Amyloid precursor protein (APP) has been shown to serve as a Go-coupled receptor in cell-free systems [Okamoto et al: J Biol Chem 1995;270:4205–4208]. However, it has not been known whether APP exerts intracellular signaling functions in living cells. In this study, we show that stimulation of APP by anti-APP antibody as well as by a mutation found in familial Alzheimer’s disease results in activation of a specific set of mitogen-activated protein kinases in multiple vertebrate cells. We conclude that APP acts as a cell surface receptor of biological relevance that turns on specific Ser/Thr kinases, and suggest that the signaling function of APP is a potential target of familial Alzheimer’s disease mutations.