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)

Activation of maturation-promoting factor at the onset of mitosis requires the tyrosine dephosphorylation of one of its components, the cdc2 protein kinase. cdc25 is the specific tyrosine phosphatase that activates cdc2. We find that Xenopus oocytes contain a relative of cdc25, p72. In Xenopus embryos the abundance of p72 does not oscillate during the cell cycle. However, p72 directly associates with cdc2-cyclin B in a cell cycle-dependent manner, reaching a peak at M phase. The M phase kinase that associates with p72 is catalytically active. These results suggest that the mechanism by which cdc25 triggers cdc2 activation involves a periodic physical association between cdc25 and the cyclin B-cdc2 complex and also that mitotic control can be affected by mechanisms other than transcriptional regulation of the cdc25 gene.
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PMID:Oscillation of MPF is accompanied by periodic association between cdc25 and cdc2-cyclin B. 131 Feb 57

The cdc25 tyrosine phosphatase is known to activate cdc2 kinase in the G2/M transition by dephosphorylation of tyrosine 15. To determine how entry into M-phase in eukaryotic cells is controlled, we have investigated the regulation of the cdc25 protein in Xenopus eggs and oocytes. Two closely related Xenopus cdc25 genes have been cloned and sequenced and specific antibodies generated. The cdc25 phosphatase activity oscillates in both meiotic and mitotic cell cycles, being low in interphase and high in M-phase. Increased activity of cdc25 at M-phase is accompanied by increased phosphorylation that retards electrophoretic mobility in gels from 76 to 92 kDa. Treatment of cdc25 with either phosphatase 1 or phosphatase 2A removes phosphate from cdc25, reverses the mobility shift, and decreases its ability to activate cdc2 kinase. Furthermore, the addition of okadaic acid to egg extracts arrested in S-phase by aphidicolin causes phosphorylation and activation of the cdc25 protein before cyclin B/cdc2 kinase activation. These results demonstrate that the activity of the cdc25 phosphatase at the G2/M transition is directly regulated through changes in its phosphorylation state.
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PMID:Periodic changes in phosphorylation of the Xenopus cdc25 phosphatase regulate its activity. 139 80

The cdc25 protein is a highly specific tyrosine phosphatase that triggers mitosis by dephosphorylating the cdc2 protein kinase. Using Xenopus extracts, we have found that the cdc25 protein is active at a low level throughout interphase. Near the onset of mitosis, the cdc25 protein undergoes a marked elevation in phosphatase activity that coincides with an extensive phosphorylation of the protein in its N-terminal region. In vitro dephosphorylation of this hyperphosphorylated form of cdc25 reduces its phosphatase activity back to the interphase level. Moreover, treatment of interphase Xenopus extracts with okadaic acid, a phosphatase inhibitor that accelerates the entry into mitosis, elicits both the premature hyperphosphorylation of cdc25 and the stimulation of its cdc2-specific tyrosine phosphatase activity. These experiments demonstrate the existence of a cdc25 regulatory system consisting of both a stimulatory kinase that phosphorylates a putative regulatory domain of the cdc25 protein and an inhibitory serine/threonine phosphatase that counteracts this kinase activity.
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PMID:Regulation of the cdc25 protein during the cell cycle in Xenopus extracts. 162 17

pp54 microtubule-associated protein-2 (MAP-2) kinase, a recently discovered protein serine/threonine kinase (Kyriakis, J., and Avruch, J. (1990) J. Biol. Chem. 265, 17355-17363), is shown to contain immunoreactive phosphotyrosine residues. Treatment with recombinant rat brain protein tyrosine phosphatase-1 deactivates pp54 MAP-2 kinase, concomitant with the removal of phosphotyrosine residues. Protein (serine/threonine) phosphatase-1 also deactivates pp54 MAP-2 kinase in a specific fashion. pp54 MAP-2 kinase joins pp42 MAP-2 kinase and cdc2/maturation-promoting factor as one of only three serine/threonine protein kinases known to be regulated by phosphorylation at both tyrosine and, independently, at serine/threonine residues. In view of these shared regulatory properties, a role for pp54 MAP-2 kinase in the control of cell division is likely.
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PMID:pp54 microtubule-associated protein-2 kinase requires both tyrosine and serine/threonine phosphorylation for activity. 164 34

Genetic and biochemical studies have indicated that the cdc25 protein controls the entry into mitosis by triggering tyrosine dephosphorylation of the cdc2 protein kinase. We show that the isolated cdc25 protein can catalyze dephosphorylation of several model phosphatase substrates, including p-nitrophenyl phosphate and two distinct tyrosine-phosphorylated peptides. The cdc25-dependent cleavage reaction closely resembles dephosphorylation by known tyrosine phosphatases: the reaction requires a reducing agent, shows high sensitivity to sodium vanadate, and proceeds efficiently in the presence of metal chelators. Moreover, the phosphatase activity of the cdc25 protein is eliminated by treatment with N-ethylmaleimide or by alteration of a single conserved cysteine residue by site-directed mutagenesis. These observations indicate that the cdc25 protein can function as a tyrosine phosphatase in the absence of any other protein.
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PMID:The cdc25 protein contains an intrinsic phosphatase activity. 165 74

