Ephexin-like, PH domain (PH_ephexin)
Type: Domain

This is the PH domain of ephexins, which is believed to act with the DH domain in mediating protein-protein interactions .

This entry includes ephexin family members which comprises ephexin-1 to 5 and related animal proteins, such as ARHGEF26, also called SGEF (SH3 domain-containing GEF) which shows structural similarities with ephexins . ARHGEF26 is highly expressed in liver and may play a role in regulating membrane dynamics . A common feature of this proteins, apart from their high sequence homology, is that they are the direct downstream proteins of Eph receptors, a large subfamily of receptor tyrosine kinases that is activated by Ephrins and involved in various cellular processes such as axon guidance, formation of tissue boundaries, long-term potentiation, angiogenesis, and cancer. The are essential for normal function of neurons and their development .

Ephexin-1 (also called NGEF/neuronal guanine nucleotide exchange factor) plays a role in the homeostatic modulation of presynaptic neurotransmitter release and plays crucial roles in axon guidance .

Literature data about Ephexin-2 (also known as RhoGEF19) is limited, however, its intrinsic role to function as a GEF for RhoA seems to be clear. It is involved in convergent extension, a developmental step of anterior-posterior axis extension in Xenopus gastrulation through RhoA activation and it also participates in pronephric tubulogenesis of Xenopus and zebrafish. Elevated levels of Ephexin-2 results in the increased activity of RhoA which causes higher cancer proliferation, migration, and invasion .

Ephexin-3 (also called Rho guanine nucleotide exchange factor 5/RhoGEF5) is ubiquitously expressed in many tissues, such as colon, kidney, trachea, prostate, liver, and pancreas, with tendency to be highly expressed in tissues containing epithelial cells. It functions as a GEF for RhoA. It plays a role in cell migration and adhesion as it is involved in Src-induced podosome formation and its deletion causes defects in immature dendritic cell migration in vivo .

Ephexin-4 (also called RhoGEF16) acts downstream of EphA2 to promote ligand-independent breast cancer cell migration and invasion toward epidermal growth factor through activation of RhoG. This in turn results in the activation of RhoG which recruits ELMO2 and Dock4 to form a complex with EphA2 at the tips of cortactin-rich protrusions in migrating breast cancer cells .

Ephexin-5 (also known as RhoGEF15 and Vsm-RhoGEF) is the specific GEF for RhoA activation and the regulation of vascular smooth muscle contractility and it is also involved in angiogenesis, as it mediates VEGF-induced Rho GTPase activity modulation. It interacts with EPHA4 PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. It is highly expressed in the brain, especially in the hippocampus, where it may act as a beacon locating sites of new spine formation keeping them in check until incoming activity promotes spine formation at these sites .

Members of the Ephexin family contain a RhoGEF (DH) followed by a PH domain and an SH3 domain, except in Ephexin-5, in which the SH3 domain is absent . The ephexin PH domain is believed to act with the DH domain in mediating protein-protein interactions .