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Inhibition of CtBP1 activity by Akt-mediated phosphorylation

Jacqueline C Merrill1, Michael H Kagey, Tiffany A Melhuish

  • 1Department of Biochemistry and Molecular Genetics and Center for Cell Signaling, University of Virginia, 800577 HSC, Charlottesville, VA 22908, USA.

Journal of Molecular Biology
|April 6, 2010
PubMed

Insights

Polycomb 2 (Pc2) protein enhances CtBP1 phosphorylation by recruiting Akt1 kinase. This process, regulated by Pc2 and Akt1, targets CtBP1 for degradation, impacting transcriptional repression.

Area of Science:

  • Molecular Biology
  • Epigenetics
  • Signal Transduction

Background:

  • Pc2 (Cbx4) is a chromobox protein and a SUMO E3 ligase for CtBP1.
  • CtBP1 is a transcriptional corepressor involved in gene regulation.
  • Akt1 kinase, activated by PI3-kinase signaling, plays a role in cellular processes.

Purpose of the Study:

  • To investigate the role of Pc2 and Akt1 in the regulation of CtBP1 phosphorylation.
  • To elucidate the mechanism by which Pc2 influences CtBP1 phosphorylation and stability.
  • To understand how these modifications affect CtBP1's transcriptional repression activity.

Main Methods:

  • Investigated protein-protein interactions between Pc2, CtBP1, and Akt1.
  • Analyzed the effect of Pc2 on Akt1-mediated phosphorylation of CtBP1.
  • Utilized phosphomimetic mutants of CtBP1 to assess functional consequences.
  • Examined CtBP1 protein stability, ubiquitylation, and transcriptional repression activity.

Main Results:

  • Pc2 and CtBP1 are phosphorylated by Akt1, a process enhanced by Pc2.
  • Pc2 facilitates CtBP1 phosphorylation by recruiting Akt1 and stabilizing activated Akt1.
  • A phosphomimetic mutation in CtBP1 reduces dimerization and protein stability, leading to decreased repression.
  • Co-expression of Pc2 and Akt1 promotes CtBP1 phosphorylation, ubiquitylation, and subsequent degradation.

Conclusions:

  • Pc2 coordinates Akt1 activity to regulate CtBP1 phosphorylation and stability.
  • Phosphorylation-induced degradation of CtBP1 by Pc2 and Akt1 impacts transcriptional repression.
  • Pc2 may integrate multiple enzymatic activities to control CtBP1 function and gene expression.

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