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PubMed2003

Ephrin B2 induces T cell costimulation.

Eph kinases form the largest family of receptor tyrosine kinases, and their ligands are ephrins (EFNs), which are cell surface proteins. Some Eph kinases and EFNs are expressed on T cells, B cells, and dendritic cells, but their functions in the immune system are largely unknown. In this study, we investigated the effect of EFNB2 on murine T cells. EFNB2 mRNA was expressed in the cortex of the thymus and white pulp of the spleen. At the protein level, it was expressed on T cells and monocytes/macrophages, but not on B cells. EFNB2Rs were expressed mainly on T cells. Solid-phase EFNB2 along with suboptimal anti-CD3 strongly stimulated T cell proliferation, with concomitant augmentation of IFN-gamma but not IL-2 or IL-4 secretion. The activity of cytotoxic T cells was also significantly enhanced in the presence of solid-phase EFNB2. These results indicate that EFNB2R cross-linking results in costimulation of T cells. EFNB2Rs were normally scattered on the T cell surface; after TCR cross-linking, they rapidly congregated to capped TCR complexes and then to patched rafts. This provides a morphological base for EFNB2Rs to participate in T cell costimulation. We also demonstrated that EFNB2R signaling led to augmented p38 and p44/42 mitogen-activated protein kinase activation. Our study shows that EFNB2 plays important roles in immune regulation.

Adjuvants, Immunologic↗
PubMed1999

High-level expression of EPHB6, EFNB2, and EFNB3 is associated with low tumor stage and high TrkA expression in human neuroblastomas.

Neuroblastoma (NB) is a common pediatric tumor of neural crest origin that is biologically and clinically heterogeneous. EPH family receptor tyrosine kinases and ephrin ligands play fundamental roles in neurodevelopmental processes. Recently, we found that NB cell lines expressed several EPHB and EFNB transcripts, which encode EPHB subgroup receptors and ephrin-B subgroup ligands, respectively. To explore the role of EPHB receptors and ephrin-B ligands in the biology of NB, we examined the expression of EPHB and EFNB transcripts in 47 primary NB specimens. Multiple EPHB and EFNB transcripts were expressed in all of the NB tumors examined, suggesting the involvement of these transcripts in modulating the biological behavior of NB. Higher levels of EPHB6, EFNB2, and EFNB3 expression were found in low-stage tumors (stage 1, 2, and 4S) than in advanced-stage tumors (stage 3 and 4; P = 0.0013, P = 0.0048, and P = 0.027, respectively). Expression of TrkA, a well-established prognostic marker of favorable NB, was positively correlated with EPHB6, EFNB2, and EFNB3 expression (P < 0.0001, P = 0.0019, and P = 0.0001, respectively). MYCN-amplified tumors expressed lower levels of EPHB6, EFNB2, EFNB3, and TrkA transcripts compared to nonamplified tumors (P = 0.0006, P = 0.0023, P = 0.0048, and P = 0.0001, respectively). These data suggest that high-level expression of EPHB6, EFNB2, and EFNB3 is associated with favorable NB and that low-level expression of EPHB6, EFNB2, and EFNB3 correlates with aggressive MYCN-amplified NB. Thus, EPHB6, EFNB2, and EFNB3 may have biological relevance in NB. Further investigation on the biology of these genes may help provide insight into the treatment of NB.

Ephrin-B2↗
PubMed2000

Spinal motor axons and neural crest cells use different molecular guides for segmental migration through the rostral half-somite.

