Presenilins (PS) have been reported to be functionally involved in amyloid precursor protein processing, notch receptor signaling, and programmed cell death, or apoptosis. To understand the role of PS1 in the signaling events, we investigated in this study the role of PS1 in the basal level of mitogen-activated protein kinase (MAPK) pathways using PS1(-/-) mouse embryonic fibroblast (MEF) cells from PS1-null mice. Interestingly, the basal level of ERK activity, but not JNK or p38 activity, is lower in PS1(-/-) MEF cells than in PS1(+/+) MEF cells. In PS1(-/-) MEF cells, the basal activities of Raf and MEK, the upstream signaling component of ERK, are also lower than in PS1(+/+) MEF cells. Furthermore, Elk-1 transcription activity also down-regulates in PS1(-/-) MEF cells. Collectively, our data suggest that PS can modulate the basal level of ERK activity through the Raf-MEK-dependent pathway.