Significance
This article adds to the body of knowledge about the mechanism of extracellular signal-regulated kinase (ERK)-mediated differentiation by describing the molecular function of phosphatase and tension homolog (PTEN) during the neuronal differentiation of human neural stem cells (hNSCs). Previous studies showed that S6K signaling promoted neuronal differentiation in hNSCs via the phosphatidylinositol 3-kinase Akt-mammalian target of rapamycin signaling pathway. A further series of studies investigated whether this S6 kinase-induced differentiation in hNSCs involves regulation of ERK signaling by PTEN. The current study identified a novel mechanism by which PTEN regulates neuronal differentiation in hNSCs, suggesting that activating PTEN function promotes dopaminergic neuronal differentiation and providing an important resource for future studies of PTEN function.