The Nedd4-like family of E3 ubiquitin ligases have been implicated in several types of human cancer. There are nine members of the Nedd4-like E3 family, all of which have an N-terminal C2 domain, two to four WW domains in the central region, and a C-terminal domain that is homologous to the C-terminus of E6-AP. This ubiquitin ligase family includes NEDD4-1, NEDD4-2, AIP4/Itch, AIP5/WWP1, SMURF1 and SMURF2. Several ubiquitin ligases in this family are overexpressed in human cancers. WWP1 has been implicated as an oncogene as it is overexpressed in prostate and breast cancers, and knockdown of this ligase reduces cell proliferation and causes apoptosis. In addition, WWP1 has been shown to negatively regulate transforming growth factor-beta (TGFbeta) signaling by targeting TGFbeta receptor 1, Smad2, and Smad4 for ubiquitin-mediated degradation. WWP1 has also been shown to regulate the protein levels of the epithelial sodium channel (ENaC), Notch, EGFR/ErbB2, Runx2, KLF2, KLF5, p53, and p63. Thus, WWP1 may regulate cell development and proliferation through the degradation of proteins involved in a variety of cell signaling pathways.
