The cellular prion protein (PrPC) is thought to be involved in protection against cell death, however the exact Cellular mechanisms involved are still controversial. Herein we present data that strongly indicate a functional link between PrPC-expression and phosphatidylinositol 3-kinase (Pl 3-kinase) activation, a protein kinase that plays a pivotal role in cell survival. Both Mouse neuroblastoma N2a cells and immortalized murine hippocampal neuronal cell lines expressing wild-type PrPC had significantly higher Pl 3-kinase activity levels than their respective controls. Moreover, PI 3-kinase activity was found to be elevated in brain lysates from wild-type mice as compared to prion protein-knockout mice. Recruitment of Pl 3-kinase by PrPC was shown to contribute to cellular survival toward oxidative stress by using 3-morpholinosydnonimine (SIN-1) and Serum deprivation. Moreover, both PI 3-kinase activation and cytoprotection by PrPC appeared to rely oil copper binding to the N-terminal octapeptide of PrPC. Thus, we propose a model in which the interaction of copper(II) with the N-terminal domain of PrPC enables transduction of a signal to PI 3-kinase: the latter. in turn, mediates downstream regulation Of Cell Survival. (c) 2005 Elsevier Inc. All rights reserved.