In contrast to the wealth of information on cellular function of protein kinases, many of which are known to be the products of proto-oncogenes, little is known about how protein dephosphorylation is involved in growth control of normal and malignant cells. In the present study, roles of protein phosphatases in cell division cycle control were examined by molecular genetic approaches using a lower eukaryote, the fission yeast Schizosaccharomyces pombe. Nine protein phosphatase genes have been so far identified and characterized in this organism. Each of two (dis2+, sds21+, and ppa1+, ppa2+) gene products is highly similar to mammalian type 1 and 2A ser/thr phosphatases, respectively. The ppx1+ product is an intermediate of type 1 and 2A, while the ppb1+ product is similar to Ca(2+)-dependent type 2B. At least two protein tyrosine phosphatase genes (pyp1+ and pyp2+) exist. The cdc25 protein is now established to be a tyrosine phosphatase that activates cdc2 kinase. Some of these phosphatase genes are interrelated but have distinct, essential functions in cell cycle control. Missense mutations, deletions or high dosage expression of these phosphatase genes affect entry into and exit from mitosis, mitotic chromosome disjunction, cell size and cell shape. They seem to interact with the main regulators of mitosis, cdc2, cdc13/cyclin, cdc25 and weel, or with mitotic structural components, such as condensed chromosomes or the spindle apparatus. We show that the product of an essential gene, sds22+, is an important, positive factor in controlling the expression and modulating the activity of dis2 phosphatase.
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PMID:Protein phosphatases in cell division: how vital are they? 166 85

Two previously unidentified human cdc25 genes have been isolated, cdc25A and cdc25B. Both genes rescue a cdc25ts mutant of fission yeast. Microinjection of anti-cdc25A antibodies into HeLa cells causes their arrest in mitosis. cdc25A and cdc25B display endogenous tyrosine phosphatase activity that is stimulated several-fold, in the absence of cdc2, by stoichiometric addition of either cyclin B1 or B2 but not A or D1. Association between cdc25A and cyclin B1/cdc2 was detected in the HeLa cells. These findings indicate that B-type cyclins are multifunctional proteins that not only act as M phase regulatory subunits of the cdc2 protein kinase, but also activate the cdc25 tyrosine phosphatase, of which cdc2 is the physiological substrate. A region of amino acid similarity between cyclins and tyrosine PTPases has been detected. This region is absent in cdc25 phosphatases. The motif may represent an activating domain that has to be provided to cdc25 by intermolecular interaction with cyclin B.
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PMID:Specific activation of cdc25 tyrosine phosphatases by B-type cyclins: evidence for multiple roles of mitotic cyclins. 183 78

To identify cyclins specifically associated with control of melanoma cell proliferation, we now compared expression of cyclin A, reported to be a marker for hematological malignancies, with that of cyclin D and its cdk4 kinase partner. All these proteins were expressed in proliferating B16 melanoma. However, L-tyrosine which induces melanoma terminal differentiation, selectively decreased cyclin D with no comparable effect on cdk4 or cyclin A. A 2-hour exposure of the cells to the tyrosine phosphatase inhibitor, sodium vanadate, further decreased cyclin D from differentiated cells, suggesting that tyrosine phosphorylation regulates cyclin D turnover. Addition of serum to starved cells also revealed that tyrosine did not block the early cyclin D increase associated with serum stimulation, but accelerated its subsequent loss. Our data suggest that cyclin D decrease with melanoma terminal differentiation could be an alternative mode of growth arrest even in cells harbouring a mutant or transcriptionally silent cdk4 inhibitor tumor suppressor p16ink4 gene. These results also imply that cyclin D may be useful as a target and as a prognostic marker in melanoma therapy.
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PMID:Suppression of cyclin D1 but not cdk4 or cyclin A with induction of melanoma terminal differentiation. 748 22

The cdc2-activator cdc25C was immunoprecipitated from HeLa cell extracts and assayed as tyrosine phosphatase (PTP) using tyrosine-phosphorylated myelin basic protein. The PTP activity was 12-fold higher in immunocomplexes from mitotic (nocodazole-arrested) than from asynchronous cells. This difference is due to enzyme activation, since the same amount of cdc25C was immunodetected in both conditions. However, mitotic cdc25C had M(r) 59,000, while a 56,000-59,000 doublet was detected in immunocomplexes from asynchronous cells. The PTP activity of mitotic cdc25C was decreased by treatment with Phosphatase-2A catalytic subunit (but not with Phosphatase-1), with re-appearance of the 56,000 polypeptide. cdc25C was also found associated with cdc2-p13-Sepharose complex and its PTP activity was 7-fold higher in samples from mitotic than from asynchronous cells. cdc25C and cdc2 co-migrated during gel filtration and the higher activity of mitotic cdc25C was retained through gel filtration.
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PMID:Activation of the cdc25C phosphatase in mitotic HeLa cells. 750 71

The three cycles of cell division immediately following the formation of the cellular blastoderm during Drosophila embryogenesis display an invariant pattern. Bursts of transcription of a gene called string are required and sufficient to trigger mitosis at this time during development. The activator of mitosis encoded by the string gene is a positive regulator of cdc2 kinase and a Drosophila homologue of the Saccharomyces pombe cdc25 tyrosine phosphatase. Evidence presented in a recent paper demonstrates that transcription of string, and hence the timing and pattern of mitosis in the postblastoderm embryo, is under complex developmental control. Several lines of evidence support this interpretation, including the analysis of string transcription in pattern formation mutants, cell cycle arrest mutants, and the preliminary characterization of an extensive cis-acting regulatory region.
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PMID:Drosophila development pulls the strings of the cell cycle. 757 98


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