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:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cholecystokinin-B and gastrin receptor is encoded by a single gene composed of five exons and spanning over 10 kilobases on human chromosome 11p 15.5-->15.4. Exon 4 has two possible alternative splicing donor sites that seem to be conserved in other species such as the canine, rat, Mastomys, and mouse. They could generate two receptor isoforms (short- and long-form), which differ in their putative third cytoplasmic domain of the serpentine G-protein-coupled receptors. In the present study, we examined whether an alternative splicing is operated in a tissue-specific manner and whether two receptor isoforms have functional differences. RNase-protection assay and S1 nuclease mapping demonstrated the preferential expression of the short-form in the human brain as well as the digestive organs, stomach and pancreas. The two putative isoforms of the cholecystokinin-B/gastrin receptor expressed in mouse fibroblasts showed the same characteristics in their ligand-bindings, the major signal transduction such as phosphoinositides production, cytoplasmic Ca2+ increase, tyrosine phosphorylation of focal adhesion kinase, activation of mitogen-activated protein kinase, and the induction of early-responsive genes such as c-fos, c-myc, and c-jun. Moreover, the ligand-dependent trophic effect was seen in both receptor isoforms. Taken together with the absence of tissue-specific expression of two receptor isoforms, these results suggest a species-specific dominant splice donor site in exon 4 of the human receptor gene.
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PMID:Functional characterization of two cholecystokinin-B/gastrin receptor isoforms: a preferential splice donor site in the human receptor gene. 784 14

The expression of several early-response genes and genes associated with malignant disease was assessed in the EMT-6/parent tumor and the EMT-6/CTX and EMT-6/CDDP in vivo resistant tumor lines growing as tumors or as monolayers in culture. In the absence of treatment the levels of mRNA for the genes c-jun, c-fos, c-myc, Ha-ras and p53 were increased in the EMT-6/CTX and EMT-6/CDDP as compared with the EMT-6/parent tumor, whereas the expression of erb-2 was similar in all three tumors. Although the cells from each of the three tumors show increased expression of early response genes after exposure to cisplatin (CDDP; 100 microM, 2 h) or 4-Hydroxyperoxycyclophosphamide (4-HC; 100 microM, 2 h) in culture, in mRNA extracted from tumor tissue these changes are absent or very small. Both C-jun and erb-2 were detectable in liver. There was increased expression of both of these genes in the livers of tumor-bearing animals as compared with non-tumor-bearing animals. The highest expression of both c-jun and erb-2 occurred in the livers of animals bearing the EMT-6/CDDP tumor. Treatment of the animals with CDDP or cyclophosphamide, in general, resulted in increased expression of both genes at 6 h post treatment. The increased expression of these genes may impart metabolic changes in the tumors and/or hosts that contribute to the resistance of these tumors to specific antitumor alkylating agents.
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PMID:Molecular characterization of the in vivo alkylating agent resistant murine EMT-6 mammary carcinoma tumors. 785 Sep 25

We have investigated the role of JAK3 in interleukin 2 (IL-2)-induced signal transduction with a human T cell line, ED40515(-), lacking expression of the IL-2 receptor gamma chain and its sublines transfected with wild-type or mutant cDNAs of the IL-2 receptor gamma chain. Our results demonstrated that the membrane-proximal cytoplasmic region, encompassing the src homology region 2 (SH2)-like subdomain, of the gamma chain is essential for association and activation of JAK3. Furthermore, IL-2-induced activation of JAK3 paralleled induction of the c-myc gene and DNA synthesis but not induction of the c-fos and c-jun genes. These results support the hypothesis that JAK3 plays a pivotal role in the IL-2 receptor-mediated signals for cell growth.
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PMID:Interleukin 2-induced activation of JAK3: possible involvement in signal transduction for c-myc induction and cell proliferation. 808 65

The neuro-intestinal peptide hormone cholecystokinin (CCK)/gastrin has been suggested to have a trophic effect on gastro-intestinal tract in vivo as well as in vitro. In the present study, the human CCK-B/gastrin receptor was expressed in mouse NIH3T3 fibroblasts to investigate the molecular basis of signal transduction pathway of the guanine nucleotide regulatory protein (G protein)-coupled receptor. Human CCK-B/gastrin receptor expressed in NIH3T3 cells coupled efficiently to phosphoinositide hydrolysis and mobilization of intracellular Ca2+, and transduced mitogenic signals assessed by [3H]thymidine incorporation in a dose-dependent manner. Moreover, CCK-8 or gastrin I alone promoted the cell growth in serum-free medium. CCK-8 induced tyrosine phosphorylation of several protein species. Among them, mitogen-activated protein (MAP) kinase was tyrosine phosphorylated and activated in response to CCK-8, as was induced by platelet-derived growth factor (PDGF). In contrast, tyrosine phosphorylation of p125FAK (focal adhesion kinase) was induced by CCK-8 but not by PDGF. CCK-8 as well as gastrin I induced the expression of early responsive genes such as c-fos and c-myc. These results suggest that CCK-B/gastrin receptors might transmit mitogenic signals by cross-talking with the tyrosine kinase cascades.
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PMID:Cholecystokinin-B/gastrin receptor signaling pathway involves tyrosine phosphorylations of p125FAK and p42MAP. 810 29

