RNF43 ubiquitinates and degrades phosphorylated E-cadherin by c-Src to facilitate epithelial-mesenchymal transition in lung adenocarcinoma
BACKGROUND: In epithelial cells, tyrosine kinases induce tyrosine phosphorylation and ubiquitination of the E-cadherin complex, which is responsible for the epithelial-mesenchymal transition (EMT). However, the precise mechanisms remain unclear.
METHODS: Protein antibody microarray analysis and E3 ligase profiling were performed to detect the unique E3 ligase underlying E-cadherin downregulation in lung adenocarcinoma tissues. Gene knockdown was performed using viral shRNA. Immunoblotting, immunofluorescence, immunoprecipitation, and xenograft models in vivo were integratively applied to explore RNF43-induced EMT in lung adenocarcinoma cell lines.
RESULTS: Protein antibody microarray analysis and E3 ligase profiling revealed that the RING finger protein 43 (RNF43) was linked to E-cadherin downregulation within the context of c-Src activation in lung adenocarcinoma tissues. In addition, the c-Src-Caspase-8 interaction markedly increased c-Src activity. Activated c-Src phosphorylated E-cadherin at the tyrosine 797 site to initiate RNF43-mediated E-cadherin ubiquitination at lysine 816 and subsequent degradation, thus allowing the nuclear translocation of β-catenin and upregulation of Vimentin and RNF43 expression in lung adenocarcinoma cells. Decreased E-cadherin expression and increased Vimentin expression induced the EMT phenotype and promoted tumor metastasis. The Frizzled 8 (Frz8)-RNF43-induced ubiquitination of phosphorylated E-cadherin was blocked by a monoclonal antibody against the cysteine-rich domain (CRD) of Frz8 but not by antibodies against the protease domain (PA) of RNF43.
CONCLUSIONS: Our data suggest that RNF43 participates in the regulation of EMT in the metastasis of lung adenocarcinoma through the ubiquitination and degradation of phosphorylated E-cadherin by activated c-Src.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:19 |
|---|---|
| Enthalten in: |
BMC cancer - 19(2019), 1 vom: 08. Juli, Seite 670 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zhang, Yunfeng [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 11.12.2019 Date Revised 25.02.2020 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1186/s12885-019-5880-1 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM299002101 |
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| 041 | |a eng | ||
| 100 | 1 | |a Zhang, Yunfeng |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a RNF43 ubiquitinates and degrades phosphorylated E-cadherin by c-Src to facilitate epithelial-mesenchymal transition in lung adenocarcinoma |
| 264 | 1 | |c 2019 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 11.12.2019 | ||
| 500 | |a Date Revised 25.02.2020 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a BACKGROUND: In epithelial cells, tyrosine kinases induce tyrosine phosphorylation and ubiquitination of the E-cadherin complex, which is responsible for the epithelial-mesenchymal transition (EMT). However, the precise mechanisms remain unclear | ||
| 520 | |a METHODS: Protein antibody microarray analysis and E3 ligase profiling were performed to detect the unique E3 ligase underlying E-cadherin downregulation in lung adenocarcinoma tissues. Gene knockdown was performed using viral shRNA. Immunoblotting, immunofluorescence, immunoprecipitation, and xenograft models in vivo were integratively applied to explore RNF43-induced EMT in lung adenocarcinoma cell lines | ||
| 520 | |a RESULTS: Protein antibody microarray analysis and E3 ligase profiling revealed that the RING finger protein 43 (RNF43) was linked to E-cadherin downregulation within the context of c-Src activation in lung adenocarcinoma tissues. In addition, the c-Src-Caspase-8 interaction markedly increased c-Src activity. Activated c-Src phosphorylated E-cadherin at the tyrosine 797 site to initiate RNF43-mediated E-cadherin ubiquitination at lysine 816 and subsequent degradation, thus allowing the nuclear translocation of β-catenin and upregulation of Vimentin and RNF43 expression in lung adenocarcinoma cells. Decreased E-cadherin expression and increased Vimentin expression induced the EMT phenotype and promoted tumor metastasis. The Frizzled 8 (Frz8)-RNF43-induced ubiquitination of phosphorylated E-cadherin was blocked by a monoclonal antibody against the cysteine-rich domain (CRD) of Frz8 but not by antibodies against the protease domain (PA) of RNF43 | ||
| 520 | |a CONCLUSIONS: Our data suggest that RNF43 participates in the regulation of EMT in the metastasis of lung adenocarcinoma through the ubiquitination and degradation of phosphorylated E-cadherin by activated c-Src | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a C-Src | |
| 650 | 4 | |a Caspase-8 | |
| 650 | 4 | |a EMT | |
| 650 | 4 | |a RNF43 | |
| 650 | 7 | |a Antibodies, Monoclonal |2 NLM | |
| 650 | 7 | |a Antigens, CD |2 NLM | |
| 650 | 7 | |a CDH1 protein, human |2 NLM | |
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| 650 | 7 | |a Cadherins |2 NLM | |
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| 650 | 7 | |a Fzd8 protein, human |2 NLM | |
| 650 | 7 | |a Oncogene Proteins |2 NLM | |
| 650 | 7 | |a Receptors, Cell Surface |2 NLM | |
| 650 | 7 | |a VIM protein, human |2 NLM | |
| 650 | 7 | |a Vimentin |2 NLM | |
| 650 | 7 | |a beta Catenin |2 NLM | |
| 650 | 7 | |a RNF43 protein, human |2 NLM | |
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| 700 | 1 | |a Sun, Liangzhang |e verfasserin |4 aut | |
| 700 | 1 | |a Gao, Xiao |e verfasserin |4 aut | |
| 700 | 1 | |a Guo, Aining |e verfasserin |4 aut | |
| 700 | 1 | |a Diao, Yan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Yang |e verfasserin |4 aut | |
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