Molecules in focus
Eph receptors and ephrins

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Abstract

The Eph receptors are the largest known family of receptor tyrosine kinases. The Eph receptors and their membrane-attached ligands, ephrins, show diverse expression patterns during development. Recent studies have demonstrated that Eph receptors and ephrins play important roles in many developmental processes, including neuronal network formation, the patterning of the neural tube and the paraxial mesoderm, the guidance of cell migration, and vascular formation. In the nervous system, Eph receptors and ephrins have been shown to act as positional labels to establish topographic projections. They also play a key role in pathway finding by axons and neural crest cells. The crucial roles of Eph receptors and ephrins during development suggest involvement of these genes in congenital disorders affecting the nervous system and other tissues. It has also been suggested that Eph receptors and ephrins may be involved in carcinogenesis. It is therefore of clinical importance to further analyse the function of these molecules, as manipulation of their function may have therapeutic applications.

Introduction

Receptor tyrosine kinases (RTKs) play crucial roles in cell proliferation, differentiation, and embryonic development. RTKs can be divided into distinct subfamilies based on their structural similarities. In 1987, the first member of the Eph subfamily, EphA1, was cloned by Hirai et al. from an erythropoietin producing hepatocellular carcinoma cell line [1]. To date, the Eph subfamily contains 14 members in vertebrates, and is by far the largest known subfamily of RTKs. Most of the members are predominantly expressed in the nervous system, with distinct and overlapping patterns [1]. Recently, a family of ligands for the Eph receptors, named ephrins, has been identified, with eight members thus far cloned in vertebrates [1]. The ephrins are all membrane-attached molecules, and this attachment appears to be crucial for function. Interactions between Eph receptors and ephrins have been implicated in many processes of embryonic patterning. Here, I discuss Eph receptors and ephrins in terms of structural features and signaling, biological functions focused on neural development, and potential clinical implications.

Section snippets

Eph receptors (Fig. 1, left)

The extracellular region of the Eph receptors consists of an N-terminal globular domain followed by a unique cystein-rich motif and two fibronectin type III motifs. The N-terminal globular domain has been identified to be the principal ligand-binding domain [2], [3], and has been recently shown by X-ray crystallography to fold into a compact jellyroll β-sandwich composed of 11 antiparallel β-strands [4].

As in other RTKs, the intracellular region of the Eph receptors contains domains which are

Biological functions

Eph receptors and ephrins have been implicated in many developmental processes, including neuronal network formation, the regional patterning of the neural tube and the paraxial mesoderm, the guidance of cell migration, and vascular formation [13]. In this review, I focus on functions in neuronal network formation.

Function of the nervous system is critically dependent upon the establishment of appropriate connections between neurons and their target cells. The initial development of these

Clinical implications

Since Eph receptors and ephrins have been found to be key regulators in axonal guidance, it is of great clinical interest to explore links between these genes and congenital diseases affecting neuronal connections, such as agenesis of the corpus callosum. It will also be important to study the regulation of these molecules during regeneration.

A number of Eph receptors have been shown to be overexpressed in tumors, including hepatoma, gastric adenocarcinoma, and malignant melanoma [28]. In

Acknowledgments

I thank John Flanagan, Miriam Osterfield, Mark Perin and Hitoshi Komuro for critically reading the manuscript. I apologize to all whose work has been cited but not referenced as an original paper, due to space restriction.

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