PLEKHG2 is a Rho guanine nucleotide exchange factor (GEF) that primarily functions as an activator of small GTPases Rac1, Rac3, and Cdc42 1. It belongs to the Dbl family of RhoGEFs and contains both pleckstrin homology and RhoGEF domains 2. Mechanistically, PLEKHG2 is activated by binding heterotrimeric G protein βγ subunits at its N-terminus, which relieves autoinhibition to expose the catalytic Dbl homology domain 3. This activation promotes actin polymerization and cytoskeletal reorganization 4. PLEKHG2 activity is negatively regulated by Gαs subunit binding, which directly masks the functional DH domain 5. The protein also interacts with regulatory partners including FHL1A isoform, which specifically enhances PLEKHG2-dependent transcription 6, and ABL1 kinase, which suppresses cell growth through NF-κB signaling 7. Clinically, PLEKHG2 mutations cause neurodevelopmental disorders. Homozygous p.Arg204Trp variants associate with microcephaly and intellectual disability 1. Loss of PLEKHG2 function impairs dendritic arbor formation, axon pathfinding, and dendritic spine morphogenesis during cortical development 1. PLEKHG2 variants also contribute to leukodystrophy pathogenesis 8, suggesting essential roles in white matter development. These findings establish PLEKHG2 as critical for neuronal maturation and proper brain development.