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

Ruwin Pandithage, Richard Lilischkis, Kai Harting, Alexandra Wolf, Britta Jedamzik, Juliane Lüscher-Firzlaff, Jörg Vervoorts, Edwin Lasonder, Elisabeth Kremmer, Bernd Knöll*, Bernhard Lüscher*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

163 Citations (Scopus)


Cyclin-dependent kinases (Cdks) fulfill key functions in many cellular processes, including cell cycle progression and cytoskeletal dynamics. A limited number of Cdk substrates have been identified with few demonstrated to be regulated by Cdk-dependent phosphorylation. We identify on protein expression arrays novel cyclin E-Cdk2 substrates, including SIRT2, a member of the Sirtuin family of NAD+-dependent deacetylases that targets α-tubulin. We define Ser-331 as the site phosphorylated by cyclin E-Cdk2, cyclin A-Cdk2, and p35-Cdk5 both in vitro and in cells. Importantly, phosphorylation at Ser-331 inhibits the catalytic activity of SIRT2. Gain- and loss-of-function studies demonstrate that SIRT2 interfered with cell adhesion and cell migration. In postmitotic hippocampal neurons, neurite outgrowth and growth cone collapse are inhibited by SIRT2. The effects provoked by SIRT2, but not those of a nonphosphorylatable mutant, are antagonized by Cdk-dependent phosphorylation. Collectively, our findings identify a posttranslational mechanism that controls SIRT2 function, and they provide evidence for a novel regulatory circuitry involving Cdks, SIRT2, and microtubules.

Original languageEnglish
Pages (from-to)915-929
Number of pages15
JournalJournal of Cell Biology
Issue number5
Publication statusPublished - 10 Mar 2008
Externally publishedYes


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