scholarly journals Mms19 is a mitotic gene that permits Cdk7 to be fully active as a Cdk-activating kinase

Development ◽  
2017 ◽  
Vol 145 (2) ◽  
pp. dev156802 ◽  
Author(s):  
Rishita Narendra Nag ◽  
Selina Niggli ◽  
Sofia Sousa-Guimarães ◽  
Paula Vazquez-Pianzola ◽  
Beat Suter
Keyword(s):  
Cdk Activating Kinase

scholarly journals Rb inactivation in cell cycle and cancer: The puzzle of highly regulated activating phosphorylation of CDK4 versus constitutively active CDK-activating kinase

Cell Cycle ◽  
2010 ◽  
Vol 9 (4) ◽  
pp. 689-699 ◽  
Author(s):  
Sabine Paternot ◽  
Laurence Bockstaele ◽  
Xavier Bisteau ◽  
Hugues Kooken ◽  
Katia Coulonval ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cdk Activating Kinase ◽  
Constitutively Active

scholarly journals The cryoelectron microscopy structure of the human CDK-activating kinase

2020 ◽  
Vol 117 (37) ◽  
pp. 22849-22857 ◽  
Author(s):  
Basil J. Greber ◽  
Juan M. Perez-Bertoldi ◽  
Kif Lim ◽  
Anthony T. Iavarone ◽  
Daniel B. Toso ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Rna Polymerase Ii ◽  
Transcription Initiation ◽  
Rational Design ◽  
Control Cell ◽  
3D Structure ◽  
Structural Basis ◽  
Pol Ii ◽  
Insight Into ◽  
Cdk Activating Kinase

The human CDK-activating kinase (CAK), a complex composed of cyclin-dependent kinase (CDK) 7, cyclin H, and MAT1, is a critical regulator of transcription initiation and the cell cycle. It acts by phosphorylating the C-terminal heptapeptide repeat domain of the RNA polymerase II (Pol II) subunit RPB1, which is an important regulatory event in transcription initiation by Pol II, and it phosphorylates the regulatory T-loop of CDKs that control cell cycle progression. Here, we have determined the three-dimensional (3D) structure of the catalytic module of human CAK, revealing the structural basis of its assembly and providing insight into CDK7 activation in this context. The unique third component of the complex, MAT1, substantially extends the interaction interface between CDK7 and cyclin H, explaining its role as a CAK assembly factor, and it forms interactions with the CDK7 T-loop, which may contribute to enhancing CAK activity. We have also determined the structure of the CAK in complex with the covalently bound inhibitor THZ1 in order to provide insight into the binding of inhibitors at the CDK7 active site and to aid in the rational design of therapeutic compounds.

A cyclin associated with the CDK-activating kinase MO15

Nature ◽  
1994 ◽  
Vol 371 (6494) ◽  
pp. 254-257 ◽  
Author(s):  
Tomi P. Mäkelä ◽  
Jean-Pierre Tassan ◽  
Erich A. Nigg ◽  
Séverine Frutiger ◽  
Graham J. Hughes ◽  
...  
Keyword(s):  
Cdk Activating Kinase

scholarly journals Phosphorylation of Steroidogenic Factor 1 Is Mediated by Cyclin-Dependent Kinase 7

2008 ◽  
Vol 22 (1) ◽  
pp. 91-104 ◽  
Author(s):  
Aurélia E. Lewis ◽  
Marte Rusten ◽  
Erling A. Hoivik ◽  
Elisabeth L. Vikse ◽  
Magnus L. Hansson ◽  
...  
Keyword(s):  
Posttranslational Modifications ◽  
Cdk Inhibitor ◽  
Structural Studies ◽  
Cyclin Dependent Kinase ◽  
Steroidogenic Factor 1 ◽  
Phosphorylation Level ◽  
Inactive Form ◽  
And Function ◽  
Cdk Activating Kinase

Abstract The nuclear receptor steroidogenic factor-1 (SF1) is critical for development and function of steroidogenic tissues. Posttranslational modifications are known to influence the transcriptional capacity of SF1, and it was previously demonstrated that serine 203 is phosphorylated. In this paper we report that serine 203 is phosphorylated by a cyclin-dependent kinase 7 (CDK7)-mediated process. As part of the CDK-activating kinase complex, CDK7 is a component of the basal transcription factor TFIIH, and phosphorylation of SF1 as well as SF1-dependent transcription was clearly reduced in cells carrying a mutation that renders the CDK-activating kinase complex unable to interact with the TFIIH core. Coimmunoprecipitation analyses revealed that SF1 and CDK7 reside in the same complex, and kinase assays demonstrated that immunoprecipitated CDK7 and purified TFIIH phosphorylate SF1 in vitro. The CDK inhibitor roscovitine blocked phosphorylation of SF1, and an inactive form of CDK7 repressed the phosphorylation level and the transactivation capacity of SF1. Structural studies have identified phosphoinositides as potential ligands for SF1. Interestingly, we found that mutations designed to block phospholipid binding dramatically decreased the level of SF1 phosphorylation. Together our results suggest a connection between ligand occupation and phosphorylation and association with the basic transcriptional machinery, indicating an intricate regulation of SF1 transactivation.

scholarly journals The CDK-activating Kinase (Cak1p) from Budding Yeast Has an Unusual ATP-binding Pocket

1999 ◽  
Vol 274 (4) ◽  
pp. 1949-1956 ◽  
Author(s):  
Deborah A. Enke ◽  
Philipp Kaldis ◽  
Jennifer K. Holmes ◽  
Mark J. Solomon
Keyword(s):  
Budding Yeast ◽  
Binding Pocket ◽  
Atp Binding ◽  
Cdk Activating Kinase

scholarly journals A dominant-negative cyclin D1 mutant prevents nuclear import of cyclin-dependent kinase 4 (CDK4) and its phosphorylation by CDK-activating kinase.

