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)

Preservation of the shape and the integrity of multicellular eukaryotes needs rigorous cell proliferation monitoring. During the prereplicative G1 phase, a finely adjusted and specific control supervises the proliferant/non proliferant states of the cells. Some molecular mechanisms of growth regulation have been identified in recent years. Changes in normal cell attachment on extracellular matrix and intercellular chemical signalling (secretion of informative molecules) activate intracellular signals for division. The transduction mechanisms of the extracellular signalling to the nucleus have been partially elucidated for steroid hormones and growth factors. Molecular biology research and proto-oncogene discoveries have led to considerable progress in understanding the role of these normal genes in the control of cellular proliferation. The initiation of the response to extracellular factors requires: i), direct transducers (specific binding of the steroid hormone on its cytoplasmic or nuclear receptor and high affinity binding of this activated complex to specific DNA sequences); and ii) indirect transducers (binding of growth factors on extracellular domains of specific receptor proteins which convert this extracellular event into several intracellular signals, secondary messengers, protein kinases and specific nuclear regulatory factors). Whatever the transduction system, nuclear events control transcription of growth regulatory genes. The series of enzymatic reactions set in motion by indirect transduction systems require strict regulation systems, the diversity and the complexity of which has been perceived in studies on jun and fos gene families. Each proliferation step is governed by growth stimulators and growth inhibitors, the transformation of normal cells to cancer cells resulting from alterations of these regulatory process. Independent of extracellular stimuli and of their transfer to the nucleus, intracellular controls coordinate cell cycle phases (G1, S, G2 and M) to produce daughter cells identical to the original cell. Two control points are particularly critical: one in G1 (the "start" point) and the other in G2 just before mitosis. Although intermediate steps between extracellular and intracellular controls are still unknown, yeast gene analyses have allowed determination of molecular regulatory mechanisms implicated in the passage of these critical points. A considerable advance was made by the discovery that some of the involved components presented strong sequence and function homologies in organisms from yeast to man, suggesting a phyllogenetically conserved mechanism. It seems likely that the phosphorylation state of protein p34, its association with a G1-phase specific cyclin or a M-phase specific cyclin, and its protein kinase activity regulate the proliferation state of higher eukaryotic cells. In spite of significant advances, much research is still necessary to elucidate all the mechanisms involved in cell cycle control.
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PMID:[Different regulation systems of cell cycle events (dysregulation of these events in the tumoral cell)]. 202 83

The protein product of the Raf-1 proto-oncogene is a protein serine/threonine kinase that is activated after stimulation of cells with insulin and other mitogens. To investigate the mechanism of this activation, we used purified Raf-1 expressed in E. coli as a substrate for a putative Raf-1 protein kinase kinase. In three different insulin-sensitive cell types, insulin activated Raf-1 kinase kinase activity in crude cytosolic cellular fractions. The insulin stimulation of this activity was evident as early as 2 min after exposure to insulin, maximal at 5-8 min, and inapparent at 15 min. Phosphoamino acid analysis of phosphorylated Raf-1 revealed that serine was the primary phosphate acceptor for the insulin-activated kinase or kinases; small amounts of phosphothreonine were also detected. The insulin effect occurred in cells depleted of protein kinase C, and in extracts depleted of endogenous Raf-1 kinase by immunodepletion; these data argue against protein kinase C or Raf-1 kinase itself being the insulin-stimulated activity. The insulin-activated kinase or kinases phosphorylated the Raf-1 protein on multiple sites in vitro, as evidenced by tryptic mapping; at least some of these appeared to overlap with sites phosphorylated in response to serum in intact cells. Several other mitogens and growth factors stimulated Raf-1 kinase kinase activity, including epidermal growth factor, platelet-derived growth factor, fibroblast growth factor, serum, and phorbol 12-myristate 13-acetate. This insulin- and mitogen-stimulated Raf-1 kinase kinase activity may play a role in mediating the phosphorylation and possibly the activation of the Raf-1 kinase by insulin and other growth factors.
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PMID:Evidence for one or more Raf-1 kinase kinase(s) activated by insulin and polypeptide growth factors. 203 87

