Temporal and spatial control of nucleophosmin by the Ran-Crm1 complex in centrosome duplication

Nat Cell Biol. 2005 Aug;7(8):823-30. doi: 10.1038/ncb1282. Epub 2005 Jul 24.


Centrosome duplication is tightly controlled during faithful cell division, and unnecessary reduplication can lead to supernumerary centrosomes and multipolar spindles that are associated with most human cancer cells. In addition to nucleocytoplasmic transport, the Ran-Crm1 network is involved in regulating centrosome duplication to ensure the formation of a bipolar spindle. Here, we discover that nucleophosmin (NPM) may be a Ran-Crm1 substrate that controls centrosome duplication. NPM contains a functional nuclear export signal (NES) that is responsible for both its nucleocytoplasmic shuttling and its association with centrosomes, which are Ran-Crm1-dependent as they are sensitive to Crm1-specific nuclear export inhibition, either by leptomycin B (LMB) or by the expression of a Ran-binding protein, RanBP1. Notably, LMB treatment induces premature centrosome duplication in quiescent cells, which coincides with NPM dissociation from centrosomes. Moreover, deficiency of NPM by RNA interference results in supernumerary centrosomes, which can be reversed by reintroducing wild-type but not NES-mutated NPM. Mutation of a potential proline-dependent kinase phosphorylation site at residue 95, from threonine to aspartic acid (T95D) within the NES motif, abolishes NPM association and inhibition of centrosome duplication. Our results are consistent with the hypothesis that the Ran-Crm1 complex may promote a local enrichment of NPM on centrosomes, thereby preventing centrosome reduplication.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Active Transport, Cell Nucleus / drug effects
  • Active Transport, Cell Nucleus / physiology
  • Amino Acid Sequence
  • Animals
  • Binding Sites / genetics
  • Binding Sites / physiology
  • Cell Fusion
  • Cell Line
  • Cell Nucleus / metabolism
  • Centrosome / metabolism*
  • Fatty Acids, Unsaturated / pharmacology
  • Gene Expression / genetics
  • HeLa Cells
  • Humans
  • Interphase / physiology
  • Karyopherins / physiology*
  • Mice
  • Molecular Sequence Data
  • Mutation / genetics
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Nuclear Proteins / physiology*
  • Nucleophosmin
  • Phosphorylation
  • Protein Binding / physiology
  • Protein Transport / drug effects
  • Protein Transport / physiology
  • RNA, Small Interfering / genetics
  • Receptors, Cytoplasmic and Nuclear / physiology*
  • Sequence Homology, Amino Acid
  • Threonine / genetics
  • Threonine / metabolism
  • Trans-Activators / genetics
  • Transfection
  • Viral Regulatory and Accessory Proteins
  • ran GTP-Binding Protein / genetics
  • ran GTP-Binding Protein / physiology*


  • Fatty Acids, Unsaturated
  • Karyopherins
  • NPM1 protein, human
  • Nuclear Proteins
  • RNA, Small Interfering
  • Receptors, Cytoplasmic and Nuclear
  • Trans-Activators
  • Viral Regulatory and Accessory Proteins
  • exportin 1 protein
  • hepatitis B virus X protein
  • ran-binding protein 1
  • Nucleophosmin
  • Threonine
  • ran GTP-Binding Protein
  • leptomycin B