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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have attempted to dissect signaling pathways involved in transmitting activating signals from the cell surface to the nucleus by reconstituting them in the baculovirus/Sf9 cell system. We have used this system to coexpress different combinations of the critical signaling proteins pp60v-src, p21v-ras, Raf-1 and ERK-1 and assayed the effects of resulting signaling cascades on the modifications of coexpressed transcription factors c-jun or c-fos. We observe that activation of ERK-1 via Raf-1 and p21ras dependent signals can result in the hyperphosphorylation of c-jun. In contrast, c-fos appears to be the target of two Raf-1 activated modifying signals: one independent of ERK-1 and the other dependent on ERK-1 stimulation. Thus, coexpression of c-fos with pp60v-src, p21v-ras or constitutively active forms of Raf-1 results in a dramatic reduction of its electrophoretic mobility in the absence of coexpressed ERK-1. Activation of this ERK-1-independent pathway together with the ERK-1 dependent pathway that modifies c-jun results in additional modification of c-fos. Our observation of a Raf-1 activated, ERK-independent signaling pathway is consistent with previous reports that constitutively active Raf-1 can, in some cell types, result in transformation or differentiation without activation of ERKs. Our data indicate the presence of multiple Raf-1 activated pathways that lead to modification of transcription factors.
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PMID:Reconstitution of signal transduction from the membrane to the nucleus in a baculovirus expression system: activation of Raf-1 leads to hypermodification of c-jun and c-fos via multiple pathways. 754 94

We have examined the mechanism of signal transduction by the hemidesmosomal integrin alpha 6 beta 4, a laminin receptor involved in morphogenesis and tumor progression. Immunoprecipitation and immune complex kinase assays indicated that antibody- or laminin-induced ligation of alpha 6 beta 4 causes tyrosine phosphorylation of the beta 4 subunit in intact cells and that this event is mediated by a protein kinase(s) physically associated with the integrin. Co-immunoprecipitation and GST fusion protein binding experiments showed that the adaptor protein Shc forms a complex with the tyrosine-phosphorylated beta 4 subunit. Shc is then phosphorylated on tyrosine residues and recruits the adaptor Grb2, thereby potentially linking alpha 6 beta 4 to the ras pathway. The beta 4 subunit was found to be phosphorylated at multiple tyrosine residues in vivo, including a tyrosine-based activation motif (TAM) resembling those found in T and B cell receptors. Phenylalanine substitutions at the beta 4 TAM disrupted association of alpha 6 beta 4 with hemidesmosomes, but did not interfere with tyrosine phosphorylation of Shc and recruitment of Grb2. These results indicate that signal transduction by the alpha 6 beta 4 integrin is mediated by an associated tyrosine kinase and that phosphorylation of distinct sites in the beta 4 tail mediates assembly of the hemidesmosomal cytoskeleton and recruitment of Shc/Grb2.
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PMID:Signal transduction by the alpha 6 beta 4 integrin: distinct beta 4 subunit sites mediate recruitment of Shc/Grb2 and association with the cytoskeleton of hemidesmosomes. 755 90

The mechanisms by which pX, the transactivator of the hepatitis B virus (HBV), exerts its effects on transcription of viral and cellular genes and affects cell-growth regulation have not yet been fully defined. Previous reports suggested the possibility of a direct interaction of pX, which lacks intrinsic DNA-binding activity, with components of the cellular transcription machinery. More recent investigations support the hypothesis that pX might activate cellular kinases involved in transcriptional regulation and growth control. We characterized the mechanisms of AP-1 transcription factor activation by pX and, in particular, the role of cellular proteins involved in the intracellular signal transduction of growth-factor receptors. The observation that the overexpression of c-fos and c-jun in the cells results in a clear augmentation of the effects of pX on TRE-directed transcription and the induction of the DNA-binding activity of c-jun/c-fos heterodimers by AP1-depleted nuclear extracts from pX-expressing cells strongly supports the involvement of post-translational modifications. In both HeLa and undifferentiated F9 cells, pX was able to increase the activity of exogenous transfected c-jun but not of c-jun mutants bearing mutations in the serine residues located in the amino-terminal transcriptional activation domain. Moreover, by use of Ha-ras and Raf-1 dominant negative mutants, we show that both Ha-ras and Raf-1 are required for pX-induced activation of c-jun transcriptional activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Modulation of intracellular signal transduction pathways by the hepatitis B virus transactivator pX. 760 67

