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PubMed2003

Association of Dishevelled with Eph tyrosine kinase receptor and ephrin mediates cell repulsion.

Eph tyrosine kinase receptors and their membrane-bound ligands, ephrins, are presumed to regulate cell-cell interactions. The major consequence of bidirectional activation of Eph receptors and ephrin ligands is cell repulsion. In this study, we discovered that Xenopus Dishevelled (Xdsh) forms a complex with Eph receptors and ephrin-B ligands and mediates the cell repulsion induced by Eph and ephrin. In vitro re-aggregation assays with Xenopus animal cap explants revealed that co-expression of a dominant-negative mutant of Xdsh affected the sorting of cells expressing EphB2 and those expressing ephrin-B1. Co-expression of Xdsh induced the activation of RhoA and Rho kinase in the EphB2-overexpressed cells and in the cells expressing EphB2-stimulated ephrin-B1. Therefore, Xdsh mediates both forward and reverse signaling of EphB2 and ephrin-B1, leading to the activation of RhoA and its effector protein Rho kinase. The inhibition of RhoA activity in animal caps significantly prevents the EphB2- and ephrin-B1-mediated cell sorting. We propose that Xdsh, which is expressed in various tissues, is involved in EphB and ephrin-B signaling related to regulation of cell repulsion via modification of RhoA activity.

Adaptor Proteins, Signal Transducing↗

PubMed2003

Dissecting the EphA3/Ephrin-A5 interactions using a novel functional mutagenesis screen.

The EphA3 receptor tyrosine kinase preferentially binds ephrin-A5, a member of the corresponding subfamily of membrane-associated ligands. Their interaction regulates critical cell communication functions in normal development and may play a role in neoplasia. Here we describe a random mutagenesis approach, which we employed to study the molecular determinants of the EphA3/ephrin-A5 recognition. Selection and functional characterization of EphA3 point mutants with impaired ephrin-A5 binding from a yeast expression library defined three EphA3 surface areas that are essential for the EphA3/ephrin-A5 interaction. Two of these map to regions identified previously in the crystal structure of the homologous EphB2-ephrin-B2 complex as potential ligand/receptor interfaces. In addition, we identify a third EphA3/ephrin-A5 interface that falls outside the structurally characterized interaction domains. Functional analysis of EphA3 mutants reveals that all three Eph/ephrin contact areas are essential for the assembly of signaling-competent, oligomeric receptor-ligand complexes.

Binding Sites↗

PubMed2000

Disruption of Eph/ephrin signaling affects migration and proliferation in the adult subventricular zone.

The subventricular zone (SVZ) of the lateral ventricles, the largest remaining germinal zone of the adult mammalian brain, contains an extensive network of neuroblasts migrating rostrally to the olfactory bulb. Little is known about the endogenous proliferation signals for SVZ neural stem cells or guidance cues along the migration pathway. Here we show that the receptor tyrosine kinases EphB1-3 and EphA4 and their transmembrane ligands, ephrins-B2/3, are expressed by cells of the SVZ. Electron microscopy revealed ephrin-B ligands associated with SVZ astrocytes, which function as stem cells in this germinal zone. A three-day infusion of the ectodomain of either EphB2 or ephrin-B2 into the lateral ventricle disrupted migration of neuroblasts and increased cell proliferation. These results suggest that Eph/ephrin signaling is involved in the migration of neuroblasts in the adult SVZ and in either direct or indirect regulation of cell proliferation.

Animals↗

PubMed2002

EphB forward signaling controls directional branch extension and arborization required for dorsal-ventral retinotopic mapping.

We report that EphB receptors direct unique axonal behaviors required for mapping the dorsal-ventral (D-V) retinal axis along the lateral-medial (L-M) axis of the superior colliculus (SC). EphBs are expressed in a D-V gradient, ephrin-B1 in a L-M gradient in SC, and ephrin-B3 at its midline. EphBs and ephrin-Bs are expressed in countergradients in retina and SC. Developmental analyses reveal that retinal axons lack D-V ordering along the L-M axis, but directionally extend branches along it to establish ordered arbors. Directed branch extension is disrupted in EphB2; EphB3-deficient mice resulting in lateral ectopic arbors. Mice with kinase-inactive EphB2 have similar D-V mapping defects indicating that forward signaling dominates over reverse signaling. Our data suggest that branches of EphB expressing axons are attracted medially by ephrin-B1, and provide molecular mechanisms for D-V mapping in visual centers.

