Sigma-1 receptors (Sig-1R) are unique endoplasmic reticulum proteins that bind (+)benzomorphans, neurosteroids, and certain psychotropic drugs such as antidepressants. We previously reported that PC12 cells stably overexpressing Sig-1R (MT 40 cells) exhibit a potentiation of the nerve growth factor (NGF)-induced neurite growth (JPET, 303:1227, 2002). Epidermal growth factor (EGF), which is known to lead to proliferation but not neurite outgrowth, however, can induce neurite outgrowth in MT 40 cells (SFN 2002). Here, we further characterized MT40 cells to examine the potential consequences of Sig-1R overexpression, especially, on the proliferation and associated-intracellular signalings. In the presence of EGF, wild type cells proliferated at least one-fold as much when compared to MT40 cells. In MT40cells, EGF-induced Akt phosphorylation, which is important in proliferation, was decreased, whereas EGF-induced phosphorylation of extracellular signaling-regulated protein kinase (ERK), critical for neurite ou...