The large subunit of the HSV-2 ribonucleotide reductase (RR) (ICP10) is a chimera consisting of a serine threonine (Ser/Thr) protein kinase domain at the amino terminus and the RR domain at the carboxy terminus. Transformed human cells that constitutively express ICP10 (JHLa1) were stained with anti-LA-1 antibody (recognizes ICP10 amino acids 13-26) and immunogold-conjugated goat anti-rabbit IgG and were examined by electron microscopy. ICP10-associated gold particles were observed on the cell surface and in structures with ultrastructural characteristics of endocytic vesicles, multivesicular bodies, and lysosomes, consistent with endocytic internalization. ICP10 was also associated with the cytoskeleton fraction of JHLa1 cells and, at least in part, it colocalized with actin filaments. This was evidenced by immunoprecipitation of [35S]methionine-labeled cell fractions and immunofluorescent staining of Triton-treated cells with anti-LA-1 antibody and phalloidin. Endocytic localization of gold particles was not seen in cells that constitutively express the ICP10 transmembrane (TM)-deleted mutant p139TM (JHL15). p139TM did not associate with the cytoskeleton and was almost entirely localized within the cytoplasm. raf and Erk evidenced decreased mobility consistent with an activated state in JHLa1, but not JHL15, cells, and chloramphenicol acetyl transferase (CAT) expression from a c-fos/cat hybrid construct was significantly increased in JHLa1 but not JHL15 cells. The data indicate that effector molecules downstream of ras are activated in JHLa1 cells and the ICP10 TM segment plays a critical role in ICP10 intracellular localization and its ability to activate signaling pathways. This behavior is analogous to that of an activated growth factor receptor kinase.
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PMID:Intracellular internalization and signaling pathways triggered by the large subunit of HSV-2 ribonucleotide reductase (ICP10). 761 72

Transformation with ras oncogenes causes loss, maintenance or modulation of differentiation, depending on the developmental history of the target cells. In the present study, we examined steps in signal transduction that may underlie some of this variation, using steroidogenic cells of adult rats as the model system. Steroidogenesis in normal cells is regulated by cyclic AMP and protein kinase A (the cAMP/PKA pathway). We showed previously that transformation with v-Ki-ras induces constitutive progesterone secretion in ovarian and adrenocortical cells that are normally steroidogenic (ovarian granulosa and adrenal glomerulosa cells) and also in developmentally related cells that are normally nonsteroidogenic (ovarian surface epithelium and adrenal capsular fibroblasts), but not in unrelated nonsteroidogenic cells, such as muscle fascia fibroblasts and peritoneal mesothelium. In the present study, basal cAMP levels in all transformed ovarian and adrenal cell-lines were increased over basal levels in normal cells, and of transformed muscle fascia and mesothelial cell-lines. As in normal cells, transformation-induced steroidogenesis was stimulated by cAMP and was PKA dependent. A comparison of malignancy-related characteristics showed that transformed cells from nonsteroidogenic organs were more tumorigenic in vivo and less sensitive to growth inhibition by cAMP in vitro than transformed ovarian and adrenocortical cells. The results show that the abnormal, constitutive steroidogenesis induced by the viral form of the Kirsten ras oncogene (v-Ki-ras) in certain cell types is associated with tissue-specific increases in basal cAMP levels. Thus, although the ras oncogenes function primarily through other signal transduction pathways, transformation with ras oncogenes alters PKA-mediated signal transduction in a manner that is developmentally determined.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Influence of cell type on the steroidogenic potential and basal cyclic AMP levels of ras-oncogene-transformed rat cells. 762 9

Apigenin, a plant flavonoid, induced the reversion of transformed phenotypes of v-H-ras-transformed NIH 3T3 cells at a quite low concentration of 12.5 microM. In the present study, we have examined the components of this Ras-mediated signaling transduction to determine whether they were involved in the apigenin-induced reversion process. Interestingly, the consitutively activated mitogen activated protein kinase (MAPK) in the ras transformant was inhibited significantly and rapidly by 25 microM apigenin within 30 min, and this reduction continued for more than 4 h. Corroborating these observations, expression of the downstream oncogenes c-jun and c-fos was also dramatically reduced during the first 4 h of treatment. We found that the levels of ras protein and mRNA were not affected by 24 h of treatment with apigenin. These findings indicate that apigenin-induced reversion of v-H-ras-transformed NIH 3T3 cells may occur by inhibiting MAPK activity and its downstream oncogenes rather than by affecting the expression of the ras gene.
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PMID:Reversion of v-H-ras-transformed NIH 3T3 cells by apigenin through inhibiting mitogen activated protein kinase and its downstream oncogenes. 762 10

