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)

Growth factor receptor tyrosine kinase regulation of the sequential phosphorylation reactions leading to mitogen-activated protein (MAP) kinase activation in PC12 cells has been investigated. In response to epidermal growth factor, nerve growth factor, and platelet-derived growth factor, B-Raf and Raf-1 are activated, phosphorylate recombinant kinase-inactive MEK-1, and activate wild-type MEK-1. MEK-1 is the dual-specificity protein kinase that selectively phosphorylates MAP kinase on tyrosine and threonine, resulting in MAP kinase activation. B-Raf and Raf-1 are growth factor-regulated Raf family members which regulate MEK-1 and MAP kinase activity in PC12 cells. Protein kinase A activation in response to elevated cyclic AMP (cAMP) levels inhibited B-Raf and Raf-1 stimulation in response to growth factors. Ras.GTP loading in response to epidermal growth factor, nerve growth factor, or platelet-derived growth factor was unaffected by protein kinase A activation. Even though elevated cAMP levels inhibited Raf activation, the growth factor activation of MEK-1 and MAP kinase was unaffected in PC12 cells. The results demonstrate that tyrosine kinase receptor activation of MEK-1 and MAP kinase in PC12 cells is regulated by B-Raf and Raf-1, whose activation is inhibited by protein kinase A, and MEK activators, whose activation is independent of cAMP regulation.
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PMID:B-Raf-dependent regulation of the MEK-1/mitogen-activated protein kinase pathway in PC12 cells and regulation by cyclic AMP. 793 74

Molecular cloning using a degenerate oligonucleotide-based polymerase chain reaction was undertaken to test the possibility that novel, developmentally regulated protein kinases are expressed in the embryonic mouse kidney. Several receptor tyrosine kinase and serine/threonine kinase cDNA clones were identified. One of these, designated DLK, represented a novel gene product whose 3.6-kilobase transcript was expressed in a tissue-specific and developmentally regulated fashion. Several clones encoding the entire open reading frame were isolated and sequenced. The identified open reading frame encodes an 888-amino acid polypeptide that defines a new subfamily within the mixed lineage protein kinase family. Sequence analysis revealed: 1) a kinase catalytic domain most characteristic of serine/threonine kinases but hybrid between members of the family of microtubule-associated protein kinase kinase kinases and the fibroblast growth factor receptor family; 2) two putative alpha-helical leucine zipper motifs separated by a 25-amino acid charged intermediate segment but lacking an NH2-terminal basic domain; and 3) COOH-terminal and NH2-terminal proline-rich domains suggestive of src homology 3 (SH3) domain binding regions. Rabbit polyclonal immune sera generated against a carboxyl-terminal bacterial fusion protein recognized a protein with an apparent molecular mass of 130 kDa in COS 7 cells that were transiently transfected with a full-length DLK cDNA expression vector. Moreover, COS 7 cells transiently transfected with an epitope-tagged DLK expression vector expressed protein with an apparent molecular mass of 130 kDa that became autophosphorylated on serine and threonine in an in vitro kinase assay.
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PMID:Identification, molecular cloning, and characterization of dual leucine zipper bearing kinase. A novel serine/threonine protein kinase that defines a second subfamily of mixed lineage kinases. 798 11

We have studied the effect of activation of the c-erbB-2 receptor tyrosine kinase on protein kinase C (PKC) in cultured SKBR-3 human breast cancer cells. Treatment with the agonistic anti-receptor monoclonal antibody TAb 250 induces receptor autophosphorylation and stimulates phospholipase C-gamma 1 (L. K. Shawver et al. Cancer Res., 54: 1367-1373, 1994). TAb 250 induced a rapid and marked translocation of PKC histone phosphorylation activity to the particulate fraction of SKBR-3 cells. By immunoblot, however, this translocation was limited to specific PKC isozymes. beta PKC and zeta PKC translocated to the particulate fraction, whereas epsilon PKC underwent "partial reversed translocation" to the cell soluble fraction after receptor stimulation. Furthermore, beta PKC was rapidly degraded following TAb 250 treatment. By immunocytochemistry, beta IPKC translocated from the perinuclear area to the cytosol and into the nucleus, whereas zeta PKC translocated to the perinuclear region and into the nucleus. Consistent with the Western blot results, epsilon PKC translocated from the nucleus to the perinuclear area and the cytosol. These changes in the localization of PKC isozymes were not observed after addition of normal IgG1 or a nonagonistic anti-c-erbB-2 monoclonal antibody to SKBR-3 cells. alpha, beta II, or delta PKC present in these cells did not translocate following receptor stimulation. These data indicate that c-erbB-2 signal transduction may involve the activation of specific PKC isozymes. The biological role of these enzymes in the phenotype and cellular responses of c-erbB-2-overexpressing carcinoma cells remains to be studied.
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PMID:Distinct responses of protein kinase C isozymes to c-erbB-2 activation in SKBR-3 human breast carcinoma cells. 798 52

