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)

To elucidate the signal transduction mechanisms used by ligands that induce differentiation and the cessation of cell division, we utilized p13suc1-agarose, a reagent that binds p34cdc2/cdk2. By using this reagent, we identified a 78- to 90-kDa species in PC12 pheochromocytoma cells that is rapidly phosphorylated on tyrosine following treatment with the differentiation factors nerve growth factor (NGF) and fibroblast growth factor but not by the mitogens epidermal growth factor or insulin. This species, called SNT (suc-associated neurotrophic factor-induced tyrosine-phosphorylated target), was also phosphorylated on tyrosine in primary rat cortical neurons treated with the neurotrophic factors neurotrophin-3, brain-derived neurotrophic factor, and fibroblast growth factor but not in those treated with epidermal growth factor. In neuronal and fibroblast cells, where NGF can also act as a mitogen, SNT was tyrosine phosphorylated to a much greater extent during NGF-induced differentiation than during NGF-induced proliferation. SNT was phosphorylated in vitro on serine, threonine, and tyrosine in p13suc1-agarose precipitates from NGF-treated PC12 cells, indicating that this protein may be a substrate of kinase activities associated with p13suc1-p34cdc2/cdk2 complexes. In addition, SNT was associated predominantly with nuclear fractions following subcellular fractionation of NGF-treated PC12 cells. Finally, in PC12 cells, NGF-stimulated tyrosine phosphorylation of SNT was dependent on the levels of Trk tyrosine kinase activity and was constitutively induced by expression of pp60v-src. However, Ras was not required for constitutive SNT tyrosine phosphorylation, suggesting that this protein functions distally to Trk and pp60v-src but in a pathway parallel to that of Ras. SNT is the first identified specific target of differentiation factor-induced tyrosine kinase activity in neuronal cells.
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PMID:SNT, a differentiation-specific target of neurotrophic factor-induced tyrosine kinase activity in neurons and PC12 cells. 768 Nov 42

The wee1 protein kinase suppresses the entry into mitosis by mediating the inhibitory tyrosine phosphorylation of p34cdc2. Genetic studies have suggested that the nim1 protein kinase (also known as cdr1) acts as a positive regulator of mitosis by down-regulating the wee1 pathway in yeast cells. We have overexpressed the nim1 protein in both bacteria and insect cells. The recombinant nim1 protein autophosphorylates on both tyrosine and serine residues and can phosphorylate the isolated wee1 protein directly in a cell-free system. The nim1-catalyzed phosphorylation of the wee1 protein occurs in its C-terminal region and leads to a substantial drop in its activity as a cdc2-specific tyrosine kinase. This nim1-dependent inhibition of the wee1 protein kinase can be reversed readily in vitro by treatment with a protein phosphatase. These experiments provide direct biochemical evidence that the wee1 protein is subject to negative regulation by phosphorylation and indicate that the nim1 protein acts as an inhibitory, wee1-specific kinase.
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PMID:Negative regulation of the wee1 protein kinase by direct action of the nim1/cdr1 mitotic inducer. 768 63

The M-phase inducer, Cdc25C, is a dual-specificity phosphatase that directly phosphorylates and activates the cyclin B/Cdc2 kinase complex, leading to initiation of mitosis. Cdc25 itself is activated at the G2/M transition by phosphorylation on serine and threonine residues. Previously, it was demonstrated that Cdc2 kinase is capable of phosphorylating and activating Cdc25, suggesting the existence of a positive feedback loop. In the present study, kinases other than Cdc2 that can phosphorylate and activate Cdc25 were investigated. Cdc25 was found to be phosphorylated and activated by cyclin A/Cdk2 and cyclin E/Cdk2 in vitro. However, in interphase Xenopus egg extracts with no detectable Cdc2 and Cdk2, treatment with the phosphatase inhibitor microcystin activated a distinct kinase that could phosphorylate and activate Cdc25. Microcystin also induced other mitotic phenomena such as chromosome condensation and nuclear envelope breakdown in extracts containing less than 5% of the mitotic level of Cdc2 kinase activity. These findings implicate a kinase other than Cdc2 and Cdk2 that may initially activate Cdc25 in vivo and suggest that this kinase may also phosphorylate M-phase substrates even in the absence of Cdc2 kinase.
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PMID:Phosphorylation and activation of the Xenopus Cdc25 phosphatase in the absence of Cdc2 and Cdk2 kinase activity. 778 47

