{"doi":"10.1074/jbc.ra120.013779","title":"A soluble derivative of PrPC activates cell-signaling and regulates cell physiology through LRP1 and the NMDA receptor","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.","journal":"Journal of Biological Chemistry","year":2020,"id":100902,"datarank":0.6419846471810549,"base_score":3.367295829986474,"endowment":3.367295829986474,"self_citation_contribution":0.5050943744979712,"citation_network_contribution":0.13689027268308362,"self_endowment_contribution":0.5050943744979712,"citer_contribution":0.13689027268308362,"corpus_percentile":null,"corpus_rank":null,"citation_count":28,"citer_count":16,"citers_with_citation_signal":9,"citers_with_endowment":9,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9494,"is_data_producer":true,"deposit_databanks":{"figshare":["10.6084/m9.figshare.12762176"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":494452,"name":"Pardis Azmoon","orcid":"0000-0002-1512-5581","position":1,"is_corresponding":false},{"id":494453,"name":"Michael A. Banki","orcid":"0000-0002-8910-4695","position":2,"is_corresponding":false},{"id":494454,"name":"Michael S. Lam","orcid":"0000-0001-9670-0025","position":3,"is_corresponding":false},{"id":335166,"name":"Christina J. Sigurdson","orcid":"0000-0002-1770-0965","position":4,"is_corresponding":false},{"id":494455,"name":"Steven L. Gonias","orcid":"0000-0003-0843-4607","position":5,"is_corresponding":false},{"id":494451,"name":"Elisabetta Mantuano","orcid":"0000-0001-5728-9261","position":0,"is_corresponding":true}],"reference_count":72,"raw_metadata":null,"created_at":"2026-07-18T22:39:01.863288Z","pmid":"32788217","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}