Early mitotic degradation of Nek2A depends on Cdc20-independent interaction with the APC/C

Nat Cell Biol. 2006 Jun;8(6):607-14. doi: 10.1038/ncb1410. Epub 2006 Apr 30.

Abstract

The temporal control of mitotic protein degradation remains incompletely understood. In particular, it is unclear why the mitotic checkpoint prevents the anaphase-promoting complex/cyclosome (APC/C)-mediated degradation of cyclin B and securin in early mitosis, but not cyclin A. Here, we show that another APC/C substrate, NIMA-related kinase 2A (Nek2A), is also destroyed in pro-metaphase in a checkpoint-independent manner and that this depends on an exposed carboxy-terminal methionine-arginine (MR) dipeptide tail. Truncation of the Nek2A C terminus delays its degradation until late mitosis, whereas Nek2A C-terminal peptides interfere with APC/C activity in an MR-dependent manner. Most importantly, we show that Nek2A binds directly to the APC/C, also in an MR-dependent manner, even in the absence of the adaptor protein Cdc20. As similar C-terminal dipeptide tails promote direct association of Cdc20, Cdh1 and Apc10-Doc1 with core APC/C subunits, we propose that this sequence also allows a substrate, Nek2A, to directly bind the APC/C. Thus, although Cdc20 is required for the degradation of Nek2A, it is not required for its recruitment and this renders its degradation insensitive to the mitotic checkpoint.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaphase-Promoting Complex-Cyclosome
  • Animals
  • Cdc20 Proteins
  • Cell Cycle Proteins
  • HeLa Cells
  • Humans
  • Mitosis*
  • Protein-Serine-Threonine Kinases / metabolism*
  • Ubiquitin-Protein Ligase Complexes / metabolism*
  • Xenopus
  • Xenopus Proteins / metabolism*

Substances

  • Cdc20 Proteins
  • Cdc20 protein, Xenopus
  • Cell Cycle Proteins
  • Xenopus Proteins
  • Ubiquitin-Protein Ligase Complexes
  • Anaphase-Promoting Complex-Cyclosome
  • NEK2 protein, Xenopus
  • Protein-Serine-Threonine Kinases