Canonical and kinase activity-independent mechanisms for extracellular signal-regulated kinase 5 (ERK5) nuclear translocation require dissociation of Hsp90 from the ERK5-Cdc37 complex
| Autor: | Gerard Ruiz-Babot, Jose M. Lizcano, Josep Espadamala, Jose R. Bayascas, Tatiana Erazo, Arantza Rodríguez-Asiain, Nicholas A. Morrice, Néstor Gómez, Ana Moreno |
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| Rok vydání: | 2013 |
| Předmět: |
Transcriptional Activation
Chaperonins Transcription Genetic MAPK7 Active Transport Cell Nucleus Cell Cycle Proteins Mitogen-activated protein kinase kinase Biology Cell Line Mice Animals Humans HSP90 Heat-Shock Proteins Kinase activity Phosphorylation RNA Small Interfering Molecular Biology Transcription factor Mitogen-Activated Protein Kinase 7 MAPK14 Cell Proliferation Cell Nucleus MAP kinase kinase kinase Autophosphorylation Ubiquitination Cell Biology Articles Cell biology HEK293 Cells Cyclin-dependent kinase 9 RNA Interference HeLa Cells Signal Transduction |
| Zdroj: | Molecular and cellular biology. 33(8) |
| ISSN: | 1098-5549 |
| Popis: | The mitogen-activated protein (MAP) kinase extracellular signal-regulated kinase 5 (ERK5) plays a crucial role in cell proliferation, regulating gene transcription. ERK5 has a unique C-terminal tail which contains a transcriptional activation domain, and activates transcription by phosphorylating transcription factors and acting itself as a transcriptional coactivator. However, the molecular mechanisms that regulate its nucleocytoplasmatic traffic are unknown. We have used tandem affinity purification to identify proteins that interact with ERK5. We show that ERK5 interacts with the Hsp90-Cdc37 chaperone in resting cells, and that inhibition of Hsp90 or Cdc37 results in ERK5 ubiquitylation and proteasomal degradation. Interestingly, activation of cellular ERK5 induces Hsp90 dissociation from the ERK5-Cdc37 complex, leading to ERK5 nuclear translocation and activation of transcription, by a mechanism which requires the autophosphorylation at its C-terminal tail. Consequently, active ERK5 is no longer sensitive to Hsp90 or Cdc37 inhibitors. Cdc37 overexpression also induces Hsp90 dissociation and the nuclear translocation of a kinase-inactive form of ERK5 which retains transcriptional activity. This is the first example showing that ERK5 transcriptional activity does not require kinase activity. Since Cdc37 cooperates with ERK5 to promote cell proliferation, Cdc37 overexpression (as happens in some cancers) might represent a new, noncanonical mechanism by which ERK5 regulates tumor proliferation. |
| Databáze: | OpenAIRE |
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