EphA2-ephrinA1 signaling in the pathogenesis of LPS-induced lung injury. Furthermore, EphA2 antagonism inhibits the phosphoinositide 3-kinase-Akt pathway and attenuates inflammation.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.5
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• pp.1931-1936
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• 2014

Background: Gastric cancer (GC) ranks as one of the major causes of mortality due to cancer worldwide. In Chile, it is currently the leading cause of cancer death. Identification of novel molecular markers that may help to improve disease diagnosis at early stages is imperative. Materials and Methods: Using whole-genome DNA microarrays we determined differential mRNA levels in fresh human GC samples compared to adjacent healthy mucosa from the same patients. Genes significantly overexpressed in GC were validated by RT-PCR in a group of 14 GC cases. Results: The genes CD248, NSD1, RAB17, ABCG8, Ephb1 and P2RY2 were detected as the top overexpressed in GC biopsies. P2RY2, Ephb1 and CD248 showed the best sensitivity for GC detection with values of 92.9%, 85.7% and 64.3% (p<0.05), respectively. Specificity was 85.7%, 71.4% and 71.4% (p<0.05), for each respectively.