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A Code of Mono-phosphorylation Modulates the Function of RB
- Sanidas, Ioannis, Morris, Robert, Fella, Katerina A., Rumde, Purva H., Boukhali, Myriam, Tai, Eric C., Ting, David T., Lawrence, Michael S., Haas, Wilhelm, Dyson, Nicholas J.
- Molecular cell 2019
- cell cycle, genes, neoplasms, oxidative phosphorylation, oxygen consumption, proteins, proteomics, transcription (genetics)
- Hyper-phosphorylation of RB controls its interaction with E2F and inhibits its tumor suppressor properties. However, during G1 active RB can be mono-phosphorylated on any one of 14 CDK phosphorylation sites. Here, we used quantitative proteomics to profile protein complexes formed by each mono-phosphorylated RB isoform (mP-RB) and identified the associated transcriptional outputs. The results show that the 14 sites of mono-phosphorylation co-ordinate RB’s interactions and confer functional specificity. All 14 mP-RBs interact with E2F/DP proteins, but they provide different shades of E2F regulation. RB mono-phosphorylation at S811, for example, alters RB transcriptional activity by promoting its association with NuRD complexes. The greatest functional differences between mP-RBs are evident beyond the cell cycle machinery. RB mono-phosphorylation at S811 or T826 stimulates the expression of oxidative phosphorylation genes, increasing cellular oxygen consumption. These results indicate that RB activation signals are integrated in a phosphorylation code that determines the diversity of RB activity.