PTEN Defect Facilitates Neuronal Cell Differentiation via ERK5 Activation

PTEN loss of function (LOF) enhances proliferation and differentiation of neuronal cells by well characterized pathways. Here, we identified ERK5 as a PTEN substrate that functions to boost NGF-induced neuronal differentiation in PC12 cells. Using knockdown approaches, we found that PTEN LOF leads to increased ERK5 phosphorylation, concomitant with increased neurite outgrowth, and upregulation of differentiation markers GAP43 and Nestin. Conversely, ERK5 overexpression produced similar outcomes, while ERK genetic LOF and pharmacological inhibition reduced neurite outgrowth and downregulated GAP43 expression. We also found that ERK5 interacted with c-Jun promoter directly to in part repress c-Jun expression. Taken together, our findings reveal that ERK5 is a novel PTEN target that mediates NGF-dependent neuronal differentiation.