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Quantitative Immunofluorescence Assay to Measure the Variation in Protein Levels at Centrosomes
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The SCF-FBXW5 E3-ubiquitin ligase is regulated by PLK4 and targets HsSAS-6 to control centrosome duplication

Anja Puklowski1, Yahya Homsi, Debora Keller

  • 1Institute for Molecular Biology, Hannover Medical School, Carl Neuberg Strasse 1, 30625 Hannover, Germany.

Nature Cell Biology
|July 5, 2011
PubMed

Insights

Centrosome duplication is controlled by FBXW5, an E3-ubiquitin ligase targeting HsSAS-6. Polo-like kinase 4 (PLK4) regulates FBXW5 activity, preventing excessive centrosome duplication and genetic instability.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • Deregulated centrosome duplication is linked to genetic instability and cancer.
  • The precise mechanisms controlling centrosome duplication remain an active area of research.

Purpose of the Study:

  • To elucidate the role of the F-box protein FBXW5 in regulating centrosome duplication.
  • To identify substrates and regulatory mechanisms of the SCF-FBXW5 complex in controlling centrosome numbers.

Main Methods:

  • Utilized FBXW5 depletion and overexpression studies.
  • Investigated the interaction and ubiquitylation of HsSAS-6 by SCF-FBXW5.
  • Examined the regulatory role of Polo-like kinase 4 (PLK4) and the anaphase-promoting complex (APC/C).

Main Results:

  • FBXW5 depletion or mutant overexpression leads to centrosome overduplication and multipolar spindles.
  • HsSAS-6 was identified as a critical substrate of the SCF-FBXW5 complex.
  • PLK4 phosphorylates FBXW5, inhibiting HsSAS-6 ubiquitylation, while APC/C targets FBXW5 for degradation.
  • FBXW5 levels peak at the G1/S transition, and its degradation resets the duplication machinery.

Conclusions:

  • The SCF-FBXW5 complex, regulated by PLK4 and APC/C, restricts centrosome re-duplication.
  • Degradation of the centriolar protein HsSAS-6 by SCF-FBXW5 is a key mechanism for controlling centrosome numbers.
  • This regulatory pathway is crucial for maintaining genomic stability and preventing tumorigenesis.

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