Phosphorylation of microtubule-binding protein Hec1 by mitotic kinase Aurora B specifies spindle checkpoint kinase Mps1 signaling at the kinetochore

J Biol Chem. 2013 Dec 13;288(50):36149-59. doi: 10.1074/jbc.M113.507970. Epub 2013 Nov 1.

Abstract

The spindle assembly checkpoint (SAC) is a quality control device to ensure accurate chromosome attachment to spindle microtubule for equal segregation of sister chromatid. Aurora B is essential for SAC function by sensing chromosome bi-orientation via spatial regulation of kinetochore substrates. However, it has remained elusive as to how Aurora B couples kinetochore-microtubule attachment to SAC signaling. Here, we show that Hec1 interacts with Mps1 and specifies its kinetochore localization via its calponin homology (CH) domain and N-terminal 80 amino acids. Interestingly, phosphorylation of the Hec1 by Aurora B weakens its interaction with microtubules but promotes Hec1 binding to Mps1. Significantly, the temporal regulation of Hec1 phosphorylation orchestrates kinetochore-microtubule attachment and Mps1 loading to the kinetochore. Persistent expression of phosphomimetic Hec1 mutant induces a hyperactivation of SAC, suggesting that phosphorylation-elicited Hec1 conformational change is used as a switch to orchestrate SAC activation to concurrent destabilization of aberrant kinetochore attachment. Taken together, these results define a novel role for Aurora B-Hec1-Mps1 signaling axis in governing accurate chromosome segregation in mitosis.

Keywords: Cenp-e; Checkpoint; Checkpoint Control; Kinetochore; Mitosis; Mitotic Spindle; Phosphorylation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aurora Kinase B / metabolism*
  • Cell Cycle Checkpoints
  • Cell Cycle Proteins / metabolism*
  • Cytoskeletal Proteins
  • Gene Expression Regulation
  • HeLa Cells
  • Humans
  • Kinetochores / metabolism*
  • M Phase Cell Cycle Checkpoints*
  • Microtubules / metabolism*
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / metabolism*
  • Phosphorylation
  • Protein Structure, Tertiary
  • Protein Transport
  • Protein-Serine-Threonine Kinases / metabolism*
  • Protein-Tyrosine Kinases / metabolism*
  • Signal Transduction*

Substances

  • Cell Cycle Proteins
  • Cytoskeletal Proteins
  • NDC80 protein, human
  • Nuclear Proteins
  • Protein-Tyrosine Kinases
  • AURKB protein, human
  • Aurora Kinase B
  • Protein-Serine-Threonine Kinases
  • TTK protein, human