Rho guanine nucleotide exchange factor 15 (ARHGEF15)

Rho guanine nucleotide exchange factor 15 (ARHGEF15) is an enzyme that acts as a specific guanine nucleotide exchange factor (GEF) for RhoA, a small Rho GTPase critical for cytoskeletal dynamics, vesicular trafficking, cell migration, and synaptic development. In the nervous system, ARHGEF15 (also known as Ephexin5) negatively regulates excitatory synapse formation and dendritic spine maturation by activating RhoA, a process subject to control by Eph receptor signaling and ubiquitination. Dysregulation or genetic variants of ARHGEF15 are implicated in neurodevelopmental disorders (such as Angelman syndrome, autism, early-onset epilepsies), and variants may cause pathological increased excitatory activity resulting in epilepsy. ARHGEF15 also has important roles in vascular smooth muscle and endothelial cell function, where it mediates angiogenesis and vascular contractility. Overexpression of ARHGEF15 is associated with increased cancer cell motility and proliferation, especially in pancreatic cancer, linking its activity to poor prognosis and supporting its consideration as a therapeutic target in oncology.

Other names

ARHGEF15Ephexin5E5KIAA0915Vsm-RhoGEFARGEF15FLJ13791MGC44868Ephexin-5ARHGF_HUMANEPHEXIN5

In epilepsy: Ketogenic diet appears to restore synaptic balance disrupted by ARHGEF15 variants—mechanistically, by altering metabolic milieu affecting neuronal excitability. No other established mechanisms for drug action targeting ARHGEF15 from the provided data.