The cdk-activating kinase (CAK): from yeast to mammals

Kaldis, Philipp

doi:10.1007/s000180050290

Cited by 206 publications

(201 citation statements)

References 143 publications

(264 reference statements)

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“…Similarly, we did not detect an effect of Fer depletion on the kinase activity of CDK4/cyclin D1 or CDK2/cyclin E complexes (data not shown). This coincides with the lack of a change in the cellular levels of the CDK activators CDK7 and cyclin H (Kaldis, 1999) or the inhibitors p21Cip1 and p27Kip1 (Coqueret, 2003) in Fer-depleted cells.…”

Section: Fer Maintains G1-s Transition In Malignant Cells O Pasder Et Alsupporting

confidence: 60%

“…Interestingly, the level of CDK2 was not changed in fer-siRNA-treated MDA-MB-231 cells (Figure 3c). In parallel, the levels of the CDK-activating kinase (CAK) components -CDK7 and cyclin H -were also not affected (Figure 3a), suggesting a lack of an effect on the functional activation of CDKs (Kaldis, 1999) upon 'knock-down' of Fer. In accordance with this conclusion, we did not see any reduction in the in vitro kinase activity of CDK4 or CDK6 in Fer-depleted cells (data not shown).…”

Section: Downregulation Of Fer Arrests Malignant Cells At the G0/g1 Pmentioning

confidence: 99%

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Downregulation of Fer induces PP1 activation and cell-cycle arrest in malignant cells

et al. 2006

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Fer is a nuclear and cytoplasmic intracellular tyrosine kinase. Herein we show that Fer is required for cell-cycle progression in malignant cells. Decreasing the level of Fer using the RNA interference (RNAi) approach impeded the proliferation of prostate and breast carcinoma cells and led to their arrest at the G0/G1 phase. At the molecular level, knockdown of Fer resulted in the activation of the retinoblastoma protein (pRB), and this was reflected by profound hypo-phosphorylation of pRB on both cyclindependent kinase CDK4 and CDK2 phosphorylation sites. Dephosphorylation of pRB was not seen upon the direct targeting of either CDK4 or CDK2 expression, and was only partially achieved by the simultaneous depletion of these two kinases. Amino-acid sequence analysis revealed two protein phosphatase 1 (PP1) binding motifs in the kinase domain of Fer and the association of Fer with the pRB phosphatase PP1a was verified using co-immunoprecipitation analysis. Downregulation of Fer potentiated the activation of PP1a and overexpression of Fer decreased the enzymatic activity of that phosphatase. Our findings portray Fer as a regulator of cell-cycle progression in malignant cells and as a potential target for cancer intervention.

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Section: Fer Maintains G1-s Transition In Malignant Cells O Pasder Et Alsupporting

confidence: 60%

Section: Downregulation Of Fer Arrests Malignant Cells At the G0/g1 Pmentioning

confidence: 99%

Downregulation of Fer induces PP1 activation and cell-cycle arrest in malignant cells

et al. 2006

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“…In addition to the association with their corresponding cyclin partners, full activation of CDK-cyclin complexes generally requires phosphorylation of a conserved threonine residue (corresponding to T161 in human CDC2) within their so-called T-loop region by a CDKactivating kinase (CAK) (Morgan, 1997;Kaldis, 1999). Biochemical puri®cation identi®ed the major CAK activity in mammalian and Xenopus cell lysates as a trimeric protein complex composed of a catalytic subunit CDK7 (Fesquet et al, 1993;Poon et al, 1993;Solomon et al, 1993), its regulatory subunit cyclin H (Fisher and Morgan, 1994;Ma È kela È et al, 1994), and a third subunit MAT1 (meÂnage-a Á-trois-1).…”

Section: Cdks Associated With the Rnap II Transcription Machinerymentioning

confidence: 99%

Regulation of RNA polymerase II activity by CTD phosphorylation and cell cycle control

Oelgeschläger

2002

Journal Cellular Physiology

128

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The carboxyl-terminal domain (CTD) of the largest subunit of mammalian RNA polymerase II (RNAP II) consists of 52 repeats of a consensus heptapeptide and is subject to phosphorylation and dephosphorylation events during each round of transcription. RNAP II activity is regulated during the cell cycle and cell cycledependend changes in RNAP II activity correlate well with CTD phosphorylation. In addition, global changes in the CTD phosphorylation status are observed in response to mitogenic or cytostatic signals such as growth factors, mitogens and DNA-damaging agents. Several CTD kinases are members of the cyclindependent kinase (CDK) superfamily and associate with transcription initiation complexes. Other CTD kinases implicated in cell cycle regulation include the mitogen-activated protein kinases ERK-1/2 and the c-Abl tyrosine kinase. These observations suggest that reversible RNAP II CTD phosphorylation may play a key role in linking cell cycle regulatory events to coordinated changes in transcription.

