Epidermal growth factor-nanoparticle conjugates change the activity from anti-apoptotic to pro-apoptotic at membrane rafts

Shota Yamamoto, Yoshifumi Iwamaru, Yoshihisa Shimizu, Yoshibumi Ueda, Moritoshi Sato, Kazuo Yamaguchi, Jun Nakanishi

Research output: Contribution to journalArticle

Abstract

The proliferation epidermal growth factor (EGF) is known to acquire contradictory apoptotic activities upon conjugation with gold nanoparticles (GNPs) through hitherto unknown mechanisms. Here, we identified an essential role of membrane rafts in the drastic activity switching of EGF-GNPs through the following intracellular signaling. (1) In contrast to the rapid diffusion of activated EGF receptor after the soluble EGF stimulation, the receptor is confined within membrane rafts upon binding to the EGF-GNPs. (2) This initial receptor confinements switch its endocytosis process from normal clathrin-mediated endocytosis to caveolin-mediated one, changing the phosphorylation dynamics of essential downstream kinases, i.e., extracellular signal-regulated kinase and AKT. Importantly, the destruction of membrane rafts by β-cyclodextrin reversed this trafficking and signaling, restoring EGF-GNPs to lost anti-apoptotic property. These results reveal the importance of GNP-mediated signal condensation at membrane rafts in conferring the unique apoptotic activity on EGF-nanoparticle conjugates. Statement of significance: Epidermal growth factor (EGF) is a small secretory protein that induces cell proliferation upon binding to its receptor existed on cellular plasma membranes. One interesting feature of the protein in the nanobiology field is, its acquisition of apoptosis-inducing (cellular suicide) activity rather than proliferative one upon conjugation to gold nanoparticles through hitherto unknown mechanisms. Here, we identified the involvement of membrane rafts, plasma membrane nanodomains enriched with cholesterol, in the apoptosis processes by changing the receptor trafficking and downstream signal transduction pathways. Moreover, the destruction of lipid rafts restored the EGF-nanoparticle conjugates with lost anti-apoptotic activity. These finding highlight potential applications of EGF-nanoparticle conjugates to cancer therapy, as the EGF receptor are highly expressed in cancer cells.

Original languageEnglish
Pages (from-to)383-391
Number of pages9
JournalActa Biomaterialia
Volume88
DOIs
Publication statusPublished - 2019 Apr 1

Fingerprint

Epidermal Growth Factor
Nanoparticles
Membranes
Gold
Epidermal Growth Factor Receptor
Cell membranes
Endocytosis
Cell death
Cell Membrane
Apoptosis
Caveolins
Signal transduction
Clathrin
Phosphorylation
Extracellular Signal-Regulated MAP Kinases
Proteins
Cyclodextrins
Cell proliferation
Suicide
Cholesterol

Keywords

  • Apoptosis
  • Epidermal growth factor
  • Gold nanoparticle
  • Membrane raft
  • Phosphorylation
  • Signal condensation

ASJC Scopus subject areas

  • Biotechnology
  • Biomaterials
  • Biochemistry
  • Biomedical Engineering
  • Molecular Biology

Cite this

Epidermal growth factor-nanoparticle conjugates change the activity from anti-apoptotic to pro-apoptotic at membrane rafts. / Yamamoto, Shota; Iwamaru, Yoshifumi; Shimizu, Yoshihisa; Ueda, Yoshibumi; Sato, Moritoshi; Yamaguchi, Kazuo; Nakanishi, Jun.

In: Acta Biomaterialia, Vol. 88, 01.04.2019, p. 383-391.

