RGL3 (ral guanine nucleotide dissociation stimulator like 3) is a guanine nucleotide exchange factor (GEF) that primarily functions as an activator of the small GTPase Ral 1. The protein serves as a downstream effector for multiple Ras-family GTPases, including Rit, H-Ras, N-Ras, R-Ras, Rap1, and Rap2, interacting with these proteins in a GTP-dependent manner through its C-terminal domain 12. RGL3 exhibits guanine nucleotide exchange activity toward Ral that is stimulated by activated Rit or Ras expression 1. The protein localizes primarily to the cytoplasm and affects cell morphology by suppressing cell-spreading induced by Rap1 and R-Ras while enhancing focus-formation induced by oncogenic Ras mutants 2. RGL3 also interacts with profilin II, an actin polymerization activator, through its characteristic N-terminal proline cluster, potentially mediating interactions between Ras/Rap-family proteins and the actin cytoskeleton 2. Clinically, RGL3 variants show significant associations with hypertensive disorders, including preeclampsia and gestational hypertension 34. A low-frequency partial deletion of RGL3 exon 6 confers protective effects against hypertension risk 5. The gene is also implicated in midbrain dopaminergic neuron development, where Rgl3 cells function as a signaling subtype promoting survival of dopaminergic neurons 6.