A soluble derivative of PrPC activates cell-signaling and regulates cell physiology through LRP1 and the NMDA receptor
Elisabetta Mantuano, Pardis Azmoon, Michael A. Banki, Michael S. Lam, Christina J. Sigurdson, Steven L. Gonias
Abstract
Cellular prion protein (PrP C ) is a widely expressed glycosylphosphatidylinositol-anchored membrane protein.Scrapie prion protein is a misfolded and aggregated form of PrP C responsible for prion-induced neurodegenerative diseases.Understanding the function of the nonpathogenic PrP C monomer is an important objective.PrP C may be shed from the cell surface to generate soluble derivatives.Herein, we studied a recombinant derivative of PrP C (soluble cellular prion protein, S-PrP) that corresponds closely in sequence to a soluble form of PrP C shed from the cell surface by proteases in the A Disintegrin And Metalloprotease (ADAM) family.S-PrP activated cell-signaling in PC12 and N2a cells.TrkA was transactivated by Src family kinases and extracellular signal-regulated kinase 1/2 was activated downstream of Trk receptors.These cell-signaling events were dependent on the N-methyl-D-aspartate receptor (NMDA-R) and low-density lipoprotein receptor-related protein-1 (LRP1), which functioned as a cell-signaling receptor system in lipid rafts.Membrane-anchored PrP C and neural cell adhesion molecule were not required for S-PrP-initiated cellsignaling.S-PrP promoted PC12 cell neurite outgrowth.This response required the NMDA-R, LRP1, Src family kinases, and Trk receptors.In Schwann cells, S-PrP interacted with the LRP1/NMDA-R system to activate extracellular signal-regulated kinase 1/2 and promote cell migration.The effects of S-PrP on PC12 cell neurite outgrowth and Schwann cell migration were similar to those caused by other proteins that engage the LRP1/NMDA-R system, including activated a 2 -macroglobulin and tissue-type plasminogen activator.Collectively, these results demonstrate that shed forms of PrP C may exhibit important biological activities in the central nervous system and the peripheral nervous system by serving as ligands for the LRP1/ NMDA-R system.