Cell Signaling via Ephrins and Eph Receptors

The ephrins, and their Eph receptors, are a novel class of proteins that enable cells to send signals to one another. Although long known to be key mediators in brain formation, ephrin signaling is also essential for the proper development of new blood vessels. Because some subsets of these important signaling molecules exhibit the additional property of localizing exclusively either to arteries or veins, ephrins have also begun to serve as the first reliable molecular marker capable of distinguishing arterial from venous identity.

In 1987 researchers working with erythropoietin-producing hepatocellular carcinoma cells happened to discover a new kind of tyrosine kinase receptor, which they accordingly named the Eph receptor [3]. With 15 subtypes subsequently identified (EphA1-9 and EphB1-6), Eph receptors now constitute the largest family of tyrosine kinase receptors in vertebrates [4]. Tyrosine kinase receptors participate broadly in many pathways controlling cell growth and differentiation. Unlike traditional tyrosine kinases, however, where soluble hormones and growth factors travel as ligands from cells much farther away, ephrin ligands are bound to the cell surface and can activate Eph receptors on neighboring cells only when their mutual cell membranes draw close enough to interact. As a result, Ephrin/Eph receptor signaling is particularly well-suited for mediating physical cell-to-cell interactions such as repulsion and attraction.

Ephrin ligands are classified into two groups: Ephrin-As and Ephrin-Bs. The six known Ephrin-As are tethered to the cell membrane by a chemical moiety known as the glyco-sylphosphatidyl inositol (GPI) anchor. The three Ephrin-B ligands, on the other hand, extend both inside and outside the cell as transmembrane proteins with active cytoplasmic tails. In general, EphA receptors tend to bind Ephrin-As, and EphB receptors bind to Ephrin-Bs.

Even more unusually for tyrosine kinase-based systems, ephrin ligands can also function as receptors unto themselves, thereby enabling a unique mode of two-way, bidirectional signaling between neighboring cells. The bipartite structure of the Ephrin-B protein particularly lends itself to this duel function, with its extracellular portion serving as the ligand to activate "forward" signaling in Eph-expressing cells, while its cytoplasmic tail controls "reverse" signaling within its own cell [5]. The mechanism for how Ephrin-A ligands may also participate in reverse signaling is, however, unknown.

In neural development, where most Ephrin/Eph research originally concentrated, Ephrin/Eph cell-to-cell signaling has proven to be fundamental to the way axons, the signal-carrying end of nerve cells, navigate their way to specific locations in the nervous system. The best-studied model is one called the retinal-tectal projection, in which axons from visual neurons in the retina migrate to an important visual relay center in a part of the brainstem known as the tectum (the superior colliculus in humans). The axons appear to navigate by way of particular gradients, where, for instance, different EphA receptor concentrations influence anterior/ posterior mapping and various EphBs affect dorsal/ventral patterning. Ephrin/Eph signaling exerts its effects by mediating repulsion and attraction between neurons within these gradients. Axonal migration in other parts of the brain also relies, in part, on Ephrin/Eph signaling, as does neural crest cell migration in the early embryo [6]. The very recent observations that EphB receptors also function in the adult brain beside excitatory NMDA glutamate receptors, and may even affect synaptic plasticity, could suggest an additional, and as-of-yet uncharacterized, role for Ephrin/Eph receptors in higher-order processes such as memory formation as well [7].

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Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

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