The peripheral nervous system in vertebrates is composed of repeating metameric units of spinal nerves. During development, factors differentially expressed in a rostrocaudal pattern in the somites confine the movement of spinal motor axons and neural crest cells to the rostral half of the somitic sclerotome. The expression patterns of transmembrane ephrin-B ligands and interacting EphB receptors suggest that these proteins are likely candidates for coordinating the segmentation of spinal motor axons and neural crest cells. In vitro, ephrin-B1 has indeed been shown to repel axons extending from the rodent neural tube (Wang & Anderson, 1997). In avians, blocking interactions between EphB3 expressed by neural crest cells and ephrin-B1 localized to the caudal half of the somite in vivo resulted in loss of the rostrocaudal patterning of trunk neural crest migration (Krull et al., 1997). The role of ephrin-B1 in patterning spinal motor axon outgrowth in avian embryos was investigated. Ephrin-B1 protein was found to be expressed in the caudal half-sclerotome and in the dermomyotome at the appropriate time to interact with the EphB2 receptor expressed on spinal motor axons. Treatment of avian embryo explants with soluble ephrin-B1, however, did not perturb the segmental outgrowth of spinal motor axons through the rostral half-somite. In contrast, under the same treatment conditions with soluble ephrin-B1, neural crest cells migrated aberrantly through both rostral and caudal somite halves. These results indicate that the interaction between ephrin-B1 and EphB2 is not required for patterning spinal motor axon segmentation. Even though spinal motor axons traverse the same somitic pathway as neural crest cells, different molecular guidance mechanisms appear to influence their movement.

Animals↗
PubMed2000

[Involvement of ephrins and their receptors in oncogenesis].

Ephrins are membrane-linked ligands with an autocrine and/or immediate paracrine action. Ephrins were previously involved in embryonic neurogenesis, axonal guidance and/or retraction. Here, we will present data of the literature describing their roles in angiogenesis and in tumor progression. The capacity for ephrins to act in opposite directions will be discussed.

Animals↗
PubMed2001

Ephrin B1 is expressed on neuroepithelial cells in correlation with neocortical neurogenesis.

To identify molecules involved in neurogenesis, we have raised monoclonal antibodies against embryonic day 12.5 mouse telencephalon. One antibody, monoclonal antibody 25H11, stains predominantly the ventricular zone of the anterior and lateral telencephalon. Purification of the 25H11 antigen, a 47 kDa integral membrane protein, from approximately 2500 mouse telencephali reveals its identity with ephrin B1. Ephrin B1 appears at the onset of neocortical neurogenesis, being first expressed in neuron-generating neuroepithelial cells and rapidly thereafter in virtually all neuroepithelial cells. Expression of ephrin B1 persists through the period of neocortical neurogenesis and is downregulated thereafter. Ephrin B1 is present on the ventricular as well as basolateral plasma membrane of neuroepithelial cells and exhibits an ventricular-high to pial-low gradient across the ventricular zone. Expression of ephrin B1 is also detected on radial glial cells, extending all the way to their pial endfeet, and on neurons in the mantle/intermediate zone but not in the cortical plate. Our results suggest that ephrin B1, presumably via ephrin-Eph receptor signaling, has a role in neurogenesis. Given the ventricular-to-pial gradient of ephrin B1 on the neuroepithelial cell surface and its known role in cell migration in other systems mediated by its repulsive properties, we propose that ephrin B1 may be involved in the migration of newborn neurons out from the ventricular zone toward the neocortex.

Animals↗
PubMed2004

Vascular remodeling marks tumors that recur during chronic suppression of angiogenesis.

The potential for avoiding acquired resistance to therapy has been proposed as one compelling theoretical advantage of antiangiogenic therapy based on the normal genetic status of the target vasculature. However, previous work has demonstrated that tumors may resume growth after initial inhibition if antiangiogenic blockade is continued for an extended period. The mechanisms of this recurrent growth are unclear. In these studies, we characterized molecular changes in vasculature during apparent resumption of xenograft growth after initial inhibition by vascular endothelial growth factor blockade, "metronome" topotecan chemotherapy, and combined agents in a xenograft murine model of human Wilms' tumor. Tumors that grew during antiangiogenic blockade developed as viable clusters surrounding strikingly remodeled vessels. These vessels displayed significant increases in diameter and active proliferation of vascular mural cells and expressed platelet-derived growth factor-B, a factor that functions to enhance vascular integrity via stromal cell recruitment. In addition, remodeled vessels were marked by expression of ephrinB2, required for proper assembly of stromal cells into vasculature. Thus, enhanced vascular stability appears to characterize tumor vessel response to chronic antiangiogenesis, features that potentially support increased perfusion and recurrent tumor growth.

