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Gravin regulates centrosome function through PLK1

Erica G Colicino1, Alice M Garrastegui1,2, Judy Freshour1

  • 1Department of Cell and Developmental Biology, Upstate Medical University, Syracuse, NY 13202.

Molecular Biology of the Cell
|December 29, 2017
PubMed

Insights

Gravin depletion increases micronuclei formation by disrupting the PLK1 scaffold, leading to chromosome segregation errors. Restoring Gravin-PLK1 interaction prevents these errors and DNA damage.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Polo-like kinase 1 (PLK1) is a crucial mitotic kinase regulating chromosome segregation.
  • Gravin acts as a scaffold protein, potentially influencing PLK1 activity and localization.
  • Chromosome segregation errors can lead to aneuploidy and genomic instability, hallmarks of cancer.

Purpose of the Study:

  • To investigate the role of Gravin in PLK1-mediated chromosome segregation.
  • To determine how Gravin depletion affects PLK1 activity and localization.
  • To elucidate the downstream consequences of Gravin-PLK1 interaction disruption on mitotic fidelity.

Main Methods:

  • Utilized three-dimensional primary prostate cancer cell cultures and Gravin short hairpin RNA (shRNA) for depletion studies.
  • Employed photokinetics and a PLK1 activity biosensor to assess PLK1 distribution and activity.
  • Analyzed chromosome misalignment, micronuclei formation, and microtubule dynamics.

Main Results:

  • Gravin depletion increased micronuclei formation and chromosome misalignment.
  • Loss of Gravin led to increased PLK1 mobility and aberrant PLK1 activity, causing CEP215 phosphorylation.
  • Defects in microtubule renucleation and kinetochore-fiber integrity were observed upon Gravin depletion.
  • Murine Gravin, but not a PLK1-binding deficient mutant, rescued these defects.

Conclusions:

  • Disruption of the Gravin-PLK1 interface results in inappropriate PLK1 activity.
  • This inappropriate activity contributes to chromosome segregation errors and micronuclei formation.
  • Targeting the Gravin-PLK1 interaction may offer therapeutic strategies for cancers with compromised Gravin function.

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