The cellular form of prion protein (PrPc) is a highly conserved cell surface GPI-anchored glycoprotein that was identified in cholesterol-enriched, detergent-resistant microdomains (‘rafts’) in neural and non-neural cells. Several physiological functions have been described for PrPC, including oxidative stress defense, metal ion homeostasis in the brain, and neuroprotection. Aβ oligomers, but not monomers or fibrils, bind tightly to PrPc (Kd ~ 0.4 nM) and, in hippocampal slices, PrPc PrPc is required for Aβ oligomer-mediated inhibition of long-term potentiation. Our results suggest that the activity of PrPc-Aβ requires lipid rafts and the transmembrane receptor, low-density lipoprotein receptor-related protein (LRP1). LRP1 functions as an endocytic receptor for a broad range of structurally and functionally diverse ligands. LRP1 also functions in cell sig¬naling, directly, in response to ligand-binding, and indirectly, by regulating levels of other signaling receptors. In neurons and neurite-generating cell lines, ligands control the sig¬naling activity of LRP1 by directing the co-receptors that are recruited into a functional signaling complex with LRP1. LRP1 is also known to control surface and biosynthetic trafficking of PrPc in neurons. Our results show that PrPc is strictly associated with gangliosides in lipid rafts in neuroblastoma cells. Scanning confocal microscopy analysis revealed co-localization of PrPc with GM1, as well as TrkA with GM1, indicating the existence of a glycosphingolipid-enriched molecular complex. In order to analyze the mechanism by which recombinant PrPc initiates cell signaling in SK-N-BE2 and PC12 neuron-like cells, we examined ERK1/2 phosphorylation. ERK1/2 was robustly phosphorylated in cells that were treated with recombinant PrPc. ERK1/2 activation required LRP1 and was strictly dependent on the integrity of rafts. ERK1/2 activation was blocked by altering sphingolipid metabolism with fumonisin B1 or by disruption of lipid microdomains with methyl-β-cyclodextrin. These findings support a model in which LRP1 initiates signal transduction specifically in lipid rafts, where it forms multimolecular complexes that may include PrPc, TrkA and gangliosides. Although association of LRP1 with lipid rafts has been reported before, this is the first study to demonstrate a potentially significant LRP1 activity that depends on its distribution between rafts, clathrin-coated pits and other membrane domains.
LRP1 activates ERK1/2 in lipid rafts in neuron-like cells / Mantuano, Elisabetta; Vincenzo, Mattei; Tasciotti, Vincenzo; Manganelli, Valeria; Stefano, Martellucci; Francesca, Santilli; Garofalo, Tina; Sorice, Maurizio; Gonias, Steven L.; Misasi, Roberta. - STAMPA. - 42(2014). ((Intervento presentato al convegno Neuroscience 2014 tenutosi a Washington DC nel 14-19 november 2014.
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|Titolo:||LRP1 activates ERK1/2 in lipid rafts in neuron-like cells|
|Data di pubblicazione:||2014|
|Citazione:||LRP1 activates ERK1/2 in lipid rafts in neuron-like cells / Mantuano, Elisabetta; Vincenzo, Mattei; Tasciotti, Vincenzo; Manganelli, Valeria; Stefano, Martellucci; Francesca, Santilli; Garofalo, Tina; Sorice, Maurizio; Gonias, Steven L.; Misasi, Roberta. - STAMPA. - 42(2014). ((Intervento presentato al convegno Neuroscience 2014 tenutosi a Washington DC nel 14-19 november 2014.|
|Appartiene alla tipologia:||04d Abstract in atti di convegno|