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

John Maciejowski1, Hauke Drechsler2, Kathrin Grundner-Culemann3

  • 1Molecular Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Developmental Cell
|April 26, 2017
PubMed

Insights

The spindle assembly checkpoint kinase Mps1 corrects erroneous chromosome attachments by destabilizing microtubule fibers, preventing aneuploidy. It targets the Ska complex, revealing a novel mechanism for faithful chromosome segregation.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • The spindle assembly checkpoint (SAC) is crucial for preventing aneuploidy.
  • Mps1 (Monopolar spindle 1) kinase is a key SAC component that inhibits anaphase onset.
  • Mps1's role in correcting erroneous kinetochore-microtubule attachments is not fully understood.

Purpose of the Study:

  • To identify Mps1's error correction substrates.
  • To elucidate Mps1's mechanism in correcting faulty chromosome-spindle attachments.
  • To understand how Mps1 regulates kinetochore-microtubule interactions.

Main Methods:

  • Chemically tuned kinetochore-targeting assay.
  • Quantitative proteomics to identify phosphorylation sites.
  • In vitro biochemical assays using the Ska complex.
  • In vivo studies using mutant analysis.

Main Results:

  • Mps1 destabilizes microtubule attachments (K-fibers) independently of Aurora B.
  • Identified Mps1-regulated phosphorylation sites at the outer kinetochore.
  • Mps1's action is opposed by PP2A-B56 phosphatases.
  • Mps1 inhibition rescues K-fiber stability upon PP2A-B56 depletion.
  • The Ska complex is a key Mps1 effector, mediating K-fiber destabilization and altered microtubule binding dynamics.

Conclusions:

  • Mps1 dynamically modifies kinetochores to correct improper attachments.
  • Mps1 ensures faithful chromosome segregation through regulation of kinetochore-microtubule interactions.
  • The Ska complex is a critical downstream target of Mps1 in error correction.
Keywords:
Mps1Ska complexSka1kinetochoremass spectrometrymicrotubulemitosismitotic spindlephosphorylationprotein kinase

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