1997 ◽  
Vol 17 (12) ◽  
pp. 7362-7374 ◽  
Author(s):  
J A Diehl ◽  
C J Sherr
Keyword(s):  
Cyclin D1 ◽  
Nuclear Localization ◽  
Mammalian Cells ◽  
Phosphorylation Site ◽  
Dominant Negative ◽  
Cyclin Dependent Kinase ◽  
Linker Peptide ◽  
Cdk Activating Kinase

Cyclins contain two characteristic cyclin folds, each consisting of five alpha-helical bundles, which are connected to one another by a short linker peptide. The first repeat makes direct contact with cyclin-dependent kinase (CDK) subunits in assembled holoenzyme complexes, whereas the second does not contribute directly to the CDK interface. Although threonine 156 in mouse cyclin D1 is predicted to lie at the carboxyl terminus of the linker peptide that separates the two cyclin folds and is buried within the cyclin subunit, mutation of this residue to alanine has profound effects on the behavior of the derived cyclin D1-CDK4 complexes. CDK4 in complexes with mutant cyclin D1 (T156A or T156E but not T156S) is not phosphorylated by recombinant CDK-activating kinase (CAK) in vitro, fails to undergo activating T-loop phosphorylation in vivo, and remains catalytically inactive and unable to phosphorylate the retinoblastoma protein. Moreover, when it is ectopically overexpressed in mammalian cells, cyclin D1 (T156A) assembles with CDK4 in the cytoplasm but is not imported into the cell nucleus. CAK phosphorylation is not required for nuclear transport of cyclin D1-CDK4 complexes, because complexes containing wild-type cyclin D1 and a CDK4 (T172A) mutant lacking the CAK phosphorylation site are efficiently imported. In contrast, enforced overexpression of the CDK inhibitor p21Cip1 together with mutant cyclin D1 (T156A)-CDK4 complexes enhanced their nuclear localization. These results suggest that cyclin D1 (T156A or T156E) forms abortive complexes with CDK4 that prevent recognition by CAK and by other cellular factors that are required for their nuclear localization. These properties enable ectopically overexpressed cyclin D1 (T156A), or a more stable T156A/T286A double mutant that is resistant to ubiquitination, to compete with endogenous cyclin D1 in mammalian cells, thereby mobilizing CDK4 into cytoplasmic, catalytically inactive complexes and dominantly inhibiting the ability of transfected NIH 3T3 fibroblasts to enter S phase.

scholarly journals Cdc37 engages in stable, S14A mutation-reinforced association with the most atypical member of the yeast kinome, Cdk-activating kinase (Cak1)

2014 ◽  
Author(s):  
Stefan Millson ◽  
Patricija van Oosten-Hawle ◽  
Mohammed A. Alkuriji ◽  
Andrew Truman ◽  
Marco Siderius ◽  
...  
Keyword(s):  
Atypical Member ◽  
Cdk Activating Kinase

scholarly journals Cell cycle analysis of the activity, subcellular localization, and subunit composition of human CAK (CDK-activating kinase).

1994 ◽  
Vol 127 (2) ◽  
pp. 467-478 ◽  
Author(s):  
J P Tassan ◽  
S J Schultz ◽  
J Bartek ◽  
E A Nigg
Keyword(s):  
Cell Cycle ◽  
Somatic Cell ◽  
Cell Cycle Control ◽  
Gel Filtration ◽  
Multiprotein Complex ◽  
Cyclin Dependent Kinases ◽  
Critical Residue ◽  
Cdk Activating Kinase

The activity of cyclin-dependent kinases (cdks) depends on the phosphorylation of a residue corresponding to threonine 161 in human p34cdc2. One enzyme responsible for phosphorylating this critical residue has recently been purified from Xenopus and starfish. It was termed CAK (for cdk-activating kinase), and it was shown to contain p40MO15 as its catalytic subunit. In view of the cardinal role of cdks in cell cycle control, it is important to learn if and how CAK activity is regulated during the somatic cell cycle. Here, we report a molecular characterization of a human p40MO15 homologue and its associated CAK activity. We have cloned and sequenced a cDNA coding for human p40MO15, and raised specific polyclonal and monoclonal antibodies against the corresponding protein expressed in Escherichia coli. These tools were then used to demonstrate that p40MO15 protein expression and CAK activity are constant throughout the somatic cell cycle. Gel filtration suggests that active CAK is a multiprotein complex, and immunoprecipitation experiments identify two polypeptides of 34 and 32 kD as likely complex partners of p40MO15. The association of the three proteins is near stoichiometric and invariant throughout the cell cycle. Immunocytochemistry and biochemical enucleation experiments both demonstrate that p40MO15 is nuclear at all stages of the cell cycle (except for mitosis, when the protein redistributes throughout the cell), although the p34cdc2/cyclin B complex, one of the major purported substrates of CAK, occurs in the cytoplasm until shortly before mitosis. The absence of obvious changes in CAK activity in exponentially growing cells constitutes a surprise. It suggests that the phosphorylation state of threonine 161 in p34cdc2 (and the corresponding residue in other cdks) may be regulated primarily by the availability of the cdk/cyclin substrates, and by phosphatase(s).

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