The International Journal of Biochemistry & Cell Biology
Molecules in focusEph receptors and ephrins
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 rythropoietin roducing epatocellular 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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