Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.22 (cdc2)
 8,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CDC37, an essential gene in Saccharomyces cerevisiae, interacts genetically with multiple protein kinases and is required for production of Cdc28p/cyclin complexes through an unknown mechanism. We have identified mammalian p50Cdc37 as a protein kinase-targeting subunit of the molecular chaperone Hsp90. Previously, p50 was observed in complexes with pp60v-src and Raf-1, but its identity and function have remained elusive. In mouse fibroblasts, a primary target of Cdc37 is Cdk4. This kinase is activated by D-type cyclins and functions in passage through G1. In insect cells, Cdc37 is sufficient to target Hsp90 to Cdk4 and both in vitro and in vivo, Cdc37/Hsp90 associates preferentially with the fraction of Cdk4 not bound to D-type cyclins. Cdc37 is coexpressed with cyclin Dl in cells undergoing programmed proliferation in vivo, consistent with a positive role in cell cycle progression. Pharmacological inactivation of Cdc37/Hsp90 function decreases the half-life of newly synthesized Cdk4, indicating a role for Cdc37/Hsp90 in Cdk4 stabilization. This study suggests a general role for p50Cdc37 in signaling pathways dependent on intrinsically unstable protein kinases and reveals a previously unrecognized chaperone-dependent step in the production of Cdk4/cyclin D complexes.
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PMID:Mammalian p50Cdc37 is a protein kinase-targeting subunit of Hsp90 that binds and stabilizes Cdk4. 866 33

We have performed biochemical analyses of cdk6 complexes in T cells. By gel filtration chromatography we observed at least three cdk6 containing complexes in the cell, the most abundant eluting at 450 kDa and 50-70 kDa and a minor complex eluting at 170 kDa. Cyclin D was present in the minor 170 kDa complex which co-eluted with the peak of cdk associated in vitro Rb kinase activity. Analysis of proteins that co-immunoprecipitated with cdk6 showed that the 450 kDa complex contained both Hsp90 and CDC37. The 50-70 kDa complex was made up of two moieties, a 66 kDa complex containing cdk6 bound to p19INK4d and monomeric cdk6. The subcellular localisation of the cdk6 complexes was analysed by preparing cytoplasmic and nuclear extracts. The 450 kDa complex was shown to be predominantly cytoplasmic, whereas the 170 kDa cyclin D/cdk6 and the 50-70 kDa complexes were present in both nuclear and cytoplasmic compartments. When these same extracts were assayed for cdk6 associated kinase activity, only the nuclear cdk6 complexes were active. These data suggest that even though there are cdk6/cyclin D complexes detectable in both the cytoplasm and nucleus, only the cdk6 that is in the nucleus is active.
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PMID:Active cdk6 complexes are predominantly nuclear and represent only a minority of the cdk6 in T cells. 948 6

Although it is known that calmodulin is involved in G1 progression, the calmodulin-dependent G1 events are not well understood. We have analyzed here the role of calmodulin in the activity, the expression, and the intracellular location of proteins involved in G1 progression. The addition of anti-calmodulin drugs to normal rat kidney cells in early G1 inhibited cyclin-dependent kinase 4 (Cdk4) and Cdk2 activities, as well as retinoblastoma protein phosphorylation. Protein levels of cdk4, cyclin D1, cyclin D2, cyclin E, p21, and p27 were not affected after CaM inhibition, whereas decreases in the amount of cyclin A and Cdc2 were observed. The decrease of Cdk4 activity was due neither to changes in its association to cyclin D1 nor to changes in the amount of p21 or p27 bound to cyclin D1-Cdk4 complexes. Calmodulin inhibition also produced a translocation of nuclear cyclin D1 and Cdk4 to the cytoplasm. This translocation could be responsible for the decreased Cdk4 activity upon calmodulin inhibition. Immunoprecipitation, calmodulin affinity chromatography, and direct binding experiments indicated that calmodulin associates with Cdk4 and cyclin D1 through a calmodulin-binding protein. The facts that Hsp90 interacts with Cdk4 and that its inhibition induced Cdk4 and cyclin D1 translocation to the cytoplasm point to Hsp90 as a good candidate for being the calmodulin-binding protein involved in the nuclear accumulation of Cdk4 and cyclin D1.
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PMID:Calmodulin is essential for cyclin-dependent kinase 4 (Cdk4) activity and nuclear accumulation of cyclin D1-Cdk4 during G1. 983