The E2F transcription factor family participates in growth control presumably through transcriptional activation of genes that promote entry into S phase. E2F activity is believed to be controlled across the cell cycle by association with various cellular proteins, including the product of the retinoblastoma gene (pRB). We find that E2F-1 proteins are heterogeneously phosphorylated in insect cells, as a result of which they migrate as a doublet on SDS-polyacrylamide gels. This electrophoretic shift is shown to be dependent upon specific phosphorylation of E2F-1 on serine-375 (S375), near the pRB-binding site. Phosphorylation on S375 also occurs in human cells. E2F-1 was most efficiently phosphorylated on this residue by cyclin A/cdk2 kinase, and to a lesser extent by cyclin A/cdk2, irrespective of the presence of the pRB-related p107 protein. Phosphorylation of E2F-1 on S375 greatly enhanced its affinity of pRB in vitro. These results suggest a novel way of regulating E2F-1 activity, namely by cell-cycle-dependent phosphorylation of this transcription factor.
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PMID:Phosphorylation of a specific cdk site in E2F-1 affects its electrophoretic mobility and promotes pRB-binding in vitro. 782 78

We have isolated two closely related cDNA clones (cATPK19 and cATPK6) with homology to protein-serine/threonine kinases from Arabidopsis thaliana using the polymerase chain reaction (PCR). The deduced amino acid sequences of the ATPK19 and ATPK6 contain all 11 conserved regions of the catalytic domain of protein kinases, and have homology to p70 ribosomal S6 kinases (52%). ATPK19 and ATPK6 have putative PEST regions in their N- and C-terminal regions, and these regions also contain putative phosphorylation sites that are recognized by casein kinases or proline-directed protein kinases such as cdc2, MAP kinase, and p54 MAP-2 kinase (SAPK). The transcription levels of the ATPK19 and ATPK6 genes rapidly and markedly increased when plants were subjected to cold or high-salt stresses. These observations suggest that ATPK19 and ATPK6 may function in the adaptation of plant cells to cold or high-salt conditions, providing an understanding of the role of protein phosphorylation in plant responses to environmental stresses.
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PMID:Two genes that encode ribosomal-protein S6 kinase homologs are induced by cold or salinity stress in Arabidopsis thaliana. 782 36

A key component of Cdc2/Cdk2-activating kinase (CAK) is p40MO15, a protein kinase subunit that phosphorylates the T161/T160 residues of p34cdc2/p33cdk2. The level and activity of p40MO15 were essentially constant during cleavage of fertilised Xenopus eggs and in growing mouse 3T3 cells, but serum starvation of these cells reduced both the level and activity of p40MO15. Although the level and activity of endogenous p40MO15 did not vary in the cell cycle, we found that bacterially expressed p40MO15 was activated more rapidly by M-phase cell extracts than by interphase cell extracts. Bacterially expressed p40MO15 was phosphorylated mainly on serine 170 (a p34cdc2 phosphorylation site) by mitotic cell extracts, but mutation of S170 to alanine did not affect the activation of p40MO15, whereas mutation of T176 (the equivalent site to T161/T160 in p34cdc2/p33cdk2) abolished the activation of P40MO15. These studies suggest that the level and activity of p40MO15 is probably not a major determinant of p34cdc2/p33cdk2 activity in the cell cycle, and that the activation of p40MO15 may require phosphorylation on T176.
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PMID:Cell cycle regulation of the p34cdc2/p33cdk2-activating kinase p40MO15. 787 47

