Presenilin regulates extracellular regulated kinase (Erk) activity by a protein kinase C alpha dependent mechanism

Presenilin (PSI and PS2) mutations cause early-onset familial Alzheimer's disease (AD). In addition to affecting beta-amyloid precursor protein (APP) processing and A beta generation, PSs regulate a number of signaling pathways. We previously showed that PSs regulate both phospholipase C (PLC) and protein kinase C (PKC) alpha and gamma activities. We also reported that PS double knockout mouse embryonic fibroblasts (MEFs) have reduced levels of PKC alpha and enhanced levels of PKC delta. Here, we determined whether the PS modulation of PLC/PKC has consequences for extracellular regulated kinase (Erk) signaling. Erk has been suggested to be important in AD pathology by modulating APP processing and tau phosphorylation. We found that knocking out PSI or PS2 alone resulted in increased Erk activity and that this effect could be reversed by the PKC alpha inhibitor Go6976. We also found that Erk activity following either PLC or PKC stimulation was significantly lower in PS double knockout cells and that treatment with the PKC activator phorbol 12,13-dibutyrate (PdBu) down-regulated total-Erk levels in all cells except PS double knockouts. These results demonstrate that PSs regulate Erk activity through a PKC alpha dependent pathway and that disruption of PLC/PKC signaling in the absence of both PSI and PS2 results in lower downstream activation of Erk. (C) 2008 Elsevier Ireland Ltd. All rights reserved.