Preventing the degradation of Mps1 at centrosomes is sufficient to cause centrosome reduplication in human cells

Christopher Kasbek, Ching Hui Yang, Adlina Mohd Yusof, Heather M. Chapman, Mark Winey, Harold A. Fisk

Research output: Contribution to journalArticle

58 Scopus citations

Abstract

Supernumerary centrosomes promote the assembly of abnormal mitotic spindles in many human tumors. In human cells, overexpression of the cyclin-dependent kinase (Cdk)2 partner cyclin A during a prolonged S phase produces extra centrosomes, called centrosome reduplication. Cdk2 activity protects the Mps1 protein kinase from proteasome-mediated degradation, and we demonstrate here that Mps1 mediates cyclin A-dependent centrosome reduplication. Overexpression of cyclin A or a brief proteasome inhibition increases the centrosomal levels of Mps1, whereas depletion of Cdk2 leads to the proteasome-dependent loss of Mps1 from centrosomes only. When a Cdk2 phosphorylation site within Mps1 (T468) is mutated to alanine, Mps1 cannot accumulate at centrosomes or participate in centrosome duplication. In contrast, phosphomimetic mutations at T468 or deletion of the region surrounding T468 prevent the proteasome-dependent removal of Mps1 from centrosomes in the absence of Cdk2 activity. Moreover, cyclin A-dependent centrosome reduplication requires Mps1, and these stabilizing Mps1 mutations cause centrosome reduplication, bypassing cyclin A. Together, our data demonstrate that the region surrounding T468 contains a motif that regulates the accumulation of Mps1 at centrosomes. We suggest that phosphorylation of T468 attenuates the degradation of Mps1 at centrosomes and that preventing this degradation is necessary and sufficient to cause centrosome reduplication in human cells.

Original languageEnglish (US)
Pages (from-to)4457-4469
Number of pages13
JournalMolecular Biology of the Cell
Volume18
Issue number11
DOIs
StatePublished - Nov 1 2007
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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