Animals↗
PubMed2004

[Detecting protein expression of EphrinB2 ligand and its receptor EphB4 in astrocytoma using confocal laser scanning microscopy].

BACKGROUND & OBJECTIVE: EphrinB2 is a novel angiogenic factor. EphrinB2 and its receptor EphB4 express in several kinds of tumor cells,and correlate with tumorigenesis and neoangiogenesis. This study was designed to explore the characteristics of EphB4 and EphrinB2 protein expression in astrocytomas. METHODS: Double labelling immunofluorescence was used to detect co-expression of EphB4/EphrinB2 with glial fibrilary acid protein (GFAP)or CD34 protein in 35 fresh glioma specimens, and 2 kinds of human glioma cell lines (CHG-5,and SHG-44). RESULTS: EphB4/EphrinB2 and CD34 proteins co-expressed in some tumor stromal microvessels, and mainly localizing in endothelial cells. Co-expression of EphB4/EphrinB2 and GFAP proteins was also noticed in tumor cells,and 2 glioma cell lines. In poorly-differentiated SHG-44 cells, the average fluorescence intensity of EphB4 was 72.48+/-33.78,and that of EphrinB2 was 96.80+/-36.98, both higher than those in well-differentiated CHG-5 cells (56.7+/-21.7, and 53.6+/-18.8). But the green fluorescence intensity of GFAP in SHG-44 cells was 22.3+/-15.3, while in CHG-5 cells was 47.5+/-16.7. CONCLUSION: Expressions of EphB4 and EphrinB2 proteins may be related to differentiation degree of tumor cells.

Antigens, CD34↗
PubMed2006

Correlation of four vascular specific growth factors with carcinogenesis and portal vein tumor thrombus formation in human hepatocellular carcinoma.

The aim of the present study was to detect the correlation between the expression of vascular endothelial growth factor (VEGF), angiopoietin 2 (Ang2), ephrinB2 and endocrine gland-derived vascular endothelial growth factor (EG-VEGF) and carcinogenesis or portal vein tumor thrombus (PVTT) formation in human hepatocellular carcinoma (HCC). The expression of VEGF, Ang2, ephrinB2 and EG-VEGF was detected by RT-PCR in 54 cases HCC without PVTT (group A), 9 cases HCC with PVTT (group B), 10 normal liver tissues (group D) and 10 cirrhosis tissues (group C). The samples were also stained with CD34 by immunohistochemistry. Quantitation of microvessel density (MVD) and semi-quantitation of VEGF, Ang2, ephrinB2 and EG-VEGF expression were analyzed to find the relations. The MVD was 146.69 +/- 77.79, 214.07 +/- 54.41, 32.85 +/- 8.49 and 34.83 +/- 8.29 in group A-D respectively with significant difference (F = 19.77, P = 0.000). The MVD in group A was higher than that in group C P = 0.006, but lower than that in group B P < or = 0.05 or 0.01. The expression levels of VEGF165, VEGF189, Ang2 and EG-VEGF mRNA were significantly different among the groups. The expression levels of VEGF165, Ang2 and EG-VEGF mRNA in group A were all higher than those in group C, but lower than those in group B P < 0.05 or 0.01. The MVD was significantly correlated with VEGF165, VEGF189, Ang2 and EG-VEGF mRNA with Spearman's related coefficient being 0.764, 0.510, 0.640 and 0.366 in HCC (P = 0.000, 0.000 0.000 and 0.003). In conclusion VEGF, Ang2 and EG-VEGF mRNA may play a role in angiogenesis and carcinogenesis of HCC. They can promote PVTT formation in HCC by modulating angiogenesis.

Angiopoietin-2↗
PubMed1996

Characterization of a ligand for receptor protein-tyrosine kinase HTK expressed in immature hematopoietic cells.

