Nucleolin is a multifunctional RNA Binding Protein (RBP) with diverse subcellular
localizations, including the nucleolus in all eukaryotic cells, the plasma membrane in tumor
cells, and the axon in neurons. Here we show that the glycine arginine rich (GAR) domain of
nucleolin drives subcellular localization via protein-protein interactions with a kinesin light
chain in the kinesin motor complex in axons and plasma membrane interactions of GAR
arginine rich sequences, in addition to its already reported involvement in liquid-liquid
phase separation in the nucleolus. Nucleolin transport to axons requires the GAR domain,
and heterozygous GAR deletion mice reveal reduced axonal localization of nucleolin cargo
mRNAs and enhanced sensory neuron growth. Thus, the GAR domain governs axonal
transport of a growth controlling RNA-RBP complex in neurons, and is a versatile localization
determinant for different subcellular compartments. Localization determination by GAR
domains may explain why GAR mutants in diverse RBPs are associated with
neurodegenerative disease.