Raf kinase inhibitory protein regulates aurora B kinase and the spindle checkpoint.
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.
Eves
Eva M
EM
Ben May Institute for Cancer Research, University of Chicago, Chicago, Illinois 60637, USA.
Shapiro
Paul
P
Naik
Karuna
K
Klein
Ulf R
UR
Trakul
Nicholas
N
Rosner
Marsha Rich
MR
D000727:Androgen-Binding Protein / Q000172:deficiency / Q000378:metabolism*; D000818:Animals; D064107:Aurora Kinase B; D064127:Aurora Kinases; D018385:Centrosome / Q000378:metabolism; D002843:Chromatin / Q000187:drug effects; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D018386:Kinetochores / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008677:Metaphase / Q000187:drug effects; D015739:Nocodazole / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology; D049488:Phosphatidylethanolamine Binding Protein; D010766:Phosphorylation; D060789:Prostatein; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D021381:Protein Transport; D051381:Rats; D060765:Secretoglobins; D008941:Spindle Apparatus / Q000187:drug effects / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014598:Uteroglobin; D048490:raf Kinases / Q000378:metabolism; D060788:Mammaglobin B
D000727:Androgen-Binding Protein; D064107:Aurora Kinase B; D064127:Aurora Kinases; D002843:Chromatin; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; D015739:Nocodazole; D017239:Paclitaxel; D049488:Phosphatidylethanolamine Binding Protein; D060789:Prostatein; D017346:Protein Serine-Threonine Kinases; D060765:Secretoglobins; D014598:Uteroglobin; D048490:raf Kinases; C511482:PEBP1 protein, human; C511484:Scgb1d2 protein, rat; C511483:Scgb1d4 protein, rat; C576921:AURKB protein, human; C576925:Aurkb protein, rat; C556468:Scgb2a1 protein, rat; D060788:Mammaglobin B