AMYLOID PRECURSOR PROTEIN REQUIRES THE INSULIN SIGNALING PATHWAY FOR NEUROTROPHIC ACTIVITY

Picomolar concentrations of purified amyloid precursor protein (APP) p otentiate the neurotrophic activity of suboptimal concentrations of NG F on PC12 cells. To understand the molecular basis for this potentiati on, we have characterized the signal transduction pathway used by APP for its neurotrophic activity, APP stimulated the tyrosine phosphoryla tion of a number of proteins including insulin receptor levels and inh ibition of APP stimulated neurite outgrowth. Phosphotidylinositol 3-ki nase became associated with IRS-1 and activated upon APP stimulation. Extracellular signal-regulated kinase (ERK 1 and ERK 2) phosphorylatio n was detected by both immunoblot analysis and immunocytochemistry usi ng antibodies directed to their phosphorylated (and hence, activated) form. There was also an elevation of ERK kinase activity. The potentia tion of NGF activity was reflected in a correspondingly synergistic el evation of tyrosine phosphorylated ERK. The pattern of signal transduc tion targets indicates that APP potentiated the neurotrophic effects o f NGF via the activation of the IRS-1 signaling pathway. (C) 1997 Else vier Science B.V.