Abstract
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 a-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.
DOI
10.1083/jcb.200707126
Publication Date
2008-03-10
Publication Title
The Journal of Cell Biology
Volume
180
Issue
5
Publisher
Rockefeller University Press
ISSN
1540-8140
Embargo Period
2024-11-19
First Page
915
Last Page
929
Recommended Citation
Pandithage, R., Lilischkis, R., Harting, K., Wolf, A., & et al. (2008) 'The regulation of SIRT2 function by cyclin-dependent kinases affects cell motility', The Journal of Cell Biology, 180(5), pp. 915-929. Rockefeller University Press: Available at: https://doi.org/10.1083/jcb.200707126
