Ephrin Receptor Signaling


Pathway Description

The Eph receptors consist of the largest group of receptor tyrosine kinases, which bind to the ephrins, a family of cell surface associated ligands. The ephrin-Eph receptor complexes influence cell behavior such as attraction/repulsion, adhesion/de-adhesion implicated in axon guidance, cell migration, angiogenesis and synaptic plasticity.

The ephrins are divided into two subclasses, the ephrin A subclass contains ephrin A1 to A5, which are tethered to the cell membrane by a GPI anchor. The ephrin B subclass contains ephrin B1 to B3, which have transmembrane domain followed by a short cytoplasmic tail. The Eph receptors are also divided into two subclasses (Eph A1 to A8) and (EphB1 to B4, EphB6) based on their sequence similarity and ligand affinity. EphA receptors typically bind to most ephrin A ligands and EphB receptors bind most of the ephrin B ligands, with the exception of EphA4, which binds both ephrin A and B ligands.

These ephrin-Eph complexes are unique in the receptor tyrosine kinase family in that their signaling is bi-directional, propagating downstream signaling in the Eph receptor bearing cells (forward signaling) and in the cells expressing ephrins (reverse signaling).

Forward signaling: upon ephrin engagement, each member of the Eph receptor dimer auto- and transphosphorylates several tyrosine residues in their cytoplasmic domain. This phosphorylation creates binding sites for SH2 domains of several adaptor proteins. EphA receptors can directly activate Rho GTPases through the exchange factor Ephexin. The activation of Rho and its downstream effectors induced growth cone collapse, axon repulsion, and cell repulsion. EphA receptors can also inhibit or promote integrin-mediated adhesion through FAK. EphB receptors interact with different exchange factors, intersectin and kalirin. The intersectin-Cdc42-WASP- actin and kalirin-Rac-PAK-actin pathways regulate cytoskeleton dynamics leading to dendritic spines morphogenesis. EphB receptors can also promote integrin-mediated adhesion through the NCK-NIK pathway and the SHEP1-CAS-CRK-C3G-RAP1 pathway. Furthermore, EphB receptors activate Src, which phosphorylates NMDA receptors and increases calcium influx, having an effect on synaptic plasticity. Both EphA and EphB can negatively regulate the Ras-MAPK pathway downstream of other receptors, such as integrins or receptor tyrosine kinases (VEGFR, PDGFR, EGFR), affecting cell proliferation and axon guidance.

Reverse signaling: upon receptor engagement, ephrin A ligands activates FYN, which regulate cell morphology and integrin-mediated adhesion. Upon binding to an EphB receptor, ephrin B ligands are phosphorylated on cytoplasmic tyrosine residues by Src. Adaptor protein GRB4 is then recruited and initiates signaling pathways that regulate cytoskeleton dynamics and lead to disassembly of focal adhesions. Ephrins B binds constitutively to RGS3, which links G-protein-coupled receptors to ephrin-Eph receptor signaling.