Functions as a guanine exchange factor (GEF) for RAB26 and thus regulates autophagy of synaptic vesicles in axon terminal of motoneurons (PubMed:29084947). Involved in the control of neuronal cell differentiation. Plays a role in angiogenesis through regulation of endothelial cells chemotaxis (PubMed:21543326). Affects also the migration, adhesion, and matrix/bone degradation in macrophages and osteoclasts (By similarity). Interacts with GIPC1/synectin and RHOA. Predominantly cytoplasmic, however when endothelial cells are stimulated with lysophosphatidic acid, PLEKHG5 is found in perinuclear regions and at the cell membrane (PubMed:16467373). Localizes at cell-cell junctions in quiescent endothelial cells, and relocalizes to cytoplasmic vesicle and the leading edge of lamellipodia in migrating endothelial cells (PubMed:21543326). Expressed in neurons and glial cells of the peripheral nervous system, with highest levels of expression in the brain and sciatic nerve endoneurium. Isoform 2 is expressed at detectable levels only in malignant cells. Regulated during development, with the highest level at postnatal days 10 to 14, suggesting a role in myelination of the peripheral nervous system. Animals develop normally and show no clear neurologic symptoms as adults. However, electrophysiologic studies indicated that mutant mice have decreased motor nerve conduction velocities and delayed compound action potentials. Mutant mice perform slightly less well than control mice in the rotarod test (PubMed:23777631). Deficient mice have no motoneuron loss during their first year. A loss of motoneurons starts at 12 months and this decrease is more prominent in 24-month-old animals. Biogenesis of autophagosomes is impaired in Plekhg5-deficient motoneurons resulting in a reduced number of retrogradely transported autophagosomes (PubMed:29084947).