In this report we describe changes in the intracellular redistribution of raf serine/threonine protein kinase (product of the raf proto-oncogene family) in hippocampal neurons following cerebral ischemia in Mongolian gerbils. For immunohistochemical localization studies polyclonal antisera specific for each of the A, B, and Raf-1 isotypes of raf, as well as a pan-raf antisera, were employed. Of these, only sera recognizing B-raf, as well as the general v-raf (raised against the conserved C-terminal region) were positive, indicating that B-raf is the major isotype in this neuronal region. Three different ischemic models were used (repeated 3 times for two min and single 5 or 15 min occlusions, of the common carotid arteries) to demonstrate that ischemic insult causes redistribution of raf protein kinase into the cell nucleus of hippocampal neurons. Increased amounts of raf protein in the nuclei of pyramidal cells following ischemia was confirmed by Western blot analysis of isolated nuclear fractionations. Moreover, an elevation in the level of nuclear raf protein also was detected in the contralateral (i.e. non-occluded hemisphere) neurons of CA1 and CA3 subfields 4 days after the ischemic insult indicating a possible transsynaptic increase in the amount of raf protein along with redistribution. The intranuclear translocation of the immunoreactive material started from the perinucleolar rim and with time extended throughout the nucleus. Enhanced levels and altered redistribution of the raf polypeptide in the nuclei of pyramidal cells of the CA3 subfield appears to be reversible and returns to the normal level 12 days following the ischemic insult.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cerebral ischemia induces transient intracellular redistribution and intranuclear translocation of the raf proto-oncogene product in hippocampal pyramidal cells. 206 47

The product of the c-src proto-oncogene (pp60c-src) is a tyrosine-specific protein kinase that is expressed in two phases of neural development. In post-mitotic neuronal cells undergoing terminal differentiation, pp60c-src is present at high levels in the membrane of nerve growth cones and proximal axon shafts. Membrane-associated forms of alpha- and beta-tubulin are the major phosphotyrosine-modified proteins in growth cone membranes in vivo. pp60c-src phosphorylates purified, unassembled tubulin subunits in vitro, inhibiting their ability to polymerize into microtubules. It is conceivable that tubulin phosphorylation by pp60c-src in the growth cone may regulate neurite extension by altering adhesion of cells to the substratum.
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PMID:Tyrosine phosphorylation of membrane-associated tubulin in nerve growth cones enriched in pp60c-src. 211 26

Cells respond to proliferative signals generated by growth factors and oncogenes with a complex array of biochemical and physiological events, culminating in DNA synthesis and cell division. One of the molecules thought to be critical for the transmission and amplification of mitogenic signals from the cell surface to the nucleus is the proto-oncogene product Raf-1. Raf-1 is a serine-threonine kinase that is itself phosphorylated in response to mitogenic stimulation. The phosphorylation state of Raf-1 appears to modulate its kinase activity. Experiments linking Raf-1 to other characterized components of the signal transduction machinery are reviewed here.
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PMID:The Raf-1 kinase as a transducer of mitogenic signals. 215 Sep 16

Treatment with insulin or progesterone or microinjection of the transforming protein product of Ha-rasVal-12,Thr-59 (p21) is known to induce germinal vesicle breakdown in Xenopus oocytes. We have investigated the effect of p21 on S6 kinase and the H1 histone kinase of maturation-promoting factor in the presence and absence of antisense oligonucleotides against the c-mosxe proto-oncogene. Injection of p21 led to a rapid increase in S6 phosphorylation, with kinetics similar to those previously observed with insulin. Microinjection of c-mosxe antisense oligonucleotides inhibited germinal vesicle breakdown induced by p21 and totally abolished S6 kinase activation by insulin or progesterone but only partially inhibited activation by p21. However, the activation of p34cdc2 protein kinase by all three stimuli was blocked by antisense oligonucleotides. The results suggest that in oocyte maturation c-mosxe functions downstream of p21 but upstream of p34cdc2 and S6 kinase activation, although not all p21-induced events require c-mosxe.
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PMID:Ha-rasVal-12,Thr-59 activates S6 kinase and p34cdc2 kinase in Xenopus oocytes: evidence for c-mosxe-dependent and -independent pathways. 215 63

The mechanism by which the calcium influx signal, triggered by membrane depolarization, is transduced to the nucleus to activate c-fos proto-oncogene transcription has been characterized. A calcium response element (CaRE) that is indistinguishable from a cAMP response element (CRE) mediates transcriptional inducibility by depolarization. Its cognate transcription factor CREB is the target for both calcium and cAMP signals. CREB is rapidly phosphorylated in response to depolarization or cAMP, at a site known to be important for the transcriptional activating function of this protein. The convergent effects of calcium and cAMP on CREB activation are mediated by distinct protein kinase signaling pathways. CREB and its binding site, the Ca/CRE, can thus function as a regulatory element that integrates both calcium and cAMP signals in the control of gene expression.
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PMID:Membrane depolarization and calcium induce c-fos transcription via phosphorylation of transcription factor CREB. 215 71