Animals↗

PubMed2004

Differential gene expression of Eph receptors and ephrins in benign human tissues and cancers.

BACKGROUND: Eph receptors and their ligands, the ephrins, represent a large class of cell-cell communication molecules with well-defined developmental functions. Their role in healthy adult tissues and in human disease is still largely unknown, although diverse roles in carcinogenesis have been postulated. METHODS: We established a set of fluorescent PCR probes and primers for the definition of individual gene expression profiles of 12 different Eph receptors and 8 ephrins in 13 different healthy tissues. The mRNA expression profiles were studied in human lung, colorectal, kidney, liver, and brain cancers. RESULTS: The family of Eph receptors/ephrins was widely expressed in adult tissues with organ-site-specific patterns: EphB6 was highest in the thymus, compatible with an involvement in T-cell maturation. Brain and testis shared a unique pattern with EphA6, EphA8, and EphB1 being the most prominent. EphA7 had a high abundance in the kidney vasculature. Ephrin-A3 was up-regulated 26-fold in lung cancer, and EphB2 was up-regulated 9-fold in hepatocellular carcinoma. EphA8 was down-regulated in colon cancer, and EphA1/EphA8 was down-regulated in glioblastomas. CONCLUSION: Eph/Ephrin genes are widely expressed in all adult organs with certain organ-site-specific patterns. Because their function in adult tissues remains unknown, further analysis of their role in disease may disclose new insights beyond their well-defined meaning in development.

Adult↗

PubMed2002

Coexpression of ephrin-Bs and their receptors in colon carcinoma.

BACKGROUND: The erythropoietin-producing hepatoma amplified sequence (Eph) family is the largest subfamily of receptor tyrosine kinases (RTKs). The Ephs (receptors) bind to specific cell-bound ligands, called ephrins. The binding of this ligand-receptor system is dependent on cell-cell interactions. The ephrin-Eph system is important in embryologic development and differentiation of the nervous and vascular systems. In the current study, the authors hypothesized that ephrins may play a role in the growth and development of colon carcinoma and may be expressed differentially in normal and malignant colonic tissues. METHODS: Reverse transcriptase-polymerase chain reaction (RT-PCR), Northern Blot analyses, and immunohistochemistry were used to examine 11 colon carcinoma cell lines and 20 human colon carcinoma specimens with adjacent uninvolved mucosa for the expression of EphB and ephrin-B family members. RESULTS: EphB2, EphB3, and EphB4 mRNA expression and ephrin-B2 mRNA expression was detected in all the cell lines and colon carcinoma specimens examined. Immunohistochemical analysis showed that ephrin-B2 had higher expression in the colon carcinoma specimens studied than in adjacent normal mucosa. Ephrin-B2 and EphB4 most frequently were expressed on the luminal surface of colon carcinoma epithelium. CONCLUSIONS: The results of the current suggest that the ephrin-Bs are expressed differentially in colon carcinoma and normal mucosa specimens and thus may play a role in the progression of colon carcinoma. Further studies are necessary to determine the functional role of ephrin-Bs in colon carcinoma angiogenesis and growth.

Biomarkers, Tumor↗

PubMed1999

Monomeric structure of the human EphB2 sterile alpha motif domain.

The sterile alpha motif (SAM) domain is a protein module found in many diverse signaling proteins. SAM domains in some systems have been shown to self-associate. Previous crystal structures of an EphA4-SAM domain dimer (Stapleton, D., Balan, I., Pawson, T., and Sicheri, F. (1999) Nat. Struct. Biol. 6, 44-49) and a possible EphB2-SAM oligomer (Thanos, C. D., Goodwill, K. E., and Bowie, J. U. (1999) Science 283, 833-836) both revealed large interfaces comprising an exchange of N-terminal peptide arms. Within the arm, a conserved hydrophobic residue (Tyr-8 in the EphB2-SAM structure or Phe-910 in the EphA4-SAM structure) is anchored into a hydrophobic cleft on a neighboring molecule. Here we have solved a new crystal form of the human EphB2-SAM domain that has the same overall SAM domain fold yet has no substantial intermolecular contacts. In the new structure, the N-terminal peptide arm of the EphB2-SAM domain protrudes out from the core of the molecule, leaving both the arm (including Tyr-8) and the hydrophobic cleft solvent-exposed. To verify that Tyr-8 is solvent-exposed in solution, we made a Tyr-8 to Ala-8 mutation and found that the EphB2-SAM domain structure and stability were only slightly altered. These results suggest that Tyr-8 is not part of the hydrophobic core of the EphB2-SAM domain and is conserved for functional reasons. Cystallographic evidence suggests a possible role for the N-terminal arm in oligomerization. In the absence of a direct demonstration of biological relevance, however, the functional role of the N-terminal arm remains an open question.

