A Cdk7-Cdk4 T-Loop Phosphorylation Cascade Promotes G1 Progression

• Chemical genetics reveals that Cdk7 is the CAK for Cdk4 and Cdk6 in human cells
• Cdk4 and Cdk6 are acutely sensitive to CAK shutoff in vivo, unlike Cdk1 or Cdk2
• Cdk4 activation is stimulated by Cdk7 T-loop phosphorylation in vitro
• Cdk7 T-loop phosphorylation is induced by mitogenic stimulation in G1

SummaryEukaryotic cell division is controlled by cyclin-dependent kinases (CDKs), which require phosphorylation by a CDK-activating kinase (CAK) for full activity. Chemical genetics uncovered requirements for the metazoan CAK Cdk7 in determining cyclin specificity and activation order of Cdk2 and Cdk1 during S and G2 phases. It was unknown if Cdk7 also activates Cdk4 and Cdk6 to promote passage of the restriction (R) point, when continued cell-cycle progression becomes mitogen independent, or if CDK-activating phosphorylation regulates G1 progression. Here we show that Cdk7 is a Cdk4- and Cdk6-activating kinase in human cells, required to maintain activity, not just to establish the active state, as is the case for Cdk1 and Cdk2. Activating phosphorylation of Cdk7 rises concurrently with that of Cdk4 as cells exit quiescence and accelerates Cdk4 activation in vitro. Therefore, mitogen signaling drives a CDK-activation cascade during G1 progression, and CAK might be rate-limiting for R point passage.

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