Cell-cell signaling via EpH receptors and ephrins

Structural Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
Current Opinion in Cell Biology (Impact Factor: 8.47). 11/2007; 19(5):534-42. DOI: 10.1016/
Source: PubMed


Eph receptors are the largest subfamily of receptor tyrosine kinases regulating cell shape, movements, and attachment. The interactions of the Ephs with their ephrin ligands are restricted to the sites of cell-cell contact since both molecules are membrane attached. This review summarizes recent advances in our understanding of the molecular mechanisms underlining the diverse functions of the molecules during development and in the adult organism. The unique properties of this signaling system that are of highest interest and have been the focus of intense investigations are as follows: (i) the signal is simultaneously transduced in both ligand-expressing cells and receptor-expressing cells, (ii) signaling via the same molecules can generate opposing cellular reactions depending on the context, and (iii) the Ephs and the ephrins are divided into two subclasses with promiscuous intrasubclass interactions, but rarely observed intersubclass interactions.

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    • "Eph (Erythropoietin Producing Hepatoma) receptors comprise the largest family of tyrosine kinases and are divided into two classes of EphAs and EphBs based on their sequence homology. Receptor activation occurs via their membrane bound ligands ephrinAs and ephrinBs, respectively [2]. "
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    ABSTRACT: EphB4 receptor tyrosine kinase is of diagnostic and therapeutic value due to its overexpression in breast tumors. Dual functions of tumor promotion and suppression have been reported for this receptor based on presence or absence of its ligand. To elucidate such discrepancy, we aimed to determine the effect of time- and dose-dependent stimulation of EphB4 on viability and invasion of breast cancer cells via recombinant ephrinB2-Fc. Cells were seeded into multiwell plates and were stimulated by various concentrations of preclustered ephrinB2-Fc. Cell viability was measured on days 3 and 6 following treatment using alamar-blue when cells were in different states of confluence. Stimulation of cells with ephrinB2 did not pose any significant effect on cell viability before reaching confluence, while inhibition of cell growth was detected after 6 days when cells were in postconfluent state following a dose-dependent manner. EphrinB2 treatment did not affect tubular formation and invasion on matrigel. This study showed that EphB4 can differentially inhibit cells at post confluent state and that presence of ligand manifests growth-inhibitory properties of EphB4 receptor. It is concluded that growth inhibition has occurred possibly due to long treatment with ligand, a process which leads to receptor downregulation.
    Disease markers 12/2013; 35(6):933-8. DOI:10.1155/2013/857895 · 1.56 Impact Factor
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    • "Eph receptor–ephrin ligand interactions depend upon direct cell–cell interactions and are unique in that they trigger bidirectional signalling within the receptor and ligand-expressing cell. Upon binding their ephrin ligands, Eph receptors cluster together and heterodimerize, leading to receptor autophosphorylation on several intracellular tyrosine residues (Himanen et al., 2007). Ephrin-B ligands can also be phosphorylated on their intracellular domains. "
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    ABSTRACT: Contact inhibition of locomotion (CIL) occurs when a cell stops migrating in a particular direction upon contact with another cell. Many cancer cells show Contact inhibition of locomotion when contacting one another but display contact-unimpeded migration following collision with noncancer cells. Here we review current understanding of Contact inhibition of locomotion, from Abercrombie's historical studies of cells in tissue culture to more recent analyses of Contact inhibition of locomotion in vivo. We discuss the cellular machinery required for CIL and the molecular signals that regulate it. We focus on our recent finding that in prostate cancer cells, Contact inhibition of locomotion is regulated by a balance between EphA and EphB receptor signalling. We show that, as recently described for chick heart fibroblasts, microtubule dynamics are required for Contact inhibition of locomotion in prostate cancer cells and we propose that stabilization of microtubules could account for defective Contact inhibition of locomotion between cancer cells and noncancer cells.
    Journal of Microscopy 03/2013; 251(3). DOI:10.1111/jmi.12024 · 2.33 Impact Factor
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    • "In this respect, extracellular receptor predimerization could also play an important role in generating the ultra high affinities observed in a physiological setting. Interestingly, a number of other RTKs, such as the IGF1 (Lawrence et al., 2007), EGFR (Chung et al., 2010; Mi et al., 2011) and Eph (Himanen et al., 2007) receptors do form oligomers in the absence of cytokine ligand. Nonetheless, hCSF-1R D1-D5 would have to undergo dramatic domain rearrangements to bind hCSF-1. "
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    ABSTRACT: The hematopoietic colony stimulating factor-1 receptor (CSF-1R or FMS) is essential for the cellular repertoire of the mammalian immune system. Here, we report a structural and mechanistic consensus for the assembly of human and mouse CSF-1:CSF-1R complexes. The EM structure of the complete extracellular assembly of the human CSF-1:CSF-1R complex reveals how receptor dimerization by CSF-1 invokes a ternary complex featuring extensive homotypic receptor contacts and striking structural plasticity at the extremities of the complex. Studies by small-angle X-ray scattering of unliganded hCSF-1R point to large domain rearrangements upon CSF-1 binding, and provide structural evidence for the relevance of receptor predimerization at the cell surface. Comparative structural and binding studies aiming to dissect the assembly principles of human and mouse CSF-1R complexes, including a quantification of the CSF-1/CSF-1R species cross-reactivity, show that bivalent cytokine binding to receptor coupled to ensuing receptor-receptor interactions are common denominators in extracellular complex formation.
    Structure 12/2011; 19(12):1762-72. DOI:10.1016/j.str.2011.10.012 · 5.62 Impact Factor
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