Rho GTPases, which play fundamental roles in numerous cellular processes, are initiated by external stimuli that signal though G-protein coupled receptors. ARHGEF15 (Rho guanine nucleotide exchange factor (GEF) 15), also known as ARGEF15 or Vsm-RhoGEF, is a 841 amino acid protein expressed in the vascular smooth muscle of coronary artery. ARHGEF15 functions as a specific guanine nucleotide exchange factor for RhoA and interacts with ephrin-A4 in vascular smooth muscle cells. Containing one DH (DBL-homology) domain, ARHGEF15 is phosphorylated on tyrosine residues upon ephrin-A1 stimulation. The DH domain consists of a region of about 150 amino acids that induces Rho family GTPases to release GDP. This effectively activates the Rho GTPase by allowing GTP binding. ARHGEF15 is encoded by a gene located on human chromosome 17, which comprises over 2.5% of the human genome and encodes over 1,200 genes.