We have previously documented that glucocorticoids suppress the proliferation of BDS1 hepatoma cells, a rat epithelial tumor cell line derived from minimal deviation Reuber H35 hepatoma cells. Flow cytometry demonstrated that, after treatment with the synthetic glucocorticoid dexamethasone, the growth of an asynchronous population of BDS1 cells was arrested within one cell cycle which resulted in an accumulation of cells with a G1-G0-like DNA content. Consistent with a glucocorticoid-induced block early in the G1 phase of the cell cycle, propidium iodide flow cytometry revealed that addition of dexamethasone up to 2 h after release from contact inhibition prevented BDS1 hepatoma cells from entering S phase, whereas dexamethasone treatment after 2 h had no effect on the entry of cells into S phase. Moreover, dexamethasone treatment did not prevent BDS1 cells from entering S phase after release from synchronization at the G1-S boundary by a double thymidine block. Analysis of DNA content, [3H]-thymidine incorporation, and autoradiography of [3H]-thymidine-labeled nuclei revealed that, after release from dexamethasone, BDS1 cells synchronously reinitiated cell cycle progression and entered S phase 8 h after hormone withdrawal. Northern blot analysis demonstrated that the level of transcripts encoding the G1 marker genes CYL-1 and CYL-2 G1 cyclins peaked 4 h after dexamethasone withdrawal. Dexamethasone induced a 20-fold increase in the level of c-jun mRNA which was reversed after hormone withdrawal, whereas expression of c-fos transcripts remained at a low level during the time course of hormone treatment and withdrawal. Transient transfections with a collagenase-chloramphenicol acetyltransferase reporter gene showed that dexamethasone inhibited 12-O-tetradecanoylphorbol-13-acetate-inducible, but not basal, AP-1 transcription factor activity. Our results demonstrate that glucocorticoids reversibly induce an early G1 block in cell cycle progression of an epithelial tumor cell line that occurs with a coordinate elevation in the expression of c-jun transcripts.
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PMID:Glucocorticoids reversibly arrest rat hepatoma cell growth by inducing an early G1 block in cell cycle progression. 846 59

The tyrosine kinase JAK1 and the transcription factors STAT1 and STAT3 are phosphorylated in response to epidermal growth factor (EGF) and other growth factors. We have used EGF receptor-transfected cell lines defective in individual JAKs to assess the roles of these kinases in STAT activation and signal transduction in response to EGF. Although JAK1 is phosphorylated in response to EGF, it is not required for STAT activation or for induction of the c-fos gene. STAT activation in JAK2- and TYK2-defective cells is also normal, and the tyrosine phosphorylation of these two kinases does not increase upon EGF stimulation in wild-type or JAK1-negative cells. In cells transfected with a kinase-negative mutant EGF receptor, there is no STAT activation in response to EGF and c-fos is not induced, showing that the kinase activity of the receptor is required, directly or indirectly, for these two responses. The data do not support a role for any of the three JAK family members tested in STAT activation and are consistent with a JAK-independent pathway in which the intrinsic kinase domain of the EGF receptor is crucial. Furthermore, data from transient transfection experiments in HeLa cells, using c-fos promoters lacking the STAT regulatory element c-sis-inducible element, indicate that this element may play only a minor role in the induction of c-fos by EGF in these cells.
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PMID:Roles of JAKs in activation of STATs and stimulation of c-fos gene expression by epidermal growth factor. 852 16

Interleukin-3 (IL-3) or granulocyte-macrophage colony-stimulating factor (GM-CSF) is known to activate JAK2 in various cells, but the role of JAK2 in IL-3 or GM-CSF receptor signal transduction is largely unknown. We have now examined the role of JAK2 in GM-CSF-induced signaling events in BA/F3 cells. In BA/F3 cells expressing hGMR, activation of JAK2 by hGM-CSF requires the box1 region of hGMR beta. Dominant negative JAK2 (delta JAK2), which lacked the kinase domain suppressed mIL-3 or hGM-CSF-induced c-fos promoter activation as well as c-myc promoter activation/cell proliferation, thereby suggesting that JAK2 is involved in the signaling of both pathways. Further analyses of the role of JAK2 in c-fos gene activation in BA/F3 cells expressing hGMR revealed that delta JAK2 inhibited hGM-CSF-induced phosphorylation of Shc and protein tyrosine phosphatase 1D. Within hGMR beta, the several tyrosine residues which exist are related to activation of Shc or protein tyrosine phosphate 1D, and are phosphorylated in response to hGM-CSF stimulation. In addition, we observed that delta JAK2 inhibited hGM-CSF-induced phosphorylation of hGMR beta. Taken together, our results suggest that JAK2 activated by the box1 region of hGMR mediates hGM-CSF-induced c-fos promoter activation through phosphorylation of hGMR.
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PMID:JAK2 is essential for activation of c-fos and c-myc promoters and cell proliferation through the human granulocyte-macrophage colony-stimulating factor receptor in BA/F3 cells. 864 82

