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.