Several deletion mutants of Raf-1 were expressed with v-ras p21 or 14-3-3 protein in COS-7 cells and Sf9 cells and the interaction of Raf-1 with ras p21 or with 14-3-3 protein in intact cells was examined. Raf(1-135) (residues 1-135) and Raf(1-322) interacted with v-ras p21, but other deletion mutants such as Raf(136-322) or Raf(321-648) did not. Raf(1-322) interacted with 14-3-3 protein much more efficiently than Raf(321-648) did. While Raf(1-135) did not interact with 14-3-3 protein, Raf(136-322) did. These results clearly indicate that Raf-1 simultaneously interacts with both ras p21 and 14-3-3 protein through the distinct binding domains in intact cells.
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PMID:Characterization of the interaction of Raf-1 with ras p21 or 14-3-3 protein in intact cells. 762 30

The activity of the P4 promoter of the parvovirus minute virus of mice (prototype strain MVMp) is stimulated in ras-transformed FREJ4 cells compared with the parental FR3T3 line. This activation may participate in the oncolytic effect of parvoviruses, given that P4 drives a transcriptional unit encoding cytotoxic nonstructural proteins. Our results suggest that the higher transcriptional activity of promoter P4 in FREJ4 cells is mediated at least in part by upstream CRE elements. Accordingly, mutations in the CRE motifs impair P4 function more strongly in the FREJ4 derivative than in its FR3T3 parent. Further evidence that these elements contribute to hyperactivity of the P4 promoter in the ras transformant is the fact that they form distinct complexes with proteins from FREJ4 and FR3T3 cell extracts. This difference can be abolished by treating the FREJ4 cell extracts with cyclic AMP-dependent protein kinase (PKA) or treating original cultures with a PKA activator. These findings can be linked with two previously reported features of ras-transformed cells: the activation of a PKA-inhibited protein kinase cascade and the reduction of PKA-induced protein phosphorylation. In keeping with these facts, P4-directed gene expression can be up- or downmodulated in vivo by exposing cells to known inhibitors or activators of PKA, respectively.
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PMID:Upstream CREs participate in the basal activity of minute virus of mice promoter P4 and in its stimulation in ras-transformed cells. 763 96

Insulin and cAMP stimulate prolactin gene transcription and prolactin-CAT expression in rat pituitary tumor GH cells. Expression of prolactin-CAT construct, pPrl(-173/+75)CAT, is stimulated 10- to 30-fold by either insulin or cAMP. Addition of both insulin and cAMP resulted in an additive 20- to 60-fold stimulation. Although the regulatory sequences have not been defined precisely, both insulin and cAMP appear to stimulate transcription of prolactin-CAT expression through possibly identical sequences in the -106/-87 region of the promoter. Insulin mediated increases in prolactin-CAT expression are not ras-dependent in GH4 cells. Thus, a number of experiments were performed to determine that the effects of insulin and cAMP are independent. First, insulin does not stimulate cAMP levels in GH4 cells. Second, cAMP action was inhibited by expression of a mutant regulatory subunit of cAMP-dependent protein kinase A that does not bind cAMP and by expression of an inhibitor of cAMP-dependent protein kinase A, while insulin action was not affected by expression of these proteins. Thus, although the regulatory sequences for insulin and cAMP may be identical, the effects of insulin and cAMP on the prolactin gene are clearly mediated through distinct response pathway.
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PMID:Insulin and cyclic adenosine monophosphate increase prolactin gene expression through different response pathways. 766 80

NIH 3T3 cells stably transfected with the gene encoding phosphatidylcholine-hydrolyzing phospholipase C (PC-PLC) from Bacillus cereus display a chronic elevation of intracellular diacylglycerol levels and a transformed phenotype. We have used such PC-PLC-transformed cells to evaluate the roles of the cytoplasmic serine/threonine kinases Raf-1, zeta protein kinase C (zeta PKC) and protein kinase A (PKA) in oncogenesis and mitogenic signal transduction elicited by phosphatidylcholine hydrolysis. We demonstrate here that stable expression of dominant negative mutants of both zeta PKC and Raf-1 lead to reversion of PC-PLC-transformed cells. Interestingly, expression of kinase defective zeta PKC also reverted NIH 3T3 cells transformed by the v-Ha-ras oncogene. Activation of PKA in response to elevation of cAMP levels also lead to reversion of PC-PLC-induced transformation, implicating PKA as a negative regulator acting downstream of PC-PLC. On the other hand, inhibition or depletion of phorbol ester responsive PKCs attenuated but did not block the ability of PC-PLC-transformed cells to induce DNA synthesis in the absence of growth factors. These results clearly implicate both Raf-1 and zeta PKC as necessary downstream components for transduction of the mitogenic/oncogenic signal generated by PLC-mediated hydrolysis of phosphatidylcholine and suggest, together with other recent evidence, a bifurcation in the signaling pathway downstream of PC-PLC.
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PMID:Evidence for a bifurcation of the mitogenic signaling pathway activated by Ras and phosphatidylcholine-hydrolyzing phospholipase C. 767 65


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