title: Activation of phosphatidylinositol 3-kinase by cellular prion protein and its role in cell survival.
abstract: The cellular prion protein (PrP(C)) 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 PrP(C) expression and phosphatidylinositol 3-kinase (PI 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 PrP(C) had significantly higher PI 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 PI 3-kinase by PrP(C) 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 PrP(C) appeared to rely on copper binding to the N-terminal octapeptide of PrP(C). Thus, we propose a model in which the interaction of copper(II) with the N-terminal domain of PrP(C) enables transduction of a signal to PI 3-kinase; the latter, in turn, mediates downstream regulation of cell survival.
authors.affiliation: Department of Physiology and Biochemistry, University of Malta, Msida MSD 06, Malta. neville.vassallo@um.edu.mt
authors.forename: Neville
authors.initials: N
authors.lastname: Vassallo
authors.forename: Jochen
authors.initials: J
authors.lastname: Herms
authors.forename: Christina
authors.initials: C
authors.lastname: Behrens
authors.forename: Bjarne
authors.initials: B
authors.lastname: Krebs
authors.forename: Keiichi
authors.initials: K
authors.lastname: Saeki
authors.forename: Takashi
authors.initials: T
authors.lastname: Onodera
authors.forename: Otto
authors.initials: O
authors.lastname: Windl
authors.forename: Hans A
authors.initials: HA
authors.lastname: Kretzschmar
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D003300:Copper / Q000378:metabolism*; D004789:Enzyme Activation; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D018621:PrPC Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D018621:PrPC Proteins; D003300:Copper; D019869:Phosphatidylinositol 3-Kinases