Molecular Cell
Volume 73, Issue 5, 7 March 2019, Pages 985-1000.e6
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Article
A Code of Mono-phosphorylation Modulates the Function of RB

https://doi.org/10.1016/j.molcel.2019.01.004Get rights and content
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Highlights

  • Mono-phosphorylation controls RB’s association with other proteins

  • Distinct mono-phosphorylated forms of RB have different transcriptional outputs

  • RB mono-phosphorylation at S811 promotes NuRD-dependent transcriptional repression

  • Mono-phosphorylation of RB’s C-terminal domain enhances expression of OXPHOS genes

Summary

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.

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