The many substrates and functions of NEDD4-1.

Tumorigenesis, tumor growth, and prognosis are highly related to gene alterations and post-translational modifications (PTMs). Ubiquitination is a critical PTM that governs practically all aspects of cellular function. An increasing number of studies show that E3 ubiquitin ligases (E3s) are important enzymes in the process of ubiquitination that primarily determine substrate specificity and thus need to be tightly controlled. Among E3s, neural precursor cell expressed developmentally downregulated 4-1 (NEDD4-1) has been shown to play a critical role in modulating the proliferation, migration, and invasion of cancer cells and the sensitivity of cancer cells to anticancer therapies via regulating multiple substrates. This review discusses some significant discoveries on NEDD4-1 substrates and the signaling pathways in which NEDD4-1 participates. In addition, we introduce the latest potential therapeutic strategies that inhibit or activate NEDD4-1 activity using small molecules. NEDD4-1 likely acts as a novel drug target or diagnostic marker in the battle against cancer.