NADPH oxidase and extracellular regulated kinases 1/2 are targets of prion protein signaling in neuronal and nonneuronal cells

Abstract

Putative functions of the cellular prion protein, PrP C , include resistance to oxidative stress, copper uptake, cell adhesion, and cell signaling. Here, we report NADPH oxidase-dependent reactive oxygen species (ROS) production and extracellular regulated kinases 1/2 (ERK1/2) phosphorylation on PrP C stimulation in the 1C11 neuroectodermal precursor, in its neuronal differentiated progenies, and in GT1-7 neurohypothalamic and BW5147 lymphoid cells. In neuroprogenitor, hypothalamic, and lymphoid cells, ERK1/2 activation is fully controlled by the NADPH oxidase-dependent ROS production. In 1C11-derived bioaminergic cells, ROS signaling and ERK1/2 phosphorylation are both controlled by Fyn kinase activation, introducing some specificity in PrP C transduction associated with this neuronal context. These data argue for an ubiquitous function of PrP C in cell-redox homeostasis through ROS production.

Modulation of Serotonergic Receptor Signaling and Cross-talk by Prion Protein*

“…While itself acting as a cell surface receptor (11,12), PrP C does not appear to be directly coupled to the PLA2 pathway (Fig. 1B).…”

“…Whatever the state of differentiation of 1C11 cells, PrP C is endogenously expressed at roughly similar levels (10). Moreover, antibody-mediated ligation of PrP C , which is assumed to mimic the interaction with a yet to be identified ligand, induces NADPH oxidase-dependent reactive oxygen species production and activation of the extracellular regulated kinases 1/2 (ERK1/2), two members of the mitogen-activated protein kinase family (11). In cells harboring a fully differentiated phenotype exclusively, PrP C associates with the membrane protein caveolin and the tyrosine kinase Fyn within a signaling platform that governs the downstream effectors, i.e.…”

“…In cells harboring a fully differentiated phenotype exclusively, PrP C associates with the membrane protein caveolin and the tyrosine kinase Fyn within a signaling platform that governs the downstream effectors, i.e. reactive oxygen species and ERK1/2 (11,12). The implementation of the PrP C -caveolin-Fyn complex depends upon the expression of neuronal and neurotransmitter-associated functions.…”

Induction of ligand-specific PrPCsignaling in human neuronal cells

“…Prion protein specific antibody has been utilized to "activate" PrP C through direct binding for investigations of PrP C function. 19 Analysis is performed through peptide arrays which offer a more global and unbiased representation of signaling events than other methods. Cluster analysis of the kinome data reveals highly distinct patterns of signaling activity under the different treatment conditions.…”

Pharmacological inhibition of neuronal NADPH oxidase protects against 1-methyl-4-phenylpyridinium (MPP+)-induced oxidative stress and apoptosis in mesencephalic dopaminergic neuronal cells

“…Several non-neuronal, neuronal, and glial cell lines including PC12 (Ibi et al, 2006), SH-SY5Y (Nikolova et al, 2005), GT1-7 (Schneider et al, 2003), IC11 (Schneider et al, 2003), Neuro2A (Reis et al, 2006), and BV-2 (Reis et al, 2006) have also been shown to express various NADPH oxidase subunit proteins.…”