The WW domain containing E3 ubiquitin protein ligase 1 upregulates ErbB2 and EGFR through RING finger protein 11.
The WW domain containing E3 ubiquitin protein ligase 1 (WWP1) is a homologous to the E6-associated protein C terminus-type E3 ligase frequently overexpressed in human prostate and breast cancers due to gene amplification. Previous studies suggest that WWP1 promotes cell proliferation and survival; however, the mechanism of WWP1 action is still poorly understood. Here, we showed that WWP1 upregulates and maintains erythroblastic leukemia viral oncogene homolog 2 (ErbB2) and epithelial growth factor receptor (EGFR) in multiple cell lines. WWP1 depletion dramatically attenuates the EGF-induced ERK phosphorylation. WWP1 forms a protein complex with RING finger protein 11 (RNF11), a negative regulator of ErbB2 and EGFR. The protein-protein interaction is through the first and third WW domains of WWP1 and the PY motif of RNF11. Although WWP1 is able to ubiquitinate RNF11 in vitro and in vivo, WWP1 neither targets RNF11 for degradation nor changes RNF11's cellular localization. Importantly, inhibition of RNF11 can rescue WWP1 siRNA-induced ErbB2 and EGFR downregulation and growth arrest. Finally, we demonstrated that RNF11 is overexpressed in a panel of prostate and breast cancer cell lines with WWP1 expression. These findings suggest that WWP1 may promote cell proliferation and survival partially through suppressing RNF11-mediated ErbB2 and EGFR downregulation.
Chen
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C
The Center for Cell Biology and Cancer Research, MS355, Albany Medical College, Albany, NY 12208, USA. chenc@mail.amc.edu
Zhou
Z
Z
Liu
R
R
Li
Y
Y
Azmi
P B
PB
Seth
A K
AK
D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology; D002455:Cell Division; D045744:Cell Line, Tumor; D002470:Cell Survival; D004268:DNA-Binding Proteins; D004815:Epidermal Growth Factor / Q000502:physiology; D066246:ErbB Receptors / Q000235:genetics*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005784:Gene Amplification; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D018734:Genes, erbB-2; D006801:Humans; D008297:Male; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D044767:Ubiquitin-Protein Ligases; C404508:RNF11 protein, human; C471642:WWP1 protein, human; C508053:ERBB2 protein, human