Molecular functions of NEDD4 E3 ubiquitin ligases in cancer

• NEDD4 subfamily of E3s has distinct, and sometimes opposite, functions in cancer.
• NEDD4 E3s have overlapping yet distinct repertoires of binding partners/substrates.
• NEDD4 E3s mediate different types of ubiquitination on different substrates.
• NEDD4 E3s mainly modulate substrate stability and/or subcellular localization.
• Regulation of substrates by NEDD4 E3s is subject to multiple layers of modulation.

The initiation, progression and cure of cancer rely heavily on altered gene expression and posttranslational functions. Protein ubiquitination is a major mechanism for posttranslational reorganization of the genome. This evolutionary conserved cascade, through regulation of protein stability, distribution, and function, governs nearly every biological process in the cell. E3 ubiquitin ligases are pivotal components of the ubiquitination pathway. Genetic alterations, abnormal expression, and dysfunctions of E3s have been implicated in the pathogenesis of a wide spectrum of human malignancies. In this review, we summarize and discuss recent discoveries on the roles of NEDD4 E3s in cancer. Over the past decade, members of this family have increasingly surfaced as fundamental components and critical regulators of molecular pathways central to the pathogenesis and cure of the disease.