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Identification of Cyclin-dependent Kinase 1 Specific Phosphorylation Sites by an In Vitro Kinase Assay
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A Cdk7-Cdk4 T-loop phosphorylation cascade promotes G1 progression
Miriam Merzel Schachter1, Karl A Merrick, Stéphane Larochelle
1Department of Structural and Chemical Biology, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA.
Molecular Cell
|April 30, 2013
Summary
The CDK-activating kinase Cdk7 activates Cdk4 and Cdk6 in human cells, maintaining their activity for cell cycle progression. This uncovers a CDK-activation cascade during G1 phase, potentially limiting passage through the restriction point.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Eukaryotic cell division relies on cyclin-dependent kinases (CDKs) for regulation.
- CDKs require phosphorylation by CDK-activating kinases (CAKs) for full activity.
- Metazoan CAK Cdk7 is known to regulate Cdk2 and Cdk1 activity during S and G2 phases.
Purpose of the Study:
- To investigate if Cdk7 also activates Cdk4 and Cdk6.
- To determine the role of Cdk7 in G1 progression and restriction point passage.
- To elucidate the regulation of Cdk4/Cdk6 activity by CDK-activating phosphorylation.
Main Methods:
- Chemical genetics approaches were utilized.
- Human cell lines were employed for experimentation.
- In vitro kinase assays were performed.
Main Results:
- Cdk7 was identified as a Cdk4- and Cdk6-activating kinase in human cells.
- Cdk7 is required for maintaining Cdk4/Cdk6 activity, not just initial activation.
- Cdk7 and Cdk4 activating phosphorylation increase concurrently as cells exit quiescence.
- Cdk7 accelerates Cdk4 activation in vitro.
Conclusions:
- Mitogen signaling initiates a CDK-activation cascade during G1 progression.
- CAK activity, specifically Cdk7, may be rate-limiting for passing the restriction point.
- This study reveals a novel role for Cdk7 in regulating G1 phase progression via Cdk4/Cdk6 activation.
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