WWP2-WWP1 Ubiquitin Ligase Complex Coordinated by PPM1G Maintains the Balance between Cellular p73 and ΔNp73 Levels

Abstract

The balance between transcription factor p73 and its functionally opposing N-terminal truncated ΔNp73 isoform is critical for cell survival but the precise mechanism that regulates their levels is not clear. In our study, we identified WWP2, an E3 ligase as a novel p73 associated protein that ubiquitinates and degrades p73. In contrast, WWP2 heterodimerizes with another E3 ligase WWP1, which specifically ubiquitinates and degrades ΔNp73. Further, we identified phosphatase PPM1G as a functional switch that controls the balance between monomeric WWP2 and WWP2/WWP1 heterodimeric state in the cell. During cellular stress WWP2 is inactivated that leads to upregulation of p73 whereas WWP2-WWP1 complex is intact to degrade ΔNp73 thus playing an important role in shifting the balance between p73 and ΔNp73. Collectively, our results reveal a new functional E3 ligase complex controlled by PPM1G that differentially regulates cellular p73 and ΔNp73.