Ubiquitin E3 ligase Nedd4-1 acts as a downstream target of PI3K/PTEN-mTORC1 signaling to promote neurite growth

Neurons develop processes called neurites to form defined networks. Neurite growth is regulated by many intracellular signaling pathways, among which signaling via phosphatase and tensin homolog (PTEN) is of particular relevance because it controls the translation of a substantial subset of mRNAs that encode proteins with a role in neurite growth. Previous studies indicated that the E3 ubiquitin ligases Nedd4-1 and Nedd4-2 may ubiquitinate and negatively regulate PTEN in various cell types, including Xenopus laevis retinal ganglion cells. We report a strikingly inverted scenario, according to which Nedd4s are dispensable for ubiquitination of PTEN in mammalian central nervous system neurons. Instead, Nedd4-1 mRNA is one of the most important targets of PTEN-dependent signaling in the regulation of neurite growth.