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¹ Abteilung Biochemie und Molekularbiologie, Institut für Biochemie, Universitätsklinikum, Rheinisch-Westfälische Technische Hochschule Aachen University, 52057 Aachen, Germany
² Interfakultäres Institut für Zellbiologie, Abt. Molekularbiologie, Universität Tübingen, 72076 Tübingen, Germany
³ Netherland Centre for Molecular Life Sciences, Centre for Molecular and Biomolecular Informatics, 6500 HB Nijmegen, Netherlands
⁴ Deutsches Forschungszentrum für Gesundheit und Umwelt, Institut für Molekulare Immunologie, 81377 München, Germany

Correspondence to Bernhard Lüscher: luescher{at}rwth-aachen.de; or Bernd Knöll: bernd.knoell{at}uni-tuebingen.de

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 -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.

R. Pandithage and R. Lilischkis contributed equally to this paper.

R. Pandithage's present address is Leica, 1170 Wien, Austria.

R. Lilischkis' present address is BTF Precise Microbiology, North Ryde Sydney, NSW 2113 Australia.

B. Jedamzik's present address is Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.

Abbreviations used in this paper: HDAC, histone deacetylase; HDF, human diploid fibroblast; HS, horse serum; KD, knockdown; MAP, microtubule-associated protein; MEF, mouse embryonic fibroblast; ppm, parts per million; STMN2, stathmin-like 2; TAP, tandem affinity purification.

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