Research output: Contribution to journalArticle

Yamamoto, Shota ; Iwamaru, Yoshifumi ; Shimizu, Yoshihisa ; Ueda, Yoshibumi ; Sato, Moritoshi ; Yamaguchi, Kazuo ; Nakanishi, Jun. / Epidermal growth factor-nanoparticle conjugates change the activity from anti-apoptotic to pro-apoptotic at membrane rafts. In: Acta Biomaterialia. 2019 ; Vol. 88. pp. 383-391.
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abstract = "The proliferation epidermal growth factor (EGF) is known to acquire contradictory apoptotic activities upon conjugation with gold nanoparticles (GNPs) through hitherto unknown mechanisms. Here, we identified an essential role of membrane rafts in the drastic activity switching of EGF-GNPs through the following intracellular signaling. (1) In contrast to the rapid diffusion of activated EGF receptor after the soluble EGF stimulation, the receptor is confined within membrane rafts upon binding to the EGF-GNPs. (2) This initial receptor confinements switch its endocytosis process from normal clathrin-mediated endocytosis to caveolin-mediated one, changing the phosphorylation dynamics of essential downstream kinases, i.e., extracellular signal-regulated kinase and AKT. Importantly, the destruction of membrane rafts by β-cyclodextrin reversed this trafficking and signaling, restoring EGF-GNPs to lost anti-apoptotic property. These results reveal the importance of GNP-mediated signal condensation at membrane rafts in conferring the unique apoptotic activity on EGF-nanoparticle conjugates. Statement of significance: Epidermal growth factor (EGF) is a small secretory protein that induces cell proliferation upon binding to its receptor existed on cellular plasma membranes. One interesting feature of the protein in the nanobiology field is, its acquisition of apoptosis-inducing (cellular suicide) activity rather than proliferative one upon conjugation to gold nanoparticles through hitherto unknown mechanisms. Here, we identified the involvement of membrane rafts, plasma membrane nanodomains enriched with cholesterol, in the apoptosis processes by changing the receptor trafficking and downstream signal transduction pathways. Moreover, the destruction of lipid rafts restored the EGF-nanoparticle conjugates with lost anti-apoptotic activity. These finding highlight potential applications of EGF-nanoparticle conjugates to cancer therapy, as the EGF receptor are highly expressed in cancer cells.",
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AU - Yamamoto, Shota

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AU - Ueda, Yoshibumi

AU - Sato, Moritoshi

AU - Yamaguchi, Kazuo

AU - Nakanishi, Jun

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AB - The proliferation epidermal growth factor (EGF) is known to acquire contradictory apoptotic activities upon conjugation with gold nanoparticles (GNPs) through hitherto unknown mechanisms. Here, we identified an essential role of membrane rafts in the drastic activity switching of EGF-GNPs through the following intracellular signaling. (1) In contrast to the rapid diffusion of activated EGF receptor after the soluble EGF stimulation, the receptor is confined within membrane rafts upon binding to the EGF-GNPs. (2) This initial receptor confinements switch its endocytosis process from normal clathrin-mediated endocytosis to caveolin-mediated one, changing the phosphorylation dynamics of essential downstream kinases, i.e., extracellular signal-regulated kinase and AKT. Importantly, the destruction of membrane rafts by β-cyclodextrin reversed this trafficking and signaling, restoring EGF-GNPs to lost anti-apoptotic property. These results reveal the importance of GNP-mediated signal condensation at membrane rafts in conferring the unique apoptotic activity on EGF-nanoparticle conjugates. Statement of significance: Epidermal growth factor (EGF) is a small secretory protein that induces cell proliferation upon binding to its receptor existed on cellular plasma membranes. One interesting feature of the protein in the nanobiology field is, its acquisition of apoptosis-inducing (cellular suicide) activity rather than proliferative one upon conjugation to gold nanoparticles through hitherto unknown mechanisms. Here, we identified the involvement of membrane rafts, plasma membrane nanodomains enriched with cholesterol, in the apoptosis processes by changing the receptor trafficking and downstream signal transduction pathways. Moreover, the destruction of lipid rafts restored the EGF-nanoparticle conjugates with lost anti-apoptotic activity. These finding highlight potential applications of EGF-nanoparticle conjugates to cancer therapy, as the EGF receptor are highly expressed in cancer cells.

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KW - Phosphorylation

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