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Alternative ERK5 regulation by phosphorylation during the cell cycle
Francisco A Iñesta-Vaquera1, David G Campbell, Cathy Tournier
1Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología/CSIC, Campus de Cantoblanco, E-28049 Madrid, Spain.
Cellular Signalling
|July 30, 2010
Summary
Mitotic regulation of ERK5 (Extracellular signal-regulated kinase 5) involves novel phosphorylation sites, distinct from its activation motif. This cyclin-dependent kinase (CDK)-dependent process inhibits ERK5 activity and controls its nuclear translocation during cell division.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Extracellular signal-regulated kinase 5 (ERK5) is a mitogen-activated protein kinase (MAPK) crucial for cell proliferation, survival, differentiation, and stress response.
- ERK5 regulates cell cycle progression, particularly G2/M phase transition and mitotic entry.
- The precise mechanisms governing ERK5 regulation during mitosis remain largely unelucidated.
Purpose of the Study:
- To investigate the molecular mechanisms of ERK5 regulation during mitosis.
- To identify specific phosphorylation sites and regulatory kinases involved in mitotic ERK5 control.
- To determine the functional consequences of mitotic ERK5 phosphorylation on its activity and localization.
Main Methods:
- Phosphoproteomic analysis to identify mitotic phosphorylation sites on ERK5.
- Site-directed mutagenesis to assess the functional significance of identified phosphorylation residues.
- In vitro kinase assays to determine the dependency on specific kinases like MEK5 and CDK.
- Cellular localization studies to track ERK5 shuttling between cytoplasm and nucleus.
Main Results:
- ERK5 undergoes phosphorylation during mitosis, but not on its canonical TEY activation motif.
- Five novel mitotic phosphorylation sites were identified, with two previously unknown.
- Mitotic ERK5 phosphorylation is dependent on cyclin-dependent kinases (CDKs), not MEK5.
- Phosphorylation of identified residues inhibits ERK5 activity and regulates its cytoplasmic-to-nuclear shuttling.
Conclusions:
- Mitosis involves a novel, CDK-dependent phosphorylation-based regulation of ERK5 activity and localization.
- This regulatory mechanism impacts ERK5 function independently of its activation motif.
- The findings establish a link between CDK and ERK5 pathways, crucial for accurate cell cycle progression.
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