PLEKHG4 is a Rho guanine nucleotide exchange factor (GEF) that regulates small GTPase signaling, particularly RhoA, Cdc42, and Rac1 activation 1. The protein contains pleckstrin homology and RhoGEF domains and plays roles in cytoskeletal dynamics and cellular signaling 2. PLEKHG4 functions in glucose homeostasis by mediating insulin-stimulated GLUT4 translocation and glucose uptake in skeletal muscle and adipose tissues 3. In neurons, PLEKHG4 binds and colocalizes with Kv3.3 potassium channels in Purkinje and auditory brainstem neurons, where it normally shows uniform cytoplasmic distribution 2. Disease relevance includes involvement in thyroid cancer progression, where PLEKHG4 is upregulated and promotes malignant phenotypes including proliferation, migration, invasion, and epithelial-mesenchymal transition through RhoGTPase activation 1. In spinocerebellar ataxia, mutations affecting Kv3.3 channels cause PLEKHG4 to form cytoplasmic aggregates, suggesting disrupted normal function 2. The protein is regulated by ubiquitin-conjugating enzyme UBE2O, which facilitates its ubiquitination and degradation 1. PLEKHG4 has been investigated as a candidate gene for hearing impairment but no causal variants were identified 4.