Dynamic autophosphorylation of mps1 kinase is required for faithful mitotic progression

PLoS One. 2014 Sep 29;9(9):e104723. doi: 10.1371/journal.pone.0104723. eCollection 2014.

Abstract

The spindle assembly checkpoint (SAC) is a surveillance mechanism monitoring cell cycle progression, thus ensuring accurate chromosome segregation. The conserved mitotic kinase Mps1 is a key component of the SAC. The human Mps1 exhibits comprehensive phosphorylation during mitosis. However, the related biological relevance is largely unknown. Here, we demonstrate that 8 autophosphorylation sites within the N-terminus of Mps1, outside of the catalytic domain, are involved in regulating Mps1 kinetochore localization. The phospho-mimicking mutant of the 8 autophosphorylation sites impairs Mps1 localization to kinetochore and also affects the kinetochore recruitment of BubR1 and Mad2, two key SAC effectors, subsequently leading to chromosome segregation errors. Interestingly, the non-phosphorylatable mutant of the 8 autophosphorylation sites enhances Mps1 kinetochore localization and delays anaphase onset. We further show that the Mps1 phospho-mimicking and non-phosphorylatable mutants do not affect metaphase chromosome congression. Thus, our results highlight the importance of dynamic autophosphorylation of Mps1 in regulating accurate chromosome segregation and ensuring proper mitotic progression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle Proteins / chemistry
  • Cell Cycle Proteins / metabolism*
  • HeLa Cells
  • Humans
  • Mitosis*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / chemistry
  • Protein-Serine-Threonine Kinases / metabolism*
  • Protein-Tyrosine Kinases / chemistry
  • Protein-Tyrosine Kinases / metabolism*
  • Serine / metabolism
  • Threonine / metabolism

Substances

  • Cell Cycle Proteins
  • Threonine
  • Serine
  • Protein-Tyrosine Kinases
  • Protein-Serine-Threonine Kinases
  • TTK protein, human

Grant support

This project was supported by Chinese 973 Project Grants 2013CB911203, 2012CB945002, 2012CB917204; Chinese Natural Science Foundation Grants 31071184, 31371363 (to Z.D.), 31271439 and 31301109 (to C.F.); grants from Hong Kong Research Grants Council and HKU seed funding programme (to C.F.) and Research Funds for Central Universities WK2340000021. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.