EphrinA-EphR Signaling
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EphrinA-EphR Signaling
Neuronal growth cones in the developing nervous system are guided to their targets by attractive and repulsive guidance molecules, which include members of the netrin, semaphorin, ephrin, and Slit protein families. The Eph family forms the largest group of RTKs (Receptor Tyrosine Kinases) comprising 14 members in mammals that play critical roles in diverse biological processes during development as well as in the mature animal. They are activated by membrane-bound ligands called Ephrins, which are classified into two subclasses based on their modes of membrane anchorage. The Ephrin-A ligands are tethered to the plasma membrane by GPI (Glycosylphosphatidylinositol) anchor and prefer to bind to EphA Receptors. The Ephrin-B ligands (EphrinB1-B3), which possess a transmembrane moiety and a short cytoplasmic domain, bind to EphB Receptors (EphB1-B6). The interactions between Ephrins and (Eph Receptors) are generally promiscuous within each subclass (Ref.1). Interactions between and Ephrins are implicated in repulsive axon guidance, cell migration, topographic mapping, and angiogenesis. Besides their functions in development, and Ephrins are implicated in the regulation of NMDA (N-Methyl D-Aspartate)-dependent synaptic function in mature synapses.

The extracellular domain is composed of the ligand-binding Glob (Globular domain), a Cys (Cystein)-rich region and two Fn (Fibronectin) Type-III repeats. The cytoplasmic part of is divided into four functional units; the juxtamembrane domain that contains two conserved residues, a classical protein tyrosine kinase domain (Eph Kinase), a SAM (Sterile Alpha Motif) and PBM (PDZ-domain Binding Motif). Upon the formation of cell-cell contact, signaling through the results in modulation of integrin activity and reorganization of the actin cytoskeleton. As a result, Ephs generate adhesive or repulsive signals, and in the neural system guide the movement of axonal growth cones, cell migration, and synapse formation (Ref.2). On ligand engagement each member of the receptor dimmer autophosphorylate several tyrosine residues that is located in the intracellular part of the partner receptor. Autophosphorylation of juxtamembrane tyrosine residues is required for full activation of the protein tyrosine kinase domain of the receptor. Once the receptor is activated, adaptor molecules such as the SH2, SHP2-FAK (Focal Adhesion Kinase), the p110Gamma isoform of PI3K (Phosphatidylinositol 3-Kinase) associate with it to transmit signals into the cell (Ref.3). EphA Receptors directly activate Rho GTPases through the exchange factor Ephexin. Exchange factors activate GTPases by catalyzing the replacement of GDP with GTP. Ephexin is preferentially expressed in the nervous system and constitutively binds the kinase domain of EphA Receptors. The activation of RhoA by Ephexin engages its downstream effector Rho Kinase (ROCK), which in turn activates LIMK (LIM Kinase), thereby modulating actin dynamics via phosphorylation of Cofilin. Other antagonistic GTPases mediating growth cone mobility signals, such as Rac1, CDC42 and PAK (p21-Activated Kinase) are also simultaneously downregulated. During synaptogenesis, the Eph Receptors help establish and modify the postsynaptic specialization by transmitting signals to the actin cytoskeleton through the Rho-family of GTPases. Intriguingly, EphA/EphrinA signals mediate a form of crosstalk between glial cells and neurons, which regulates the morphology of excitatory synapses in the mature hippocampus (Ref.4).

EphrinA ligands can also convey reverse signals that modify cell behavior. The EphrinA molecules, like many GPI-anchored proteins, are targeted to lipid rafts, where they presumably assemble into protein complexes that transduce intracellular signals. Clustering of EphrinA molecules with EphA-fusion proteins recruits the Src family kinase Fyn to lipid rafts. This is accompanied by the redistribution of Vinculin, activation of MAPK (Mitogen Activated Protein Kinase), tyrosine phosphorylation of a p120 KD lipid raft protein, and increased cell substrate adhesion (Ref.5). EphrinA reverse signal is also modulated by cell surface shedding of the ligand through its association with the metalloprotease ADAM10. Upon binding of EphA Receptors, ADAM10 cleaves EphrinA2 from the cell surface. This serves a dual function. EphrinA cleavage from the cell surface allows -bearing structures such as growth cones to change their response to EphrinA molecules from adhesion to repulsion. In addition, the cleaved ligand is no longer able to transmit signals or activate EphA Receptors, and hence both reverse and forward signaling is terminated.

Eph receptors and their ligands have been implicated in developmental patterning events, including assembly of the vasculature, retinotectal axonal targeting, and developmental segmentation of embryonic tissues into boundary zones defined by reciprocal spatial gradients of ligands and their receptors. Eph proteins also play a critical role in the cellular organization and function of non-neural tissues. Furthermore, Eph proteins play a role in platelet clustering and hence may be important for blood clotting at sites of vascular injury. The EphA Receptors tyrosine kinases play a central role in the establishment of topographic maps in the vertebrate visual system. They are expressed in a graded fashion, with high levels in retinal ganglion cell axons in the temporal retina, and low levels on axons from the nasal retina (Ref.6).