RNF43 ubiquitinates and degrades phosphorylated E-cadherin by c-Src to facilitate epithelial-mesenchymal transition in lung adenocarcinoma.
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.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.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 ?-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.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.
Mesh Terms:
A549 Cells, Adenocarcinoma of Lung, Animals, Antibodies, Monoclonal, Antigens, CD, CSK Tyrosine-Protein Kinase, Cadherins, Caspase 8, Cells, Cultured, DNA-Binding Proteins, Epithelial-Mesenchymal Transition, Follow-Up Studies, Humans, Lung Neoplasms, Male, Mice, Mice, Inbred BALB C, Mice, Nude, Oncogene Proteins, Phosphorylation, Proteolysis, Receptors, Cell Surface, Ubiquitin-Protein Ligases, Ubiquitination, Vimentin, beta Catenin
A549 Cells, Adenocarcinoma of Lung, Animals, Antibodies, Monoclonal, Antigens, CD, CSK Tyrosine-Protein Kinase, Cadherins, Caspase 8, Cells, Cultured, DNA-Binding Proteins, Epithelial-Mesenchymal Transition, Follow-Up Studies, Humans, Lung Neoplasms, Male, Mice, Mice, Inbred BALB C, Mice, Nude, Oncogene Proteins, Phosphorylation, Proteolysis, Receptors, Cell Surface, Ubiquitin-Protein Ligases, Ubiquitination, Vimentin, beta Catenin
BMC Cancer
Date: Jul. 08, 2019
PubMed ID: 31286874
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