Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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 the multicomponent interleukin-2 receptor (IL-2R) complex leads to a rapid increase in tyrosine phosphorylation of a number of cellular proteins including the IL-2R beta and IL-2R gamma chains of the IL-2R and the RAF-1 serine threonine kinase. In addition, phosphatidylinositol 3-kinase (PI-3K) protein and activity can be immunoprecipitated with anti-phosphotyrosine and anti-IL-2R beta antibodies from IL-2-activated but not resting T lymphocytes. We have demonstrated that the SH2 (SRC homology 2) domains of the 85 kDa subunit of PI-3K are sufficient to mediate binding of the PI-3K complex to tyrosine phosphorylated, but not non-phosphorylated IL-2R beta, suggesting that tyrosine phosphorylation is an integral component of the activation of PI-3K by the IL-2R. Since none of the members of the IL-2R complex contains an intrinsic tyrosine kinase domain, IL-2-induced tyrosine phosphorylation must be the consequence of activation of intracellular tyrosine kinases. SRC family members including lck, lyn and fyn have been demonstrated to associate with IL-2R beta through binding of the kinase domain to the acidic domain of IL-2R beta. However, we have demonstrated that the serine rich (SD) region of the cytosolic domain of IL-2R beta is also required for association of a tyrosine kinase with the IL-2R complex and that IL-2 can induce proliferation and tyrosine phosphorylation in cell lines which lack the known SRC family kinases expressed by T lymphocytes. Thus members of other kinase families besides SRC may also be involved in mediating IL-2 signal transduction. Biochemical studies and studies of cells expressing mutant IL-2 receptors indicate that IL-2-induced tyrosine kinase activation initiates a complex signaling cascade. The cascade includes SRC family kinase members such as lck, fyn, and lyn, activation of Raf-1 and PI-3K, and ras, and increased expression of the fos, fra-1, and jun protooncogenes. In addition, ligation of the IL-2R leads to rapid increases in myc expression and more delayed increases in the expression of the cdc2 and cdk2 kinases and the cyclins through a tyrosine phosphorylation independent pathway. Whether other biochemical processes initiated by IL-2R ligation, including activation of the MAP2, p70S6 and p90RSK serine threonine kinases, activation of NF-kappa B, and increased expression of Raf-1, Pim-1, bcl-2, IL-2R alpha and IL-2R beta, are consequences of the IL-2-induced tyrosine kinase cascade remains to be determined.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Transmembrane signaling by the interleukin-2 receptor: progress and conundrums. 826 Jun 51

The wee1 tyrosine kinase and cdc25 tyrosine phosphatase of fission yeast play antagonistic roles in the induction of mitosis through cdc2 regulation. We show here that the human wee1-like tyrosine kinase is a nuclear protein that ensures the completion of DNA replication prior to mitosis in cells expressing otherwise catastrophic levels of cdc2 activators. Paradoxically, wee1-rescued cells display very high levels of mitotic cdc2 kinase activity. We account for this anomaly by our observation that the cdc2 activator, cdc25C, is a cytoplasmic protein that, like cyclin B1, enters the nucleus at the G2/M transition. Thus, cdc2 is likely to be activated in the cytoplasm and requires nuclear localization to initiate both cytoplasmic and nuclear mitotic transformations. The human wee1 kinase appears to coordinate the transition between DNA replication and mitosis by protecting the nucleus from this cytoplasmically activated cdc2 kinase.
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PMID:Human wee1 maintains mitotic timing by protecting the nucleus from cytoplasmically activated Cdc2 kinase. 834 13

We have characterized a murine protein kinase gene, rck, which was identified by crosshybridization with sequences from the v-ros tyrosine kinase gene under conditions of reduced stringency. cDNA analysis indicated that rck encodes a putative protein kinase related to the cdc2 subclass of the gene family and that the gene is identical to mak identified previously in the rat. An extensive expression analysis in the mouse performed by a combination of in situ hybridization and RNase protection revealed a novel and restricted pattern of expression: rck transcripts are found in two cell types involved in sensory transduction, photoreceptors and olfactory receptors as well as in epithelia of the respiratory tract and choroid plexus. Specific transcripts are also found in pre- and postmeiotic male germ cells. We suggest therefore that rck participates in signalling pathways important in a distinct set of cells, remarkably among them cells involved in sensory signal transduction.
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PMID:Characterization and expression analysis of the murine rck gene: a protein kinase with a potential function in sensory cells. 835 91

