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The regulation of SIRT2 function by cyclin-dependent kinases affects cell motility

Ruwin Pandithage1, Richard Lilischkis, Kai Harting

  • 1Abteilung Biochemie und Molekularbiologie, Institut für Biochemie, Universitätsklinikum, Rheinisch-Westfälische Technische Hochschule Aachen University, 52057 Aachen, Germany.

The Journal of Cell Biology
|March 12, 2008
PubMed

Insights

Cyclin-dependent kinases (Cdks) regulate SIRT2 deacetylase activity through phosphorylation at Ser-331, impacting cell migration and neuronal development. This reveals a novel Cdk-SIRT2-microtubule regulatory pathway.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Neuroscience

Background:

  • Cyclin-dependent kinases (Cdks) are crucial regulators of cellular processes.
  • Identifying Cdk substrates and their regulation by phosphorylation is essential for understanding cell function.
  • Sirtuin 2 (SIRT2) is an NAD(+)-dependent deacetylase that targets alpha-tubulin.

Purpose of the Study:

  • To identify novel substrates of cyclin E-Cdk2.
  • To investigate the functional consequences of Cdk-mediated phosphorylation of SIRT2.
  • To elucidate a novel regulatory circuitry involving Cdks, SIRT2, and microtubules.

Main Methods:

  • Protein expression arrays to identify novel Cdk substrates.
  • In vitro and cellular phosphorylation assays to define the phosphorylation site (Ser-331).
  • Gain- and loss-of-function studies in cell models and hippocampal neurons.

Main Results:

  • SIRT2 was identified as a novel substrate of cyclin E-Cdk2.
  • Phosphorylation of SIRT2 at Ser-331 by cyclin E-Cdk2, cyclin A-Cdk2, and p35-Cdk5 inhibits its catalytic activity.
  • SIRT2 negatively regulates cell adhesion, migration, neurite outgrowth, and growth cone collapse.
  • Cdk-dependent phosphorylation antagonizes SIRT2-mediated effects.

Conclusions:

  • A posttranslational mechanism controlling SIRT2 function via Cdk-dependent phosphorylation at Ser-331 was identified.
  • This phosphorylation event inhibits SIRT2 deacetylase activity.
  • A novel regulatory pathway involving Cdks, SIRT2, and microtubules in cellular processes and neuronal development was uncovered.

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