Sequential protein kinase reactions involve the phosphorylation and activation of multiple kinases in a pathway. The growth factor receptor tyrosine kinase regulation of the mitogen-activated protein kinase (MAPK) pathway was defined in 1993. The MAPK pathway involves sequential protein kinase reactions. Notable advances were made in defining tyrosine kinase receptor regulation of Ras, and these discoveries were combined with the identification of Raf-1, a serine-threonine protein kinase in the MAPK pathway, as an effector for Ras GTP.
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PMID:Sequential protein kinase reactions controlling cell growth and differentiation. 802 15

Tyrphostins are synthetic compounds which have been described as in vitro inhibitors of epidermal growth factor (EGF)-receptor tyrosine kinase activity. In NIH3T3 cells, stimulation of EGF-receptor tyrosine kinase leads to an increase of intracellular protein phosphorylations, among them the phosphorylation of mitogen-activated protein (MAP) kinase and the S6 kinases p90rsk and p70S6K. Phosphorylation of these proteins, either on tyrosine or serine/threonine residues or on both residues increases their protein kinase activity. Unexpectedly, treatment of NIH3T3 cells with both tyrphostin (RG 50864) and EGF results in an increase in the level of tyrosine phosphorylation of the MAP kinase. During this treatment, we also observed an increase in MAP kinase and S6 kinase p90rsk activities. Tyrphostin treatment diminishes the level of c-fos mRNA but has no effect on c-myc mRNA expression nor on S6 kinase p70S6K activity. Mitogenic signalling induced by EGF in NIH3T3 cells was blocked by tyrphostin, suggesting that the target(s) for this event may be elements downstream from the MAP kinase or independent of this signal transduction.
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PMID:Activation of the mitogen-activated protein kinase cascade by tyrphostin (RG 50864). 806 37

The intracellular domain of the insulin receptor possesses activity as a tyrosine-specific protein kinase which is stimulated by insulin binding to the extracellular domain of the receptor. We have identified a patient with a genetic form of insulin resistance who is heterozygous for a mutation substituting Glu for Ala1135 in the putative "catalytic loop" of the tyrosine kinase domain of the receptor. In this investigation, the Glu1135 mutant receptor was expressed by transfection of mutant cDNA into NIH-3T3 cells. Like previously described mutations in the tyrosine kinase domain, the Glu1135 mutation impairs receptor tyrosine kinase activity and inhibits the ability of insulin to stimulate thymidine incorporation and receptor endocytosis. These data support the hypothesis that the receptor tyrosine kinase activity plays a necessary role in the ability of the receptor to mediate insulin action in vitro and in vivo. However, unlike previously described mutations in the intracellular domain of the receptor, the Glu1135 mutation impairs proteolytic cleavage of the proreceptor into separate subunits and impairs the transport of the receptor to the cell surface. These latter defects provide an explanation for the decrease in the number of receptors on the cell surface observed in the patient's circulating monocytes despite the fact that the mutant receptor is resistant to endocytosis and insulin-induced down-regulation.
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PMID:Substitution of glutamic acid for alanine 1135 in the putative "catalytic loop" of the tyrosine kinase domain of the human insulin receptor. A mutation that impairs proteolytic processing into subunits and inhibits receptor tyrosine kinase activity. 809 18

Ras, a small GTP-binding protein, is required for functional receptor tyrosine kinase signaling. Ultimately, Ras alters the activity of specific nuclear transcription factors and regulates novel patterns of gene expression. Using a rat prolactin promoter construct in transient transfection experiments, we show that both oncogenic Ras and activated forms of Raf-1 kinase selectively stimulated the cellular rat prolactin promoter in GH4 rat pituitary cells. We also show that the Ras signal is completely blocked by an expression vector encoding a dominant-negative Raf kinase. Additionally, using a molecular genetic approach, we determined that inhibitory forms of p42 mitogen-activated protein kinase and an Ets-2 transcription factor interfere with both the Ras and the Raf activation of the rat prolactin promoter. These findings define a functional requirement for these signaling constituents in the activation of the prolactin gene, a cell-specific gene which marks the lactotroph pituitary cell type. Further, this analysis allowed us to order the components in the Ras signaling pathway as it impinges on regulation of prolactin gene transcription as Ras-->Raf kinase-->mitogen-activated protein kinase-->Ets. In contrast, we show that intact c-Jun expression inhibited the Ras-induced activation of the prolactin promoter, defining it as a negative regulator of this pathway, whereas c-Jun was able to enhance the Ras activation of an AP-1-driven promoter in GH4 cells. These data show that c-Jun is not the nuclear mediator of the Ras signal for the highly specialized, pituitary cell-specific prolactin cellular promoter. Thus, we have defined a model system which provides an ideal paradigm for studying Ras/Raf signaling pathways and their effects on neuroendocrine cell-specific gene regulation.
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PMID:Identification of the functional components of the Ras signaling pathway regulating pituitary cell-specific gene expression. 811 93

