Chapter category: Cell Cycle
The Evolution of CDK-Activating Kinases
The CDK-Activating Kinase (CAK)
Edited by: Philipp KaldisISBN: 0-306-47438-7
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Chapter authors:
Ji Liu, Edward T. Kipreos
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Cyclin-dependent kinases (CDKs) are essential regulators of the cell cycle and transcription. In the budding yeast Saccharomyces cerevisiae and the fission yeast Saccharomyces pombe, a single CDK (Cdc28p or its ortholog Cdc2, respectively) catalyzes all major cell cycle transitions.1,2 In higher eukaryotes, there has been an expansion in the number of CDKs that regulate the cell cycle. For example, in mammals, CDK4, CDK6, and CDK3 regulate the G1S phase transition; CDK2 controls entry into S phase and DNA replication; and CDK1 (CDC2) is essential for mitosis.3-7
CDKs also regulate transcription. In budding yeast, Kin28p, Srb10p, and Ctk1p regulate mRNA synthesis by phosphorylating the carboxyl-terminal domain (CTD) of RNA polymerase II.8-11 The budding yeast CDK Sgv1p also functions to regulate transcription, but its substrates are unknown.12 In metazoa, the ortholog of Sgv1p, CDK9, is a component of the positive transcription elongation factor b (pTEFb) that promotes productive RNA Pol II transcription elongation by phosphorylating the CTD.13,14
CDK activity is highly regulated in cells. There are four major regulatory mechanisms: 1) most CDKs require binding to cyclin proteins to become active; 2) CDK activity is inhibited by the binding of cyclin-dependent kinase inhibitors (CKIs); 3) phosphorylation of conserved residues in the ATP-binding pocket of the CDK inhibits its activity; and 4) phosphorylation of a conserved residue in the T-loop of CDKs is required for the activation of most CDKs.
The activating phosphorylation of CDKs is catalyzed by a CDKactivating kinase (CAK). CAK phosphorylates a conserved serine (Ser) or threonine (Thr) site in the T-loop of the CDKs. We will refer to this site as Thr 160 (T160) based on its location in human CDK2. When not phosphorylated, the T-loop blocks the entrance of the CDK active site cleft to prevent the binding of protein substrates.15 Phosphorylation on T160 induces a conformational change in the CDK, resulting in enhanced CDKcyclin interaction and substrate binding.16 Both cell cycle CDKs such as CDK1, CDK2, and CDK4, and transcription CDKs such as CDK7 and Kin28p have been shown to require CAK phosphorylation to be active.17-23 A loss of CAK activity leads to cell cycle arrest as well as transcription defects.22-24
Additional chapters from this book:
Structural Aspects of CDK Activation
Nick R. Brown and Jane A. Endicott
Sequential activation of members of the cyclin-dependent kinase (CDK) family orders the events required for DNA replication and cell division. Both the CDK and cyclin families ha...
Activation of CDKs by CAK: CAK in TFIIH
Anne Keriel and Jean-Marc Egly
TFIIH was originally identified as a basal transcription factor involved in protein-coding genes transcription.1,2 The systematic cloning of its nine subunits r...
CDK-Activation in Fission Yeast Schizosaccharomyces pombe: Specificity Mediated
Thomas Westerling, Damien Hermand and Tomi P. Mäkelä
Activation of cyclin dependent kinases (CDKs) by phosphorylation of the conserved Tloop is a regulatory step of cell cycle progression that was discovered just a decade ago. A we...
Activating Phosphorylation of Cyclin-Dependent Kinases in Budding Yeast
Philipp Kaldis, Vasiliki Tsakraklides, Karen E. Ross, Edward Winter
The eukaryotic cell division cycle is controlled via the sequential activation and inactivation of cyclin-dependent protein kinases (cdks). In the budding yeast Sacchar...
CDK-Activating Kinases in Higher Plants
Masaaki Umeda
Recent development in plant molecular genetics has facilitated our understanding of how plants accomplish their body plans in response to various environmental signals. Plants h...
Drosophila CDK7: A Paradigm for CAK in Metazoans
Stéphane Larochelle and Robert P. Fisher
Activation of cyclin dependent kinases (CDKs) by phosphorylation of the conserved Tloop is a regulatory step of cell cycle progression that was discovered just a decade ago. A wealth o...
The Evolution of CDK-Activating Kinases
Ji Liu, Edward T. Kipreos
Cyclin-dependent kinases (CDKs) are essential regulators of the cell cycle and transcription. In the budding yeast Saccharomyces cerevisiae and the fission ...
CAK from Marine Invertebrates to Human
Randy Y.C. Poon
The eukaryotic cell cycle is driven by an evolutionarily conserved engine consisting of a series of cyclin-dependent kinase (CDK)-cyclin modules. The orderly events of the cell cyc...
