WWP2-WWP1 ubiquitin ligase complex coordinated by PPM1G maintains the balance between cellular p73 and ΔNp73 levels.
The balance between transcription factor p73 and its functionally opposing N-terminally 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 a WWP2/WWP1 heterodimeric state in the cell. During cellular stress, WWP2 is inactivated, leading 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.
Mesh Terms:
Apoptosis, Cisplatin, DNA-Binding Proteins, Gene Expression Regulation, HEK293 Cells, HeLa Cells, Humans, Nuclear Proteins, Phosphoprotein Phosphatases, Protein Isoforms, Protein Multimerization, Protein Phosphatase 2C, Proteolysis, Tumor Protein p73, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases, Ubiquitination
Apoptosis, Cisplatin, DNA-Binding Proteins, Gene Expression Regulation, HEK293 Cells, HeLa Cells, Humans, Nuclear Proteins, Phosphoprotein Phosphatases, Protein Isoforms, Protein Multimerization, Protein Phosphatase 2C, Proteolysis, Tumor Protein p73, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases, Ubiquitination
Mol. Cell. Biol.
Date: Oct. 01, 2014
PubMed ID: 25071155
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