PrP C regulates epidermal growth factor receptor function and cell shape dynamics in Neuro2a cells

The prion protein (PrP) plays a key role in prion disease pathogenesis. Although the misfolded and pathologic variant of this protein (Pr P SC ) has been studied in depth, the physiological role of Pr P C remains elusive and controversial. Pr P C is a cell‐surface glycoprotein involved in multiple cellular functions at the plasma membrane, where it interacts with a myriad of partners and regulates several intracellular signal transduction cascades. However, little is known about the gene expression changes modulated by Pr P C in animals and in cellular models. In this article, we present Pr P C ‐dependent gene expression signature in N2a cells and its implication in the most overrepresented functions: cell cycle, cell growth and proliferation, and maintenance of cell shape. Pr P C over‐expression enhances cell proliferation and cell cycle re‐entrance after serum stimulation, while Pr P C silencing slows down cell cycle progression. In addition, MAP kinase and protein kinase B ( AKT ) pathway activation are under the regulation of Pr P C in asynchronous cells and following mitogenic stimulation. These effects are due in part to the modulation of epidermal growth factor receptor ( EGFR ) by Pr P C in the plasma membrane, where the two proteins interact in a multimeric complex. We also describe how Pr P C over‐expression modulates filopodia formation by Rho GTP ase regulation mainly in an AKT ‐Cdc42‐N‐ WASP ‐dependent pathway.In this study, we analyzed the PrP C ‐dependent gene expression signature of neuroblastoma (N2a) cells after transient acute up‐regulation and down‐regulation of PrP C . We demonstrate that PrP C plays roles in proliferation and neuritogenesis through modulation of EGFR activity. This approach will give new insights into the molecular mechanisms by which PrP C regulates key cellular functions in cell physiology.