The Nedd4-like family of E3 ubiquitin ligases and cancer

Abstract

Accumulating evidence suggests that E3 ubiquitin ligases play important roles in cancer development. In this article, we provide a comprehensive summary of the roles of the Nedd4-like family of E3 ubiquitin ligases in human cancer. There are nine members of the Nedd4-like E3 family, all of which share a similar structure, including a C2 domain at the N-terminus, two to four WW domains in the middle of the protein, and a homologous to E6-AP COOH terminus domain at the C-terminus. The assertion that Nedd4-like E3s play a role in cancer is supported by the overexpression of Smurf2 in esophageal squamous cell carcinoma, WWP1 in prostate and breast cancer, Nedd4 in prostate and bladder cancer, and Smurf1 in pancreatic cancer. Because Nedd4-like E3s regulate ubiquitin-mediated trafficking, lysosomal or proteasomal degradation, and nuclear translocation of multiple proteins, they modulate important signaling pathways involved in tumorigenesis like TGFbeta, EGF, IGF, VEGF, SDF-1, and TNFalpha. Additionally, several Nedd4-like E3s directly regulate various cancer-related transcription factors from the Smad, p53, KLF, RUNX, and Jun families. Interestingly, multiple Nedd4-like E3s show ligase independent function. Furthermore, Nedd4-like E3s themselves are frequently regulated by phosphorylation, ubiquitination, translocation, and transcription in cancer cells. Because the regulation and biological output of these E3s is such a complex process, study of the role of these E3s in cancer development poses some challenges. However, understanding the oncogenic potential of these E3s may facilitate the identification and development of biomarkers and drug targets in human cancer.

WW domain-containing E3 ubiquitin protein ligase 1 targets p63 transcription factor for ubiquitin-mediated proteasomal degradation and regulates apoptosis

“…1 Laine et al, 13 reported that UV-irradiation or g-irradiation decreases WWP1 mRNA expression in mouse embryonic fibroblasts in a p53-dependent manner. However, we found that several DNA damage chemotherapeutic drugs including doxorubicin, cisplatin and etoposide induces the WWP1 expression in HCT116 and breast cell lines in a p53-dependent manner.…”

“…1 All family members share a distinctive domain structure: a C2 domain at the N terminus for calcium-dependent phospholipid binding, 2-4 WW domains in the middle for protein-protein interaction with PY motifs, and a HECT domain at the C terminus for the ubiquitin transfer. Four family members including WWP1, 2,3 NEDD4, 4 SMURF1, 5 and SMURF2, 6 have been shown to be overexpressed in different tumor types.…”

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

“…EPS15 and Cbl have been demonstrated to be RNF11-interacting proteins in yeast two-hybrid experiments (Azmi and Seth, 2005). WWP1 has been shown to increase the ubiquitination of EPS15 (Woelk et al, 2006;Chen and Matesic, 2007). In addition, a WWP1 family member, Itch/AIP4, has been shown to promote Cbl ubiquitination (Magnifico et al, 2003).…”

“…The WW domain containing E3 ubiquitin protein ligase 1 (WWP1/AIP5/Tiul1) belongs to the Nedd4-like homologous to the E6-associated protein C terminus (HECT)-type E3 family (Chen and Matesic, 2007). Nedd4-like E3s can be identified by their distinctive domain structure: an HECT domain at the C terminus for the ubiquitin transfer (Verdecia et al, 2003), a C2 domain at the N terminus for calcium-dependent phospholipid binding, and 2-4 WW domains in the middle for protein-protein interaction with PY motifs (Mosser et al, 1998).…”

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

“…The WW domain containing E3 ubiquitin protein ligase 1 (WWP1) belongs to the C2-WW-HECT type E3 family, which comprises of nine members including AIP4/Itch and WWP1 (Chen and Matesic, 2007). The N-terminal C2 domain is responsible for calciumdependent phospholipid binding.…”