In Xenopus oocytes, mitogen-activated protein (MAP) kinase can be activated by progesterone treatment or by microinjection of cyclin A, both of which lead to activation of the cdc2 protein kinase. The tyrosine kinase pp60v-src has previously been shown to accelerate progesterone-induced oocyte maturation and to increase the phosphorylation of ribosomal protein S6 by pp90rsk, most likely by activating MAP kinase. In extracts of resting oocytes, MAP kinase kinase and MAP kinase were activated by addition of pp60v-src or cyclin A. Activation by pp60v-src was blocked by a dominant-negative p21ras protein (RAST), but activation by cyclin A/cdc2 was unaffected. Thus these two pathways that converge at MAP kinase kinase but are clearly divergent upstream of a p21ras-dependent step can be studied in a cell-free system.
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PMID:Reconstitution of p21ras-dependent and -independent mitogen-activated protein kinase activation in a cell-free system. 839 92

The v-abl oncogene of Abelson murine leukemia virus encodes a deregulated form of the cellular nonreceptor tyrosine kinase. v-Abl activates c-myc transcription, and c-Myc is an essential downstream component in the v-Abl transformation program. To explore the mechanism by which v-Abl activates c-myc transcription, a cotransfection assay was developed. We show that transactivation of a c-myc promoter by v-Abl requires the SH1 (tyrosine kinase) and SH2 domains of v-Abl; the C-terminal domains are not required for transactivation. The assay also identified the E2F site in the c-myc promoter as a v-Abl-responsive element. In addition, multimerized E2F sites were shown to be sufficient to confer v-Abl-dependent activation on a minimal promoter. This is the first identification of a v-Abl response element for transcriptional activation. v-Abl tyrosine kinase-dependent changes in proteins binding the c-myc E2F site were also demonstrated, including induction of a complex containing DP1, p107, cyclin A, and cdk2. Identification of v-Abl-dependent changes in E2F-binding proteins provides an important link between v-Abl, transcription, cell cycle regulation, and control of cellular growth.
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PMID:v-Abl activates c-myc transcription through the E2F site. 852 18

Activation of the cyclin dependent kinases (CDK4/CDK6 and CDK2) is required for G1 phase progression and entry into S-phase. The activation of these kinases is regulated by checkpoints that monitor environmental and intracellular conditions. Progression into S-phase is controlled, in part, by the availability of growth factors, and we have investigated the relationship between growth factor availability and the activation of the CDK kinases. Blocking activation of epidermal growth factor (EGF) receptor tyrosine kinase with anti-EGF receptor monoclonal antibody (mAb) 225 induces G1 phase cell cycle arrest in DiFi human colon adenocarcinoma cells. When DiFi cells are treated with mAb 225 for 24 h, we observe marked decreases in the activities of CDK2 kinase and cyclin E-associated CDK kinase which are not accompanied by reduced levels of cyclin E and CDK2 proteins. However, the amount of cyclin/CDK kinase inhibitor p27KIP1 increases in the mAb-treated cells and p27KIP1 is bound to CDK2 in increasing amounts. Immunodepletion of p27KIP1 removes an inhibitory activity from lysates of mAb-treated cells: the immunodepleted and heated lysates lose the capacity to inhibit cyclin E/CDK2 activity in an in vitro assay. The results suggest that G1 arrest in the cell cycle induced by EGF receptor blockade involves p27KIP1.
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PMID:Involvement of p27KIP1 in G1 arrest mediated by an anti-epidermal growth factor receptor monoclonal antibody. 862 55

To determine if nitration of tyrosine residues by peroxynitrite (PN), which can be generated endogenously, can disrupt the phosphorylation of tyrosine residues in proteins involved in cell signaling networks, we studied the effect of PN-promoted nitration of tyrosine residues in a pentadecameric peptide, cdc2(6-20)NH2, on the ability of the peptide to be phosphorylated. cdc2(6-20)NH2 corresponds to the tyrosine phosphorylation site of p34cdc2 kinase, which is phosphorylated by lck kinase (lymphocyte-specific tyrosine kinase, p56lck). PN nitrates both Tyr-15 and Tyr-19 of the peptide in phosphate buffer (pH 7.5) at 37 degrees C. Nitration of Tyr-15. which is the phosphorylated amino acid residue, inhibits completely the phosphorylation of the peptide. The nitration reaction is enhanced by either Fe(III)EDTA or Cu(II)-Zn(II)-superoxide dismutase (Cu,Zn-SOD). The kinetic data are consistent with the view that reactions of Fe(111)EDTA or Cu,Zn-SOD with the cis form of PN yield complexes in which PN decomposes more slowly to form N02+, the nitrating agent. Thus, the nitration efficiency of PN is enhanced. These results are discussed from the point of view that PN-promoted nitration will result in permanent impairment of cyclic cascades that control signal transduction processes and regulate cell cycles.
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PMID:Peroxynitrite disables the tyrosine phosphorylation regulatory mechanism: Lymphocyte-specific tyrosine kinase fails to phosphorylate nitrated cdc2(6-20)NH2 peptide. 862 43