In Schizosaccharomyces pombe, wee1 encodes a tyrosine kinase that inhibits entry into mitosis by phophorylating Cdc2, the universal cyclin-dependent kinase (Cdk) that regulates the G2/M transition in all eukaryotic cells. A search for suppressors of the G2 arrest caused by overexpression of weel led to the isolation of a new allele of swo1 (named swo1-w1), the gene coding for chaperone Hsp90, which is required to stabilise Weel. The swo1-w1 allele carries a glycine to aspartic acid substitution at amino acid 155 that results in a partial loss of Hsp90 function. Cells bearing the swo1-w1 mutation in combination with the point mutation cdc2-33 or cdc2-M26 showed severe mitotic defects. Genetic interactions were not observed in combination with point mutations in other cdc genes, suggesting that Cdc2 specifically interacts with Hsp90. This synthetic lethal swo1-w1 cdc2-33 (or cdc2-M26) strain had normal levels of Cdc2 protein and histone H1 phosphorylation activity, indicating that Hsp90 is required to enable Cdc2 to interact with its mitotic substrates or regulators, rather than for its proper folding or stabilisation. In a wild-type background, swo1-w1 mutant cells were sensitive to temperature as well as to other stress agents, such as KCI, ethanol and formamide. Under these stressful growth conditions, the swo1-w1 cells displayed anaphase B arrest and aberrant septation patterns, indicating that a subset of proteins involved in mitosis and cytokinesis is highly dependent on chaperone Hsp90 for function.
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PMID:Genetic interactions between Hsp90 and the Cdc2 mitotic machinery in the fission yeast Schizosaccharomyces pombe. 1010 58

The Wee1 kinase inhibits entry into mitosis by phosphorylation of the Cdc2 kinase. Searching for multicopy suppressors that abolish this inhibition in the fission yeast, we have identified a novel gene, here named wos2, encoding a protein with significant homology to human p23, an Hsp90-associated cochaperone. The deletion mutant has a modest phenotype, being heat-shock sensitive. Using antibodies raised against bacterially produced protein, we determined that Wos2 is very abundant, ubiquitously distributed in the yeast cell, and its expression dropped drastically as cells entered into early stationary phase, indicating that its function is associated with cell proliferation. In proliferating cells, the amount of Wos2 protein was not subjected to cell cycle regulation. However, in vitro assays demonstrated that this Hsp90 cochaperone is potentially regulated by phosphorylation. In addition to suppressing Wee1 activity, overproduction of Wos2 displayed synthetic lethality with Cdc2 mutant proteins, indicating that this Hsp90 cochaperone functionally interacts with Cdc2. The level of Cdc2 protein and its associated H1 kinase activity under synthetic lethal conditions suggested a regulatory role for this Wos2-Cdc2 interaction. Hsp90 complexes are required for CDK regulation; the synergy found between the excess of Wos2 and a deficiency in Hsp90 activity suggests that Wos2 could specifically interfere with the Hsp90-dependent regulation of Cdc2. In vitro analysis indicated that the above genetic interactions could take place by physical association of Wos2 with the single CDK complex of the fission yeast. Expression of the budding yeast p23 protein (encoded by the SBA1 gene) in the fission yeast indicated that Wos2 and Sba1 are functionally exchangeable and therefore that properties described here for Wos2 could be of wide significance in understanding the biological function of cochaperone p23 in eukaryotic cells.
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PMID:The identification of Wos2, a p23 homologue that interacts with Wee1 and Cdc2 in the mitotic control of fission yeasts. 1058 Dec 66

Hyperactivation of Cdc2 in fission yeast causes cells to undergo a lethal premature mitosis, a phenomenon called mitotic catastrophe. This phenotype is observed in cdc2-3w wee1-50 cells at high temperature and is suppressed by a single recessive mutant, mcs3-12. Mcs3 acts independently of the Wee1 kinase and Cdc25 phosphatase, two major regulators of Cdc2. We have isolated multicopy suppressors of the cell cycle arrest phenotype of mcs3-12 wee1-50 cdc25-22 cells, but did not identify the mcs3 gene itself. Instead several known mitotic regulators were isolated, including the Cdc25 phosphatase, Wis2 cyclophilin, Cek1 kinase, and an Hsp90 homologue, Swo1. We also isolated clones encoding non-functional, truncated forms of the Wee1 kinase and Dis2 type 1 phosphatase. In addition we identified a multicopy suppressor that encodes a structural homologue of the budding yeast SPO12 gene. We find that overexpression of fission yeast spo12 not only suppresses the phenotype of the mcs3-12 wee1-50 cdc25-22 strain, but also that of a win1-1 wee1-50 cdc25-22 strain at high temperature, indicating that the function of spo12 is not directly related to mcs3. We show that spo12 mRNA is periodically expressed during the fission yeast cell cycle, peaking at the G2/M transition coincidently with cdc15. Deletion of spo12, however, has no overt effect on either the mitotic or meiotic cell cycles, except when the function of the major B type cyclin, Cdc13, is compromised.
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PMID:spo12 is a multicopy suppressor of mcs3 that is periodically expressed in fission yeast mitosis. 1108 71

