TY - JOUR
T1 - A Cdk7-Cdk4 T-Loop Phosphorylation Cascade Promotes G1 Progression
AU - Schachter, Miriam Merzel
AU - Merrick, Karl A.
AU - Larochelle, Stéphane
AU - Hirschi, Alexander
AU - Zhang, Chao
AU - Shokat, Kevan M.
AU - Rubin, Seth M.
AU - Fisher, Robert P.
N1 - Funding Information:
We thank S. Blain (SUNY Downstate) for Rb constructs and advice, P. Roger (Université Libre de Bruxelles) for the Cdk4-T172P antibody and for communicating results prior to publication, and Fisher lab members for helpful discussions. The work was supported by a fellowship from the National Institutes of Health to M.M.S. (T32 CA78207) and by NIH grants GM056985 to R.P.F., EB001987 to K.M.S., and CA132685 to S.M.R.
PY - 2013/4/25
Y1 - 2013/4/25
N2 - Eukaryotic 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 tomaintain 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 acceleratesCdk4 activation invitro. Therefore, mitogen signaling drives a CDK-activation cascade during G1 progression, and CAK might be rate-limiting for R point passage.
AB - Eukaryotic 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 tomaintain 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 acceleratesCdk4 activation invitro. Therefore, mitogen signaling drives a CDK-activation cascade during G1 progression, and CAK might be rate-limiting for R point passage.
UR - https://www.scopus.com/pages/publications/84876860706
U2 - 10.1016/j.molcel.2013.04.003
DO - 10.1016/j.molcel.2013.04.003
M3 - Article
C2 - 23622515
AN - SCOPUS:84876860706
SN - 1097-2765
VL - 50
SP - 250
EP - 260
JO - Molecular Cell
JF - Molecular Cell
IS - 2
ER -