IL-2-, IL-12-, and IFN-alpha-mediated signaling pathways were analyzed in primary NK cells and in the NK3.3 cell line. Gel mobility shift and immunoprecipitation analyses revealed that in addition to activating STAT3 (signal transducer and activator of transcription-3) and STAT5, IL-2 induced tyrosine and serine phosphorylation of STAT1 alpha, which formed IFN-gamma-activated sequence-binding complexes by itself and with STAT3. Although IL-2 and IFN-alpha activated STAT1 alpha and STAT5, IL-2 predominantly activated STAT5, while IFN-alpha predominantly activated STAT1 alpha. IL-2 induced less STAT1 alpha activation and IFN-alpha induced greater STAT5 activation in NK3.3 cells compared with preactivated primary NK cells. In NK3.3 cells, IL-2 induced comparable formation of c-fos promoter sis-inducible element IFN-gamma-activated sequence-binding complexes containing STAT3 alone with complexes containing STAT3 and STAT1 alpha, while in preactivated primary NK cells, it preferentially induced complexes containing STAT3 and STAT1 alpha. Thus, signaling in NK3.3 cells is not always identical with that in primary NK cells. In contrast to IL-2 and IFN-alpha, IL-12 induced strong tyrosine phosphorylation of STAT4 and variable weak phosphorylation of STAT3. However, supershift analyses using the c-fos promoter sis-inducible element probe showed that IL-12 activated STAT4, STAT1 alpha, and STAT3, and induced complexes containing STAT4 only, STAT4 with STAT1 alpha, STAT3 with STAT1 alpha, or STAT1 alpha only in preactivated primary NK cells. STAT1 alpha activation by IL-12 correlated with increased phosphorylation of serine, but not tyrosine. Finally, IL-2 induced tyrosine phosphorylation of JAK1 and JAK3, while IL-12 induced phosphorylation of JAK2 and TYK2 in both preactivated primary NK and NK3.3 cells. Differential phosphorylation and consequent differential activation of both separate and overlapping STAT proteins by IL-2, IL-12, and IFN-alpha may provide a molecular basis for the similarities and differences in the actions of these cytokines on NK cells.
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PMID:Differential utilization of Janus kinase-signal transducer activator of transcription signaling pathways in the stimulation of human natural killer cells by IL-2, IL-12, and IFN-alpha. 868 6

The demonstration that RNA can be cleaved by cis or trans ribozymes (catalytic RNAs, RNA enzymes) has potentially important therapeutic implications. Since their discovery in the 1980s, the biochemistry and conserved sequences of ribozymes have been well characterized. Ribozymes are effective modulators of gene expression because of their simple structure, sitespecific cleavage activity, and catalytic potential. The targets of ribozyme-mediated gene modulation have ranged from cancer cells to foreign genes that cause infectious diseases. Additional target sites for ribozymes are in initial phases of development and design. Ribozymes have been targeted against a myriad of genes, including oncogenes (ras, BCR-ABL, c-fos) and drug resistance genes, as well as the human immunodeficiency virus-type I genome. These ribozymes have cleaved the target RNAs in vitro and altered the cellular pathology. Currently, the therapeutic application of ribozymes to human diseases is limited by gene transfer systems. It is anticipated that ribozymes ultimately will play an important role in human gene therapy.
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PMID:Therapeutic applications of ribozymes. 871 70

PRL regulates milk gene expression, at least in part, by activating JAK2 kinase and STAT5 (signal transducer and activator of transcription 5), initially termed mammary gland factor (MGF). These experiments were initiated to gain a better understanding of the mechanisms of transcriptional activation via PRL receptor (PRL-R) signaling. Binding of PRL to the recombinant pigeon PRL-R-activated transcription driven by a 2.8 kbp 5'-fragment of the rat beta-casein gene. PRL enhanced the expression of chimeric reporters containing the beta-casein PRL response element (PRE), but not the c-fos sis-inducible element, when the reporters were transfected into Chinese hamster ovary cells with the PRL-R. Wild type receptor, which contains a duplication of the entire extracellular ligand-binding domain, was only slightly more effective than a truncation mutant with a single extracellular domain. Transfection with either JAK1, JAK2, or JAK3 increased basal transcription through both the PRE and sis-inducible element. Coexpression of JAK2 with PRL-R resulted in amplification of the induction of the PRE by PRL, whereas JAKs 1 and 3 did not amplify the PRL effect. Overexpression of JAK2 mutants blocked PRE activation by PRL. Mutant JAK2 also interfered with PRE activation by JAK3 but did not affect JAK1's stimulatory effect.
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PMID:Interactions among Janus kinases and the prolactin (PRL) receptor in the regulation of a PRL response element. 881 25


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