A multimolecular signaling complex including PrPC and LRP1 is strictly dependent on lipid rafts and is essential for the function of tissue plasminogen activator

Vincenzo Mattei, Valeria Manganelli, Stefano Martellucci, Antonella Capozzi, Elisabetta Mantuano, Agostina Longo, Alberto Ferri, Tina Garofalo, Maurizio Sorice, Roberta Misasi

Research output: Contribution to journalArticle

Abstract

Prion protein (PrPC) localizes stably in lipid rafts microdomains and is able to recruit downstream signal transduction pathways by the interaction with promiscuous partners. Other proteins have the ability to occasionally be recruited to these specialized membrane areas, within multimolecular complexes. Among these, we highlight the presence of the low-density lipoprotein receptor-related protein 1 (LRP1), which was found localized transiently in lipid rafts, suggesting a different function of this receptor that through lipid raft becomes able to activate a signal transduction pathway triggered by specific ligands, including Tissue plasminogen activator (tPA). Since it has been reported that PrPC participates in the tPA-mediated plasminogen activation, in this study, we describe the role of lipid rafts in the recruitment and activation of downstream signal transduction pathways mediated by the interaction among tPA, PrPC and LRP1 in human neuroblastoma SK-N-BE2 cell line. Co-immunoprecipitation analysis reveals a consistent association between PrPC and GM1, as well as between LRP1 and GM1, indicating the existence of a glycosphingolipid-enriched multimolecular complex. In our cell model, knocking-down PrPC by siRNA impairs ERK phosphorylation induced by tPA. Moreover the alteration of the lipidic milieu of lipid rafts, perturbing the physical/functional interaction between PrPC and LRP1, inhibits this response. We show that LRP1 and PrPC, following tPA stimulation, may function as a system associated with lipid rafts, involved in receptor-mediated neuritogenic pathway. We suggest this as a multimolecular signaling complex, whose activity depends strictly on the integrity of lipid raft and is involved in the neuritogenic signaling. (Figure presented.).

Original languageEnglish
JournalJournal of Neurochemistry
DOIs
Publication statusAccepted/In press - Jan 1 2019

Fingerprint

Lipoprotein Receptors
Tissue Plasminogen Activator
Lipids
Signal transduction
Proteins
Signal Transduction
PrPC Proteins
Chemical activation
Low Density Lipoprotein Receptor-Related Protein-1
Glycosphingolipids
Phosphorylation
Plasminogen
PrPC receptor
Neuroblastoma
Immunoprecipitation
Small Interfering RNA
Cells
Association reactions
Ligands
Membranes

Keywords

  • GM1
  • lipid rafts
  • LRP1
  • methyl-β-cyclodextrin
  • prion protein
  • tPA

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

A multimolecular signaling complex including PrPC and LRP1 is strictly dependent on lipid rafts and is essential for the function of tissue plasminogen activator. / Mattei, Vincenzo; Manganelli, Valeria; Martellucci, Stefano; Capozzi, Antonella; Mantuano, Elisabetta; Longo, Agostina; Ferri, Alberto; Garofalo, Tina; Sorice, Maurizio; Misasi, Roberta.

In: Journal of Neurochemistry, 01.01.2019.

Research output: Contribution to journalArticle

Mattei, Vincenzo ; Manganelli, Valeria ; Martellucci, Stefano ; Capozzi, Antonella ; Mantuano, Elisabetta ; Longo, Agostina ; Ferri, Alberto ; Garofalo, Tina ; Sorice, Maurizio ; Misasi, Roberta. / A multimolecular signaling complex including PrPC and LRP1 is strictly dependent on lipid rafts and is essential for the function of tissue plasminogen activator. In: Journal of Neurochemistry. 2019.
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abstract = "Prion protein (PrPC) localizes stably in lipid rafts microdomains and is able to recruit downstream signal transduction pathways by the interaction with promiscuous partners. Other proteins have the ability to occasionally be recruited to these specialized membrane areas, within multimolecular complexes. Among these, we highlight the presence of the low-density lipoprotein receptor-related protein 1 (LRP1), which was found localized transiently in lipid rafts, suggesting a different function of this receptor that through lipid raft becomes able to activate a signal transduction pathway triggered by specific ligands, including Tissue plasminogen activator (tPA). Since it has been reported that PrPC participates in the tPA-mediated plasminogen activation, in this study, we describe the role of lipid rafts in the recruitment and activation of downstream signal transduction pathways mediated by the interaction among tPA, PrPC and LRP1 in human neuroblastoma SK-N-BE2 cell line. Co-immunoprecipitation analysis reveals a consistent association between PrPC and GM1, as well as between LRP1 and GM1, indicating the existence of a glycosphingolipid-enriched multimolecular complex. In our cell model, knocking-down PrPC by siRNA impairs ERK phosphorylation induced by tPA. Moreover the alteration of the lipidic milieu of lipid rafts, perturbing the physical/functional interaction between PrPC and LRP1, inhibits this response. We show that LRP1 and PrPC, following tPA stimulation, may function as a system associated with lipid rafts, involved in receptor-mediated neuritogenic pathway. We suggest this as a multimolecular signaling complex, whose activity depends strictly on the integrity of lipid raft and is involved in the neuritogenic signaling. (Figure presented.).",
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AU - Mattei, Vincenzo

AU - Manganelli, Valeria

AU - Martellucci, Stefano

AU - Capozzi, Antonella

AU - Mantuano, Elisabetta

AU - Longo, Agostina

AU - Ferri, Alberto

AU - Garofalo, Tina

AU - Sorice, Maurizio

AU - Misasi, Roberta

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AB - Prion protein (PrPC) localizes stably in lipid rafts microdomains and is able to recruit downstream signal transduction pathways by the interaction with promiscuous partners. Other proteins have the ability to occasionally be recruited to these specialized membrane areas, within multimolecular complexes. Among these, we highlight the presence of the low-density lipoprotein receptor-related protein 1 (LRP1), which was found localized transiently in lipid rafts, suggesting a different function of this receptor that through lipid raft becomes able to activate a signal transduction pathway triggered by specific ligands, including Tissue plasminogen activator (tPA). Since it has been reported that PrPC participates in the tPA-mediated plasminogen activation, in this study, we describe the role of lipid rafts in the recruitment and activation of downstream signal transduction pathways mediated by the interaction among tPA, PrPC and LRP1 in human neuroblastoma SK-N-BE2 cell line. Co-immunoprecipitation analysis reveals a consistent association between PrPC and GM1, as well as between LRP1 and GM1, indicating the existence of a glycosphingolipid-enriched multimolecular complex. In our cell model, knocking-down PrPC by siRNA impairs ERK phosphorylation induced by tPA. Moreover the alteration of the lipidic milieu of lipid rafts, perturbing the physical/functional interaction between PrPC and LRP1, inhibits this response. We show that LRP1 and PrPC, following tPA stimulation, may function as a system associated with lipid rafts, involved in receptor-mediated neuritogenic pathway. We suggest this as a multimolecular signaling complex, whose activity depends strictly on the integrity of lipid raft and is involved in the neuritogenic signaling. (Figure presented.).

KW - GM1

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