Functional role of WW domain-containing proteins in tumor biology and diseases: Insight into the role in ubiquitin-proteasome system

The ubiquitin-proteasome system (UPS) governs the protein degradation process and balances proteostasis and cellular homeostasis. It is a well-controlled mechanism, in which removal of the damaged or excessive proteins is essential in driving signal pathways for cell survival or death. Accumulation of damaged proteins and failure in removal may contribute to disease initiation such as in cancers and neurodegenerative diseases. In this notion, specific protein-protein interaction is essential for the recognition of targeted proteins in UPS. WW domain plays an indispensable role in the protein-protein interactions during signaling. Among the 51 WW domain-containing proteins in the human proteomics, near one-quarter of them are involved in the UPS, suggesting that WW domains are crucial modules for driving the protein-protein binding and subsequent ubiquitination and degradation. In this review, we detail a broad spectrum of WW domains in protein-protein recognition, signal transduction, and relevance to diseases. New perspectives in dissecting the molecular interactions are provided.