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“…The dual-specificity phosphatase CDC25 removes phosphates from inhibitory phosphorylation sites (Thr-14 and Tyr-15 in human CDK2) that have been phosphorylated by the WEE1/MYT1 protein kinases . Phosphorylation of an activating threonine (Thr-160 in CDK2 and Thr-177 in CDK6) by the cdk-activating kinase (CAK; reviewed by Kaldis, 1999) is accompanied by structural changes in the T-loop (also called the activation segment), allowing the phosphate group to interact with several other residues and thereby acting as an organizing center in the catalytic cleft (Russo et al, 1996b). Mutation of the acti- vating threonine to an unphosphorylatable amino acid prevents activation of vertebrate cdks (Desai et al, 1992;Solomon et al, 1992;Connell-Crowley et al, 1993;Kato et al, 1994;Matsuoka et al, 1994) and equivalent mutants are unable to support growth in yeast (Gould et al, 1991;Cismowski et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

CAK-independent Activation of CDK6 by a Viral Cyclin

Kaldis

Ojala

Tong

et al. 2001

MBoC

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In normal cells, activation of cyclin-dependent kinases (cdks) requires binding to a cyclin and phosphorylation by the cdk-activating kinase (CAK). The Kaposi's sarcoma-associated herpesvirus encodes a protein with similarity to D-type cyclins. This KSHV-cyclin activates CDK6, alters its substrate specificity, and renders CDK6 insensitive to inhibition by the cdk inhibitor p16 INK4a . Here we investigate the regulation of the CDK6/KSHV-cyclin kinase with the use of purified proteins and a cell-based assay. We find that KSHV-cyclin can activate CDK6 independent of phosphorylation by CAK in vitro. In addition, CAK phosphorylation decreased the p16 INK4a sensitivity of CDK6/KSHV-cyclin complexes. In cells, expression of CDK6 or to a lesser degree of a nonphosphorylatable CDK6 T177A together with KSHV-cyclin induced apoptosis, indicating that CDK6 activation by KSHV-cyclin can proceed in the absence of phosphorylation by CAK in vivo. Coexpression of p16 partially protected cells from cell death. p16 and KSHV-cyclin can form a ternary complex with CDK6 that can be detected by binding assays as well as by conformational changes in CDK6. The Kaposi's sarcoma-associated herpesvirus has adopted a clever strategy to render cell cycle progression independent of mitogenic signals, cdk inhibition, or phosphorylation by CAK. INTRODUCTIONThe sequential activation of cyclin-dependent kinases (cdks) promotes cell cycle transitions. CDK4 and CDK6 bind to D-type cyclins and are active in G1, CDK2/cyclin E complexes function in late G1, CDK2/cyclin A complexes function in S phase, and CDC2/cyclin B and A complexes function in G2/M. The activities of cdks are regulated by protein-protein interactions (with cyclins, inhibitors, and assembly factors), protein degradation, transcriptional control, subcellular localization, and multiple phosphorylations (Pines, 1995;Sherr and Roberts, 1995;King et al., 1996;Solomon and Kaldis, 1998). Viral infection frequently targets downstream targets of cdks, resulting in inappropriate cell cycle progression.Cyclin binding activates cdks by inducing conformational changes in the structure of cdks (Jeffrey et al., 1995;Pavletich, 1999). Cyclins are unstable proteins that are synthesized and degraded periodically during the cell cycle. Transcriptional control (Koch and Nasmyth, 1994) and ubiquitin-mediated degradation (King et al., 1996) ensure the proper and irreversible timing of cell cycle regulatory events. Cyclins have also been shown to affect the substrate specificity of cdks (Peeper et al., 1993;Kelly et al., 1998;Schulman et al., 1998;Cross et al., 1999).Maximal activation of cdks requires phosphorylation of certain residues as well as dephosphorylation of others. The dual-specificity phosphatase CDC25 removes phosphates from inhibitory phosphorylation sites (Thr-14 and Tyr-15 in human CDK2) that have been phosphorylated by the WEE1/MYT1 protein kinases . Phosphorylation of an activating threonine (Thr-160 in CDK2 and Thr-177 in CDK6) by the cdk-activating kinase (CAK; reviewed by Kaldis, 199...

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The cdk-activating kinase (CAK): from yeast to mammals

Cited by 206 publications

References 143 publications

Downregulation of Fer induces PP1 activation and cell-cycle arrest in malignant cells

Downregulation of Fer induces PP1 activation and cell-cycle arrest in malignant cells

Regulation of RNA polymerase II activity by CTD phosphorylation and cell cycle control

CAK-independent Activation of CDK6 by a Viral Cyclin

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