Rb inactivation in cell cycle and cancer: the puzzle of highly regulated activating phosphorylation of CDK4 versus constitutively active CDK-activating kinase.
Cyclin-dependent kinase (CDK) 4 is a master integrator that couples mitogenic/oncogenic signalling cascades with the inactivation of the central oncosuppressor Rb and the cell cycle. Its activation requires binding to a D-type cyclin and then T-loop phosphorylation at T172 by the only identified CDK-activating kinase in animal cells, cyclin H-CDK7. In contrast with the observed constitutive activity of cyclin H-CDK7, we have recently identified the T172-phosphorylation of cyclin D-bound CDK4 as a crucial cell cycle regulatory target. Intriguingly, the homologous T177-phosphorylation of CDK6 is weak in several systems and does not present this regulation. In this Perspective, we review the recent advances and debates on the multistep mechanism leading to activation of D-type cyclin-CDK4 complexes. This involves a re-evaluation of the implication of Cip/Kip CDK "inhibitors" and CDK7 in this process.
Paternot
Sabine
S
Institute of Interdisciplinary Research (IRIBHM), Faculté de Médecine, Université Libre de Bruxelles, Brussels, Belgium.
Bockstaele
Laurence
L
Bisteau
Xavier
X
Kooken
Hugues
H
Coulonval
Katia
K
Roger
Pierre P
PP
D000818:Animals; D002453:Cell Cycle; D056748:Cyclin H / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000378:metabolism*; D000095043:Cyclin-Dependent Kinase-Activating Kinase
D056748:Cyclin H; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016160:Retinoblastoma Protein; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; D000095043:Cyclin-Dependent Kinase-Activating Kinase