Raf kinase inhibitory protein regulates aurora B kinase and the spindle checkpoint

Mol Cell. 2006 Aug;23(4):561-74. doi: 10.1016/j.molcel.2006.07.015.

Abstract

Raf kinase inhibitory protein (RKIP or PEBP) is an inhibitor of the Raf/MEK/MAP kinase signaling cascade and a suppressor of cancer metastasis. We now show that RKIP associates with centrosomes and kinetochores and regulates the spindle checkpoint in mammalian cells. RKIP depletion causes decreases in the mitotic index, the number of metaphase cells, and traversal times from nuclear envelope breakdown to anaphase, and an override of mitotic checkpoints induced by spindle poisons. Raf-1 depletion or MEK inhibition reverses the reduction in the mitotic index, whereas hyperactivation of Raf mimics the RKIP-depletion phenotype. Finally, RKIP depletion or Raf hyperactivation reduces kinetochore localization and kinase activity of Aurora B, a regulator of the spindle checkpoint. These results indicate that RKIP regulates Aurora B kinase and the spindle checkpoint via the Raf-1/MEK/ERK cascade and demonstrate that small changes in the MAP kinase (MAPK) pathway can profoundly impact the fidelity of the cell cycle.

Publication types

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

MeSH terms

  • Androgen-Binding Protein / deficiency
  • Androgen-Binding Protein / metabolism*
  • Animals
  • Aurora Kinase B
  • Aurora Kinases
  • Centrosome / metabolism
  • Chromatin / drug effects
  • Enzyme Activation
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • HeLa Cells
  • Humans
  • Kinetochores / metabolism
  • MAP Kinase Kinase Kinases / metabolism
  • Metaphase / drug effects
  • Nocodazole / pharmacology
  • Paclitaxel / pharmacology
  • Phosphatidylethanolamine Binding Protein
  • Phosphorylation
  • Prostatein
  • Protein Transport
  • Protein-Serine-Threonine Kinases / metabolism*
  • Rats
  • Secretoglobins
  • Spindle Apparatus / drug effects
  • Spindle Apparatus / metabolism*
  • Tumor Cells, Cultured
  • Uteroglobin
  • raf Kinases / metabolism

Substances

  • Androgen-Binding Protein
  • Chromatin
  • PEBP1 protein, human
  • Phosphatidylethanolamine Binding Protein
  • Prostatein
  • Scgb1d2 protein, rat
  • Scgb1d4 protein, rat
  • Scgb2a2 protein, rat
  • Secretoglobins
  • Uteroglobin
  • AURKB protein, human
  • Aurkb protein, rat
  • Aurora Kinase B
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases
  • raf Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • MAP Kinase Kinase Kinases
  • Paclitaxel
  • Nocodazole