CDK1, not ERK1/2 or ERK5, is required for mitotic phosphorylation of BIMEL.
The pro-apoptotic BH3 only protein BIM(EL) is phosphorylated by ERK1/2 and this targets it for proteasome-dependent degradation. A recent study has shown that ERK5, an ERK1/2-related MAPK, is activated during mitosis and phosphorylates BIM(EL) to promote cell survival. Here we show that treatment of cells with nocodazole or paclitaxel does ... cause phosphorylation of BIM(EL), which is independent of ERK1/2. However, this was not due to ERK5-catalysed phosphorylation, since it was not reversed by the MEK5 inhibitor BIX02189 and proceeded normally in ERK5-/- fibroblasts. Indeed, although ERK5 is phosphorylated at multiple sites in the C-terminal transactivation region during mitosis, these do not include the activation-loop and ERK5 kinase activity does not increase. Mitotic phosphorylation of BIM(EL) occurred at proline-directed phospho-acceptor sites and was abolished by selective inhibition of CDK1. Furthermore, cyclin B1 was able to interact with BIM and cyclin B1/CDK1 complexes could phosphorylate BIM in vitro. Finally, we show that CDK1-dependent phosphorylation of BIM(EL) drives its polyubiquitylation and proteasome-dependent degradation to protect cells during mitotic arrest. These results provide new insights into the regulation of BIM(EL) and may be relevant to the therapeutic use of agents such as paclitaxel.
Mesh Terms:
Antineoplastic Agents, Apoptosis, Apoptosis Regulatory Proteins, Bcl-2-Like Protein 11, CDC2 Protein Kinase, Cell Cycle Checkpoints, Enzyme Activation, Enzyme Assays, Genes, Reporter, HEK293 Cells, Humans, Leupeptins, Luciferases, Renilla, Membrane Proteins, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinase 7, Mitosis, Nocodazole, Paclitaxel, Phosphorylation, Proteasome Endopeptidase Complex, Proteasome Inhibitors, Protein Binding, Protein Processing, Post-Translational, Protein Structure, Tertiary, Proteolysis, Proto-Oncogene Proteins, Recombinant Fusion Proteins
Antineoplastic Agents, Apoptosis, Apoptosis Regulatory Proteins, Bcl-2-Like Protein 11, CDC2 Protein Kinase, Cell Cycle Checkpoints, Enzyme Activation, Enzyme Assays, Genes, Reporter, HEK293 Cells, Humans, Leupeptins, Luciferases, Renilla, Membrane Proteins, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinase 7, Mitosis, Nocodazole, Paclitaxel, Phosphorylation, Proteasome Endopeptidase Complex, Proteasome Inhibitors, Protein Binding, Protein Processing, Post-Translational, Protein Structure, Tertiary, Proteolysis, Proto-Oncogene Proteins, Recombinant Fusion Proteins
Cell Signal
Date: Jan. 01, 2012
PubMed ID: 21924351
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