Amino Acid Motifs↗

PubMed1999

Misexpression of the Emx-related homeobox genes cVax and mVax2 ventralizes the retina and perturbs the retinotectal map.

The mechanisms that establish the dorsal-ventral (D-V) axis of the eye are poorly understood. We isolated two homeobox genes from mouse and chicken, mVax2 and cVax, whose expression during early eye development is restricted to the ventral retina. In chick, ectopic expression of either Vax leads to ventralization of the early retina, as assayed by expression of the transcription factors Pax2 and Tbx5, and the Eph family members EphB2, EphB3, ephrinB1, and ephrinB2, all of which are normally dorsally or ventrally restricted. Moreover, the projections of dorsal but not ventral ganglion cell axons onto the optic tectum showed profound targeting errors following cVax misexpression. mVax2/cVax thus specify positional identity along the D-V axis of the retina and influence retinotectal mapping.

Amino Acid Sequence↗

PubMed2006

A mutation in RYK is a genetic factor for nonsyndromic cleft lip and palate.

OBJECTIVE: The RYK, EPHB2, and EPHB3 genes are attractive candidates for cleft lip and/or palate and cleft palate only pathogenesis. Both the Ryk-deficient mouse and Ephb2/Ephb3 (genes for interaction molecules with RYK) double-mutant mouse show cleft palate. SETTING: Mutation searches for RYK, EPHB2, and EPHB3 were carried out in a large number of Japanese and Vietnamese patients with cleft lip and/or palate and cleft palate only. Case-control study and transmission disequilibrium tests were performed also, using three single nucleotide polymorphisms within a linkage disequilibrium block in RYK. Seven haplotypes were constructed from the single nucleotide polymorphisms. RESULTS: A missense mutation, 1355G>A (Y452C), in RYK was identified in one Vietnamese patient with cleft lip and/or palate. This mutation was not found among 1646 Vietnamese, Japanese, and Caucasians, including 354 cleft lip and/ or palate and cleft palate only patients. Colony formation assay using NIH3T3 cells transfected with mutant cDNA revealed that mutant RYK had significantly reduced protein activity, compared with those with wild-type RYK, implying that the transformation ability of RYK is depleted by this mutation. Although a case-control study and transmission disequilibrium tests on three individual single nucleotide polymorphisms provided no evidence for association with oral clefts, a case-control study on one rare haplotype suggested a positive association in Japanese patients with cleft lip and/or palate and cleft palate only. No mutations in EPHB2 and EPHB3 were found in any patients examined. CONCLUSION: The findings suggested that a missense mutation, 1355G>A, and one rare single nucleotide polymorphisms haplotype may play a role in the development of cleft lip and/or palate in the Vietnamese, and cleft lip and/ or palate and cleft palate only in the Japanese.

3T3 Cells↗

PubMed2006

Foxl1-deficient mice exhibit aberrant epithelial cell positioning resulting from dysregulated EphB/EphrinB expression in the small intestine.

The winged helix transcription factor Foxl1, expressed in the gut mesenchyme, regulates epithelial cell proliferation and differentiation through the Wnt/beta-catenin pathway. To better understand the role of Foxl1 in epithelial morphogenesis, we examined the tissue structure and positioning of epithelial cells in the small intestine of Foxl1-deficient mice. The small intestine of Foxl1-deficient mice manifested aberrant crypt structure, including widely distributed Paneth cells, which coincided with the ectopic and increased expression of EphB2 and EphB3, which are key regulators of epithelial cell positioning. Furthermore, real-time quantitative PCR indicated that a subset of Wnt family genes was highly expressed in the gut mesenchyme of Foxl1-deficient mice compared with that of wild-type mice. Such an increase in Wnt expression was remarkable in the mesenchyme, where the aberrant Paneth cell positioning was observed by in situ hybridization. Foxl1 plays an important role in the maintenance of crypt architecture and epithelial cell positioning through the mesenchymal-epithelial interaction in the small intestine. This interaction is essential for the normal regulation of the Wnt/beta-catenin pathway and the subsequent EphB/EphrinB expression.

Animals↗