The co-chaperone murine stress-inducible protein 1 (mSTI1), a Hsp70/Hsp90 organizing protein (Hop) homolog, functions as a physical link between Hsp70 and Hsp90 by mediating the formation of the mSTI1/ Hsp70/Hsp90 chaperone heterocomplex. We show here that mSTI1 is an in vitro substrate of cell cycle kinases. Casein kinase II (CKII) phosphorylates mSTI1 at S189, and cdc2 kinase (p34cdc2) at T198, substantiating a predicted CKII-p34cdc2-NLS (CcN) motif. The possible implications of this phosphorylation as a cell cycle checkpoint are discussed.
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PMID:The in vitro phosphorylation of the co-chaperone mSTI1 by cell cycle kinases substantiates a predicted casein kinase II-p34cdc2-NLS (CcN) motif. 1115 72

CCAAT/enhancer binding protein alpha (C/EBPalpha) causes growth arrest via direct interaction with the cyclin-dependent kinases cdk2 and cdk4. In this paper, we present evidence showing that C/EBPalpha enhances a proteasome-dependent degradation of cdk4 during growth arrest in liver of newborn mice and in cultured cells. Overexpression of C/EBPalpha in several biological systems leads to a reduction of cdk4 protein levels, but not mRNA levels. Experiments with several tissue culture models reveal that C/EBPalpha enhances the formation of cdk4-ubiquitin conjugates and induces degradation of cdk4 through a proteasome-dependent pathway. As a result, the half-life of cdk4 is shorter and protein levels of cdk4 are reduced in cells expressing C/EBPalpha. Gel filtration analysis of cdk4 complexes shows that a chaperone complex cdk4-cdc37-Hsp90, which protects cdk4 from degradation, is abundant in proliferating livers that lack C/EBPalpha, but this complex is weak or undetectable in livers expressing C/EBPalpha. Our studies show that C/EBPalpha disrupts the cdk4-cdc37-Hsp90 complex via direct interaction with cdk4 and reduces protein levels of cdk4 by increasing proteasome-dependent degradation of cdk4.
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PMID:C/EBPalpha triggers proteasome-dependent degradation of cdk4 during growth arrest. 1186 21

The Cdc37 protein in Saccharomyces cerevisiae is thought to be a kinase-targeting subunit of the chaperone Hsp90. In a genetic screen, four protein kinases were identified as interacting with Cdc37 - Cdc5, Cdc7, Cdc15 and Cak1. This result underlines the importance of Cdc37 for the folding of protein kinases. In addition, we showed that Ydj1, a yeast DnaJ homolog belonging to the Hsp40 family of chaperones, genetically interacts with Cdc37. No physical interaction has so far been detected between Cdc37 and Cdc28, although genetic interactions (synthetic lethality and mutation suppression), and biochemical studies have suggested that these two proteins functionally interact. We found that, when separately expressed, the N-terminal lobe of Cdc28 interacted strongly with the C-terminal moiety of Cdc37 in a two-hybrid system. This was not the case for the full-length Cdc28 protein. We present models to explain these results.
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PMID:Physical interaction of Cdc28 with Cdc37 in Saccharomyces cerevisiae. 1211 52

Hsp90 is a chaperone required for the conformational maturation of certain signaling proteins including Raf, cdk4, and steroid receptors. Natural products and synthetic small molecules that bind to the ATP-binding pocket in the amino-terminal domain of Hsp90 inhibit its function and cause the degradation of these client proteins. Inhibition of Hsp90 function in cells causes down-regulation of an Akt kinase-dependent pathway required for D-cyclin expression and retinoblastoma protein-dependent G(1) arrest. Intracellular Akt is associated with Hsp90 and Cdc37 in a complex in which Akt kinase is active and regulated by phosphatidylinositol 3-kinase. Functional Hsp90 is required for the stability of Akt in the complex. Occupancy of the ATP-binding pocket by inhibitors is associated with the ubiquitination of Akt and its targeting to the proteasome, where it is degraded. This results in a shortening of the half-life of Akt from 36 to 12 h and an 80% reduction in its expression. Akt and its activating kinase, PDK1, are the only members of the protein kinase A/protein kinase B/protein kinase C-like kinase family that are affected by Hsp90 inhibitors. Thus, transduction of growth factor signaling via the Akt and Raf pathways requires functional Hsp90 and can be coordinately blocked by its inhibition.
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PMID:Akt forms an intracellular complex with heat shock protein 90 (Hsp90) and Cdc37 and is destabilized by inhibitors of Hsp90 function. 1217 97


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