Mps1 Regulates Kinetochore-Microtubule Attachment Stability via the Ska Complex to Ensure Error-Free Chromosome Segregation

Dev Cell. 2017 Apr 24;41(2):143-156.e6. doi: 10.1016/j.devcel.2017.03.025.


The spindle assembly checkpoint kinase Mps1 not only inhibits anaphase but also corrects erroneous attachments that could lead to missegregation and aneuploidy. However, Mps1's error correction-relevant substrates are unknown. Using a chemically tuned kinetochore-targeting assay, we show that Mps1 destabilizes microtubule attachments (K fibers) epistatically to Aurora B, the other major error-correcting kinase. Through quantitative proteomics, we identify multiple sites of Mps1-regulated phosphorylation at the outer kinetochore. Substrate modification was microtubule sensitive and opposed by PP2A-B56 phosphatases that stabilize chromosome-spindle attachment. Consistently, Mps1 inhibition rescued K-fiber stability after depleting PP2A-B56. We also identify the Ska complex as a key effector of Mps1 at the kinetochore-microtubule interface, as mutations that mimic constitutive phosphorylation destabilized K fibers in vivo and reduced the efficiency of the Ska complex's conversion from lattice diffusion to end-coupled microtubule binding in vitro. Our results reveal how Mps1 dynamically modifies kinetochores to correct improper attachments and ensure faithful chromosome segregation.

Keywords: Mps1; Ska complex; Ska1; kinetochore; mass spectrometry; microtubule; mitosis; mitotic spindle; phosphorylation; protein kinase.

Publication types

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

MeSH terms

  • Anaphase / physiology
  • Aurora Kinase B / metabolism
  • Cell Cycle Proteins / metabolism
  • Chromosomal Proteins, Non-Histone / metabolism
  • Chromosome Segregation / physiology*
  • Humans
  • Kinetochores / metabolism*
  • M Phase Cell Cycle Checkpoints / genetics
  • Metalloproteins / metabolism*
  • Microtubules / metabolism*
  • Mitosis / physiology*
  • Nuclear Proteins / metabolism*
  • RNA-Binding Proteins / metabolism*
  • Ribosomal Proteins / metabolism*


  • Cell Cycle Proteins
  • Chromosomal Proteins, Non-Histone
  • Metalloproteins
  • Nuclear Proteins
  • RNA-Binding Proteins
  • RPS27 protein, human
  • Ribosomal Proteins
  • SKA1 protein, human
  • Aurora Kinase B