The WW domain containing E3 ubiquitin protein ligase 1 upregulates ErbB2 and EGFR through RING finger protein 11

Abstract

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 EGFinduced ERK phosphorylation. WWP1 forms a protein complex with RING finger protein 11 (RNF11), a negative regulator of ErbB2 and EGFR. The proteinprotein 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.

WW domain containing E3 ubiquitin protein ligase 1 targets the full-length ErbB4 for ubiquitin-mediated degradation in breast cancer

“…Although transient WWP1 overexpression does not change the exogenous EGFR, ErbB2 and ErbB3 protein levels in COS7 cells (Feng et al, 2009), we previously found that WWP1 upregulates EGFR and ErbB2 in MCF10A and PC-3 (Chen et al, 2008). As EGFR and ErbB2 do not have a PY motif, the regulation of EGFR and ErbB2 by WWP1 is indirectly mediated through RNF11 (Chen et al, 2008) and may be cell line specific.…”

“…Maatta et al (2006) reported that JMa-CYT1, but not JMA-CYT2, is localized to early endosomes. WWP1 is also localized to endosomes (Chen et al, 2008). However, the proteasome inhibitor, MG132, but not the lysosome inhibitor, chloroquine, partially block the WWP1-mediated ErbB4-CYT1 degradation (Figure 3).…”

“…As EGFR and ErbB2 do not have a PY motif, the regulation of EGFR and ErbB2 by WWP1 is indirectly mediated through RNF11 (Chen et al, 2008) and may be cell line specific. In contrast, the direct regulation of ErbB4 by WWP1 is broadly detected in multiple cell lines.…”

“…WWP1 is an intrinsic E3 ubiquitin ligase for multiple PY motifs containing transcription factors, including Smad2 (Seo et al, 2004), RunX2 (Jones et al, 2006), KLF5 (Chen et al, 2005) and p63 (Li et al, 2008b). In addition, WWP1 may indirectly regulate several receptors, including ER-a (Chen et al, 2009), epidermal growth factor receptor (EGFR) and ErbB2 (Chen et al, 2008).…”

Overexpression of WWP1 is associated with the estrogen receptor and insulin‐like growth factor receptor 1 in breast carcinoma

“…Several studies suggest that WWP1 negatively regulates the transforming growth factor-b (TGF-b) signaling by targeting its molecular components, including TGF-b receptor 1 (TbR1), 8 Smad2 9 and Smad4, 10 for ubiquitin mediated degradation. In addition, WWP1 has been reported to regulate the expression levels of the epithelial Na 1 channel (ENaC), 11 Notch, 12 EGFR/ErbB2, 13 Runx2, 14,15 KLF2, 16 KLF5, 17 p53 18 and p63. 19 WWP1 is a potential oncogene that undergoes genomic amplification and overexpression in human breast and prostate cancer.…”