A CEP215-HSET complex links centrosomes with spindle poles and drives centrosome clustering in cancer

Nat Commun. 2016 Mar 18;7:11005. doi: 10.1038/ncomms11005.

Abstract

Numerical centrosome aberrations underlie certain developmental abnormalities and may promote cancer. A cell maintains normal centrosome numbers by coupling centrosome duplication with segregation, which is achieved through sustained association of each centrosome with a mitotic spindle pole. Although the microcephaly- and primordial dwarfism-linked centrosomal protein CEP215 has been implicated in this process, the molecular mechanism responsible remains unclear. Here, using proteomic profiling, we identify the minus end-directed microtubule motor protein HSET as a direct binding partner of CEP215. Targeted deletion of the HSET-binding domain of CEP215 in vertebrate cells causes centrosome detachment and results in HSET depletion at centrosomes, a phenotype also observed in CEP215-deficient patient-derived cells. Moreover, in cancer cells with centrosome amplification, the CEP215-HSET complex promotes the clustering of extra centrosomes into pseudo-bipolar spindles, thereby ensuring viable cell division. Therefore, stabilization of the centrosome-spindle pole interface by the CEP215-HSET complex could promote survival of cancer cells containing supernumerary centrosomes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle Proteins
  • Cell Line
  • Centrosome / metabolism*
  • Chickens
  • Cluster Analysis
  • Humans
  • Intracellular Signaling Peptides and Proteins / chemistry
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Kinesin / chemistry
  • Kinesin / metabolism*
  • Mice
  • Mutation / genetics
  • Neoplasms / metabolism*
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / metabolism*
  • Protein Binding
  • Protein Interaction Maps
  • Protein Structure, Tertiary
  • Spindle Poles / metabolism*

Substances

  • CDK5RAP2 protein, human
  • Cell Cycle Proteins
  • Intracellular Signaling Peptides and Proteins
  • Nerve Tissue Proteins
  • human spleen, embryo, and testes expressed protein, human
  • Kinesin