The dauer larva is a developmentally arrested, non-feeding dispersal stage normally formed in response to overcrowding and limited food. The daf-1 gene specifies an intermediate step in a hierarchy of genes thought to specify a pathway for neural transduction of environmental cues. Mutations in daf-1 result in constitutive formation of dauer larvae even in abundant food. This gene has been cloned by Tc1-transposon tagging, and it appears to encode a new class of serine/threonine kinase. A daf-1 probe detects a 2.5 kb mRNA of low abundance, and the DNA sequence indicates that the gene encodes a 669 amino acid protein, with a putative transmembrane domain and a C-terminal protein kinase domain most closely related to the cytosolic, raf proto-oncogene family. Hence, the daf-1 product appears to be a cell-surface receptor required for transduction of environmental signals into an appropriate developmental response.
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PMID:daf-1, a C. elegans gene controlling dauer larva development, encodes a novel receptor protein kinase. 216 Aug 53

Previous studies have demonstrated that expression of the c-jun proto-oncogene is induced by phorbol esters and other agents that activate protein kinase C. The present work has examined the involvement of cAMP-dependent signaling mechanisms in the regulation of c-jun gene expression. Low levels of c-jun transcripts were detectable in untreated HL-60 myeloid leukemia cells. In contrast, treatment of these cells with 8-bromoadenosine 3',5'-cyclic monophosphate was associated with increases in c-jun expression that were maximal at 3 h and then declined to pretreatment levels. Similar findings were obtained with N6,2'-O-dibutyryladenosine 3',5'-cyclic monophosphate and 8-(4-chlorophenylthio)-adenosine 3',5'-cyclic monophosphate, but not with 8-bromoguanosine 3',5'-cyclic monophosphate. c-jun transcripts were also increased with agents, such as prostaglandin E2 and forskolin, that increase intracellular cAMP levels. The effects of these agents on c-jun expression were associated with activation of cAMP-dependent protein kinase. Moreover, inhibition of this kinase activity with the isoquinolinesulfonamide derivative H8 was associated with a block in the induction of c-jun expression by cAMP. Nuclear run-on analysis further demonstrated that while c-jun transcription is a low levels in untreated HL-60 cells, treatment with cAMP analogs is associated with an increase in the transcriptional rate of this gene. Taken together, these findings suggested that, in addition to activation of protein kinase C, stimulation of cAMP-dependent protein kinase activity is also involved in the transcriptional induction of c-jun gene expression. The present results similarly demonstrate that c-fos gene transcription is induced in HL-60 cells through a mechanism involving cAMP-dependent protein kinase activity. Since heterodimers of the Jun and Fos proteins have been shown to bind to the phorbol ester-responsive element (AP-1-binding site), the present findings indicate that cAMP-induced signaling events may also regulate gene transcription through formation of Fos/Jun heterodimers and that interaction between phorbol ester- and cAMP-dependent pathways could occur through induction of the c-jun gene in these cells.
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PMID:Regulation of c-jun gene expression by cAMP in HL-60 myeloid leukemia cells. 217 93

Insulin was found to stimulate the serine/threonine kinase activity of the proto-oncogene product Raf-1. This stimulation was observed in HeLa, NIH 3T3, and Chinese hamster ovary cells, all overexpressing the human insulin receptor. In the HeLa cells, 100 pM insulin gave a significant increase in Raf-1 kinase activity, and 100 nM insulin caused a maximal 2-5-fold increase in activity. The increase in activity was detected after 2 min of insulin treatment and peaked after 5 min. In addition to stimulating Raf-1 kinase activity, insulin caused a shift in the electrophoretic mobility of the Raf-1 protein and an increase in the amount of serine phosphorylation of Raf-1. Moreover, a serine/threonine-specific phosphatase, phosphatase 1, but not two tyrosine-specific phosphatases, was found to deactivate the insulin-activated Raf-1 kinase activity. These findings indicate that insulin activates the serine/threonine kinase activity of the Raf-1 proto-oncogene by increasing its content of phosphoserine.
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PMID:Insulin activates the kinase activity of the Raf-1 proto-oncogene by increasing its serine phosphorylation. 219 70


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