Protein ubiquitination is a dynamic multifaceted post-translational modification in which ubiquitin (Ub), a small 76 amino acid (aa) protein, is covalently conjugated to lysine residues in substrate proteins through the sequential actions of E1 Ub-activating enzyme, E2 Ub-conjugating enzyme, and E3 Ub-protein ligase (Zheng and Shabek, 2017). Successive rounds of E3-catalyzed reactions can produce substrates with polyUb chains that are linked through the lysine residues (Lys6, Lys11, Lys27, Lys29, Lys33, Lys48, and Lys63) or the N-terminal methionine of Ub (Buetow and Huang, 2016). Different ubiquitination patterns of substrates lead to distinct downstream signals (Buetow and Huang, 2016). The E3 Ub ligases represent the core components of this cascade owing to their tight regulation of both the substrate specificity and reaction efficiency of the ubiquitination (Buetow and Huang, 2016). Through regulating the ubiquitination and stability of specific target proteins, mammalian E3 Ub ligases have emerged as critical regulators of cellular homeostasis.

E3 ligases are divided into three main classes: HECT (Homologous to E6AP C-Terminus), RING (Really Interesting New Gene), and RBR (RING-between-RING) (Buetow and Huang, 2016). Among 28 human HECT E3 ligases, the largest and best-characterized class comprises the NEDD4 family, including WWP1, WWP2, ITCH, NEDD4, NEDD4L, SMURF1, SMURF2, HECW1 and HECW2 (Bernassola et al., 2008; Rotin and Kumar, 2009). WWP2 (WW domain-containing E3 Ub-protein ligase 2), also known as AIP2, is a member of the NEDD4 family of HECT E3s. Despite the discovery of WWP2 more than 20 years ago (Pirozzi et al., 1997), this unique E3 Ub ligase has been relatively obscure, and its biological functions have been largely ignored.

In recent years, studies have established WWP2 as a crucial regulator of multiple biological processes, including DNA repair, gene expression, signal transduction, and cell-fate decisions. In this context, WWP2 has evolved to play a key role in organismal homeostasis, and its dysregulation has been linked to a plethora of diseases, including cancer, bone diseases, cardiovascular diseases, and others. Unfortunately, up to now a comprehensive understanding of the multiple roles of WWP2 is still lacking. Several earlier reviews briefly described the WWP2 biology (Zhang et al., 2019a; Chen et al., 2014a). Here, we comprehensively summarize the biochemical, physiological, and pathophysiological roles of WWP2. Moreover, we also discuss the endogenous and chemical modulators of WWP2 and the pharmacological characteristics of these modulators in vivo and in vitro. We attempt to provide an overview of WWP2 biology and provide insights into potential therapeutic venues to target WWP2 against cancer and other WWP2-mediated diseases.