The HER-2/neu gene product, p185(neu), is a membrane-bound receptor with tyrosine kinase activity. High levels of p185(neu) is correlated with intrinsic chemoresistance of non-small cell lung cancer (NSCLC) cell lines. We investigated the effects of tyrphostin AG825, a selective tyrosine kinase inhibitor preferentially inhibiting HER-2/neu kinase, on the chemosensitivities and on the drug-induced cell cycle changes of NSCLC cell lines that expressed different levels of p185(neu). Compared to the low-p185(neu) expressing cell lines, we found that the high-p185(neu) expressing cell lines were more resistant to doxorubicin, etoposide, and cis-diamminedichloroplatinum(II) but more sensitive to AG825. AG825 was able to significantly enhance the chemosensitivities of the high-p185(neu) expressing cell lines, whereas it had little effect on the chemosensitivities of the low-p185(neu) expressing cells, with a few exceptions in which minor antagonistic effects were observed. Although high concentrations of AG825 could reduce the drug-induced G(2) arrest that was accompanied by the activation of phosphorylated p34(cdc2), we failed to find any remarkably differential effects of AG825 on drug-induced G(2), arrest and the accompanying phosphorylation status of p34(cdc2) of the high- and and the low-p185(neu) expressing cell lines. In summary, tyrphostin AG825 can enhance chemosensitivity in high- but not in low-p185(neu) expressing NSCLC cell lines. This differential effect cannot be explained by the alterations of drug-induced cell cycle changes by AG825. Our results provide a rationale to develop p185(neu)- specific tyrphostin and to test them in combination with anticancer agents in vivo and in clinical trials.
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PMID:Enhancement of chemosensitivity by tyrphostin AG825 in high-p185(neu) expressing non-small cell lung cancer cells. 864 Jul 63

The Cdk6 protein level rapidly decreased after treatment with the tyrosine kinase inhibitor herbimycin A in human T-cell lines. This decrease is fairly specific, because the level of other Cdks such as Cdk2 and Cdk4 and cyclins such as cyclin D2, cyclin E and cyclin A, did not change significantly even after 24 h treatment with herbimycin A. Pulse-chase analysis revealed that the decrease in the Cdk6 protein level results from reduced stability of the protein. Our results suggest that herbimycin A-sensitive protein tyrosine kinase(s) are involved in the regulation of the Cdk6 protein level.
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PMID:Tyrosine kinase inhibitor herbimycin A reduces the stability of cyclin-dependent kinase Cdk6 protein in T-cells. 871 Mar 79

An enzyme-linked immunosorbent assay is described for the determination of protein tyrosine kinase activity originating from the presence of src-like tyrosine kinases in biological samples. In this assay a peptide derived from p34cdc2, cdc2(6-20)NH2, is coupled to the wells of a maleic anhydride-activated microtiter plate. This particular peptide has been described as an efficient and specific substrate for protein tyrosine kinases belonging to the src family kinases (Cheng et al., J.Biol.Chem. 267 (1992) 9248-9256). After incubation of the coated substrate with sample and ATP, the amount of phosphorylated tyrosyl residues is determined with phosphotyrosine specific antibodies and a secondary peroxidase-labeled antibody. The assay appears to be very sensitive and is linear with sample protein concentration and phosphorylation time. Intra-assay variation is < 5%, whereas day-to-day variation is < 10%. The results of the assay have been compared with an ELISA in which the broad-specificity tyrosine kinase substrate poly(GluNa,Tyr)4:1 was coated. The results of both assays in 27 cytosolic breast cancer samples correlated very well (r = 0.94), in accordance with the predominant expression of src kinase activity in breast cancers (Ottenhoff-Kalff et al., Cancer Res. 52 (1992), 4773-4778). The present assay provides an easy, reproducible, and quick alternative for the usual radioactive methods used for the determination of src-kinase activities including immunecomplex kinase assay and TCA-precipitation assays. It allows the determination of src-like activities in human tumors for routine diagnostic purposes.
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PMID:An enzyme-linked immunosorbent assay for the determination of src-family tyrosine kinase activity in breast cancer. 887 22


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