By low-stringency screening of a human hepatoma HepG2 cell cDNA library, using the genomic fragment of chick c-sea receptor tyrosine kinase as a probe, we isolated overlapping cDNAs encoding a novel protein kinase, which we termed LIM-kinase (LIMK).* The predicted open reading frame encodes a 647-amino-acid polypeptide containing a putative protein kinase structure in the C-terminal half. In addition, LIMK has two repeats of cysteine-rich LIM/double zinc finger motif at the most N-terminus. To our knowledge, this is the first protein kinase seen to contain the LIM motif(s) in the molecule. Although the protein kinase domain of LIMK has highly conserved sequence elements of protein kinases, phylogenetic analysis revealed that LIMK cannot be classified into any subfamily of known protein kinases. Northern blot analysis revealed that the single species of LIMK mRNA of 3.3 kb was expressed in various human epithelial and hematopoietic cell lines. In rat tissues, LIMK mRNA was expressed in the brain, at the highest level. LIM is suggested to be involved in protein-protein interactions by binding to another LIM motif. As the LIM domain is frequently present in the homeodomain-containing transcriptional regulators and oncogenic nuclear proteins, LIMK may be involved in developmental or oncogenic processes through interactions with these LIM-containing proteins.
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PMID:Identification of a human cDNA encoding a novel protein kinase with two repeats of the LIM/double zinc finger motif. 818 54

Signal transduction pathways that respond to external signals through the MAP kinase family of protein kinases are involved in diverse responses in eukaryotic cells. MAP kinases are one element in a series of kinases that serve to connect the plasma membrane with cytoplasmic and nuclear events. MAP kinases have the unusual feature that their activation requires threonine and tyrosine phosphorylation carried out by a dual specificity protein kinase. Recent advances have shown that in two MAP kinase pathways (the mating response pathway in the fission yeast Schizosaccharomyces pombe, and receptor tyrosine kinase signalling), the small GTP binding protein ras p21 links membrane events to kinase pathway activation.
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PMID:MAP kinase kinase kinase, MAP kinase kinase and MAP kinase. 819 45

The role of Raf and MAPK (mitogen-activated protein kinase) during the maturation of Xenopus oocytes was investigated. Treatment of oocytes with progesterone resulted in a shift in the electrophoretic mobility of Raf at the onset of germinal vesicle breakdown (GVBD), which was coincident with the activation of MAPK. Expression of a kinase-defective mutant of the human Raf-1 protein (KD-RAF) inhibited progesterone-mediated MAPK activation. MAPK activation was also inhibited by KD-Raf in oocytes expressing signal transducers of the receptor tyrosine kinase (RTK) pathway, including an activated tyrosine kinase (Tpr-Met), a receptor tyrosine kinase (EGFr), and Ha-RasV12. KD-RAF completely inhibited GVBD induced by the RTK pathway. In contrast, KD-RAF did not inhibit GVBD and the progression to Meiosis II in progesterone-treated oocytes. Injection of Mos-specific antisense oligodeoxyribonucleotides inhibited MAPK activation in response to progesterone and Tpr-Met, but failed to inhibit these events in oocytes expressing an oncogenic deletion mutant of Raf-1 (delta N'Raf). Injection of antisense oligodeoxyribonucleotides to Mos also reduced the progesterone- and Tpr-Met-induced electrophoretic mobility shift of Xenopus Raf. These results demonstrate that RTKs and progesterone participate in distinct yet overlapping signaling pathways resulting in the activation of maturation or M-phase promoting factor (MPF). Maturation induced by the RTK pathway requires activation of Raf and MAPK, while progesterone-induced maturation does not. Furthermore, the activation of MAPK in oocytes appears to require the expression of Mos.
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PMID:Requirement for Raf and MAP kinase function during the meiotic maturation of Xenopus oocytes. 833 90


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