We have constructed point mutations in human lamin A cDNA at conserved serine and threonine residues, some of which were shown to be phosphorylated in vitro by cdc2-kinase and protein kinase C and in vivo. Using a functional in vivo assay system, we identified three categories of mutant phenotypes. (i) Dominant negative phenotypes in mitosis result from mutation of Thr-19 and Ser-22 within the amino-terminal cdc2-kinase motif of lamin A. An increase of aberrant mitotic phenotypes in the double mutants Thr-19/Ser-392 and Ser-22/Ser-392 suggests that concomitant phosphorylation of the three residues regulates mitotic lamin A disassembly. (ii) Mutation of both Ser-403/Ser-404 within a PKC motif flanking the nuclear localization signal inhibits transport of mutant lamin A to the nucleus in 64% of the cells. It is proposed that phosphorylation of the motif in vivo positively regulates nuclear localization together with the nuclear localization sequence. (iii) The assembly of lamin A into the perinuclear lamina is disturbed by mutation of the carboxy-terminal Ser-525, previously shown to be interphase-specifically phosphorylated (Eggert et al., Eur. J. Biochem. 213, 659-671 (1993)). The phenotype shows discontinuous and patch-like aggregates of the mutant protein in the nucleus. We suggest that phosphorylation of the site either regulates lamina assembly or lamina-chromatin interaction in interphase.
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PMID:Functional analysis of phosphorylation sites in human lamin A controlling lamin disassembly, nuclear transport and assembly. 792 82

A 100kD microtubule-bundling protein dynamin was phosphorylated in vitro by cdc2 kinase to approximately 1 mol of phosphate/mol of dynamin at a serine residue. These phosphorylations of dynamin greatly reduced its binding ability to microtubules.
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PMID:Phosphorylation of dynamin by cdc2 kinase. 804 26

Rap1GAP (for Rap1 GTPase Activating Protein) is an 89 kD protein that highly stimulates the intrinsic GTPase activity of the small GTP binding protein Rap1. It has been shown that Rap1GAP is phosphorylated in vitro by purified p34cdc2 kinase, which regulates the G2/M transition of the cell cycle. In this work, we have studied the phosphorylation of Rap1GAP during the cell cycle and showed that Rap1GAP is phosphorylated in vivo in interphasic and mitotic Hela cells; the electrophoretic mobility of Rap1GAP from mitotic cells is reduced compared with that from interphasic cells, suggesting that the mitotic form of the protein is hyperphosphorylated. As the cdc2 kinase is specifically active during mitosis, we sought to investigate whether it actually phosphorylates Rap1GAP during this phase of the cell cycle. We show that p34cdc2 co-immunoprecipitated from mitotic Hela cell lysates with an anti human cyclin B1 antibody, but not from interphasic cell lysates, is able to phosphorylate efficiently wild-type Rap1GAP, but not a mutant in which the putative consensus site for phosphorylation by the cdc2 kinase (serine 484) has been altered. Moreover, depletion of p34cdc2 from mitotic extracts abolishes the phosphorylation of Rap1GAP by such lysates. These results therefore strongly suggest that Rap1GAP is indeed a substrate of the cdc2 kinase during mitosis. This phosphorylation does not affect the stimulation of the GTPase activity of Rap1 by Rap1GAP but may play a role in regulating the interaction of Rap1GAP with other proteins involved in the cellular functions regulated by Rap1 and Rap1GAP.
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PMID:Phosphorylation of Rap1GAP during the cell cycle. 804 70

The insulin-like growth factors (IGFs) stimulate cell division by modulating events occurring during the prereplicative (G1) phase of the cell cycle, but identification of the critical events has proved difficult. Recent observations suggest that progression through the cell cycle is dependent on the activation of a group of serine-threonine-specific protein kinases whose activities are regulated by accessory proteins, termed cyclins. The identification of cyclin species expressed during G1 has led to the hypothesis that modulation of cyclin expression may be the critical event regulated by growth factors. The present studies were undertaken to determine whether the IGFs regulate the expression of specific G1 cyclins in MG63, a human cell line that is unusually responsive to IGF, and to characterize this effect. We found that in these cells IGF-I stimulates the cyclin-dependent kinases, and that stimulation is associated with an increase in cyclin-D1 mRNA and protein expression. The increase in cyclin-D1 occurs early in G1 and corresponds to the portion of the cell cycle in which IGF acts on these cells. The increase in cyclin-D1 mRNA is due at least in part to an increase in the rate of transcription initiation of the gene. The mRNA levels of cyclin-B1 (a G2 cyclin) and two cyclin-dependent kinases, cdc2 and cdk2, also increased in response to IGF, but at later times. These results are consistent with the hypothesis that IGF modulation of D-type cyclin expression plays a role in the regulation of cell replication.
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PMID:Insulin-like growth factor-I induces cyclin-D1 expression in MG63 human osteosarcoma cells in vitro. 805 69


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