HTK is a receptor tyrosine kinase that belongs to the Eph subfamily. An extensive screening using BIAcore system revealed that a colon cancer cell line, C-1, expressed the ligand for HTK. From the conditioned medium of C-1 cells, a soluble form of ligand was purified by receptor affinity chromatography, and the isolation of full-length cDNA revealed that this ligand is identical to the human HTK ligand (HTKL) previously reported. HTK receptor tyrosine phosphorylation was induced by membrane-bound or clustered soluble HTKL but not by unclustered soluble HTKL, indicating that HTKL requires cell-to-cell interaction for receptor activation. Binding analysis demonstrated that HTKL binds to HTK with a much higher affinity (Kd: 1.23 nM) than the other transmembrane-type ligand for Eph family, LERK-2/ELKL (Kd: 135 nM). The expression of HTK in cord blood cells was upregulated after the culture in the presence of stem cell factor. Clustered soluble HTKL stimulated the proliferation of sorted HTK+ cord blood cells and a hematopoietic cell line, UT-7/EPO from which HTK was isolated. These findings suggest the involvement of HTK-HTKL system in the proliferation of HTK+ hematopoietic progenitor cells in the hematopoietic environment.

Amino Acid Sequence↗
PubMed1997

Selective expression of the receptor tyrosine kinase, HTK, on human erythroid progenitor cells.

HTK is a receptor tyrosine kinase of the Eph family. To characterize the involvement of HTK in hematopoiesis, we generated monoclonal antibodies against HTK and investigated its expression on human bone marrow cells. About 5% of the bone marrow cells were HTK+, which were also c-Kit+, CD34(low), and glycophorin A(-/low). Assays of progenitors showed that HTK+ c-Kit+ cells consisted exclusively of erythroid progenitors, whereas HTK- c-Kit+ cells contained progenitors of granulocytes and macrophages as well as those of erythroid cells. Most of the HTK+ erythroid progenitors were stem cell factor-dependent for proliferation, indicating that they represent mainly erythroid burst-forming units (BFU-E). During the erythroid differentiation of cultured peripheral CD34+ cells, HTK expression was upregulated on immature erythroid cells that corresponded to BFU-E and erythroid colony-forming units and downregulated on erythroblasts with high levels of glycophorin expression. These findings suggest that HTK is selectively expressed on the restricted stage of erythroid progenitors, particularly BFU-E, and that HTK is the first marker antigen that allows the purification of erythroid progenitors. Furthermore, HTKL, the ligand for HTK, was expressed in the bone marrow stromal cells. Our findings provide a novel regulatory system of erythropoiesis mediated by the HTKL-HTK signaling pathway.

Antibodies, Monoclonal↗
PubMed1998

Overexpression of Lerk-5/Eplg5 messenger RNA: a novel marker for increased tumorigenicity and metastatic potential in human malignant melanomas.

The Lerks, ligands of eph-related receptor tyrosine kinases, are a rapidly expanding family of genes thought to play an important role in the development and oncogenesis of various tissues. However, very little experimental evidence supports this hypothesis. Using RNA fingerprinting, we detected increased expression of Lerk-5 mRNA in human melanocytes as a response to the tumor-promoting drug 12-O-tetradecanoylphorbol-13-acetate, which suggests a possible role of the Lerks in melanoma tumorigenesis and progression. Therefore, we studied Lerk-5 mRNA expression in various melanoma cell lines and tissues of melanocytic tumors by semiquantitative reverse transcription-PCR. Modest expression of Lerk-5 mRNA was found in two melanoma cell lines derived from early primary tumors (WM35 and WM1645B); two metastatic cell lines tested showed a 3.9-fold increased transcript abundance when compared to the primary cell lines (RPMI-7951 and SK-Mel5). Progeny of a melanoma cell line with very low Lerk-5 mRNA abundance (WM35) showed a 5-fold increase in Lerk-5 mRNA expression when it was selected for higher tumorigenicity and multicytokine resistance by passaging in nude mice or repeated high-dose UVB irradiation. Consistent with these experimental data, we found high levels of Lerk-5 mRNA expression in advanced primary malignant melanomas and metastases (n = 22) but significantly lower or undetectable mRNA expression in benign melanocytic nevi (n = 9; P < 0.001). We conclude that increased Lerk-5 expression possibly reflects or induces an increased potential of growth, tumorigenicity, and metastatic abilities in human melanomas. This makes the yet to be elucidated eph-related receptor tyrosine kinase/Lerk signaling system a potential new source for molecular markers as well as a target for new therapies.

Animals↗