This entry represents the ligand-binding domain found in ephrin type-A receptor 2 (EphA2). EphA2 negatively regulates cell differentiation and has been shown to be overexpressed in tumor cells and tumor blood vessels in a variety of cancers including breast, prostate, lung, and colon. As a result, it is an attractive target for drug design since its inhibition could affect several aspects of tumor progression [, , ]. Class EphA receptors bind GPI-anchored ephrin-A ligands. There are ten vertebrate EphA receptors (EphA1-10), which display promiscuous interactions with six ephrin-A ligands [, ]. Ephrin receptors (EphRs) comprise the largest subfamily of receptor tyrosine kinases (RTKs). EphRs contain a ligand binding domain and two fibronectin repeats extracellularly, a transmembrane segment, and a cytoplasmic tyrosine kinase domain. Binding of the ephrin ligand to EphR requires cell-cell contact since both are anchored to the plasma membrane. The resulting downstream signals occur bidirectionally in both EphR-expressing cells (forward signaling) and ephrin-expressing cells (reverse signaling) [].
ARHGEF16, also called ephexin-4, acts as a guanine nucleotide exchange factor (GEF) for RhoG, activating it by exchanging bound GDP for free GTP. RhoG is a small GTPase that is a crucial regulator of Rac in migrating cells. ARHGEF16 interacts directly with the ephrin receptor EphA2 and mediates cell migration and invasion in breast cancer cells by activating RhoG [, ]. ARHGEF26, also called SGEF (SH3 domain-containing GEF), also activates RhoG. It is highly expressed in liver and may play a role in regulating membrane dynamics []. ARHGEF16 and ARHGEF26 contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology(PH), and SH3 domains. The SH3 domains of ARHGEFs play an autoinhibitory role through intramolecular interactions with a proline-rich region N-terminal to the DH domain. The SH3 domain of ARHGEF16 also binds to Elmo, and this interaction may relieve the self-inhibitory state ofARHGEF16 [].This entry represents the SH3 domains of ARHGEF16 and ARHGEF26.
