A substantial body of evidence indicates that protein kinase C (PKC) is involved in the -secretory processing of the amyloid precursor protein (APP), an event that reduces the formation of the pathogenic amyloid- peptide. Recently, we have shown that trafficking and processing of APP are both impaired by knockdown of myosin II-B, one of the major neuronal motor proteins. Here, we provide evidence that the -secretory processing of APP is mediated by PKC-dependent phosphorylation of myosin II-B. This signaling pathway provides an important link between APP and the neuronal cytoskeleton and might be crucial for the understanding of the biological and pathological roles of APP.—Argellati, F., Domenicotti, C., Passalacqua, M., Janda, E., Melloni, E., Marinari, U. M., Pronzato, M. A., Ricciarelli, R. Protein kinase C-dependent -secretory processing of the amyloid precursor protein is mediated by phosphorylation of myosin II-B.