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)

In a study that was reported from this laboratory, the mitogenic potency of an apparent mol wt (appMr) of 15,000 precursor form of human insulin-like growth factor-II (hIGF-II) was shown to be greater than that of completely processed hIGF-II for human fetal-derived fibroblasts, and both were more potent than rIGF-I. Since it is generally acknowledged that the stimulation of cell replication by the IGFs is mediated by IGF-I receptors, we undertook to determine whether differences between the receptors' affinity for the two Mr forms of hIGF-II and recombinant IGF-I (rIGF-I) or between its efficiency to couple specific growth factor occupancy to the activation of protein kinase could explain the greater replicating potential of appMr 15,000 hIGF-II. Equilibrium dissociation, i.e. Kd, and inhibition, i.e. Ki, constants were determined by measuring the ability of rIGF-I, hIGF-II, appMr 15,000 hIGF-II, insulin, and the antireceptor monoclonal antibody alpha IR-3 to compete with 125I-labeled rIGF-I and hIGF-II for binding to purified preparations of IGF-I receptors prepared from an enriched source of fetal membrane, i.e. human term placenta. The results of these experiments established that 1) hIGF-II and appMr 15,000 hIGF-II bind to the IGF-I receptor with the same affinity as rIGF-I, e.g. with Kd and Ki values between 0.03-0.07 nM; 2) the total binding capacity, i.e. Ro, for IGF-I binding was not statistically different from the Ro calculated for IGF-II binding; and 3) the statistical analysis of 12 data sets from the competitive binding experiments for goodness of fit indicated that a 1-site model for IGF-I and -II binding was a better fit of the data than a 2-site model. Measurements of the stimulation of IGF-I receptor autophosphorylation at low ligand concentrations established that appMr 15,000 hIGF-II and hIGF-II were more effective than rIGF-I in coupling receptor occupancy to the activation of its protein kinase. At saturating ligand concentrations, the 3 had similar potencies. The original preparation of appMr 15,000 hIGF-II contains a mixture of forms with acidic isoelectric points (pIs) and was more potent than Mr 7,500 IGF-II in stimulating receptor autophosphorylation. These results are consistent with the relative potencies of this preparation, hIGF-II, and rIGF-I in stimulating the replication of 12-week-old fetal dermal fibroblasts.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Binding specificities and transducing function of the different molecular weight forms of insulin-like growth factor-II (IGF-II) on IGF-I receptors. 165 23

The pathways depicted in Figure 1 summarize the data discussed in this article. In neurons, the binding of insulin and IGF-I to their respective receptors triggers autophosphorylation of the receptor beta-subunits. IGF-II binds to both neuronal insulin and IGF-I receptors and can stimulate autophosphorylation of either receptor type. In addition to enhancing insulin and IGF-I receptor autophosphorylation, all 3 peptides stimulate the tyrosine phosphorylation of a 70 kDa protein with a similar time course and dose response to receptor phosphorylation. The identity of pp70 is unknown, although the close temporal relationship between pp70 phosphorylation and neurite outgrowth suggests a potential role for this protein. Subsequent to these very early events, two neuronal serine kinases are activated by insulin. One has S6 kinase activity and may represent either the pp90rsk or pp70 class of S6 kinases. Since S6 kinases are activated by direct phosphorylation rather than by second messengers, it is likely that a neuronal S6 kinase kinase exists. The activation of S6 kinase is likely to mediate insulin's effects on neuronal protein synthesis or other growth-related processes. The second serine kinase that is activated by insulin is PKC epsilon. This enzyme is largely restricted to the nervous system, so this signalling pathway may be neuronal-specific. The mechanism of activation of PKC epsilon is unknown, although preliminary data suggests that enhanced phosphorylation of the enzyme is involved. Studies are currently underway to investigate the potential role of diacylglycerol, a potential second messenger generated from either phosphotidylinositol or phosphotidylcholine hydrolysis, in the activation of PKC epsilon by insulin.
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PMID:Regulation of protein phosphorylation by insulin and insulin-like growth factors in cultured fetal neurons. 166 64

Insulin and the insulin-like growth factors (IGF) I and II are structurally related peptides that elicit a large number of similar biological effects in target cells. Three well-characterized receptor complexes bind one or more of these peptides with high affinity. Two of these receptors, denoted as type I, are ligand-activated tyrosine kinases with similar heterotetrameric alpha 2 beta 2 subunit structures which bind insulin or IGF-I, respectively, with highest affinity. Ligand-stimulated tyrosine autophosphorylation of these receptors further activates their intrinsic tyrosine kinase activities both in vitro and in intact cells. Rapid signal transduction follows such receptor autophosphorylation and tyrosine kinase activation, leading to increased serine phosphorylation of many cellular proteins and decreased serine phosphorylation of several others. Experiments in our laboratory have identified three distinct insulin-activated serine kinase activities in cell-free extracts that appear to account for the insulin-stimulated serine phosphorylation of the insulin receptor itself, ATP citrate lyase, and acetyl CoA carboxylase, respectively. A third receptor in this group binds IGF-I and II, lacks kinase activity and is denoted as type II IGF receptor. Amino acid sequences of this receptor deduced from isolated rat cDNA clones show a high degree of homology with those of the bovine cation-independent mannose 6-phosphate (Man-6-P) receptor. We demonstrated that these receptors are indeed identical. The IGF-II/Man-6-P receptor rapidly recycles between the cell surface membrane and intracellular membrane compartments, providing for the rapid uptake of both IGF-II and mannose 6-phosphate-linked lysosomal enzymes. Insulin action markedly increases the proportion of receptors in the plasma membrane and the uptake of bound ligands. We also observe that large amounts of the extracellular domain of the IGF-II/Man-6-P receptor are released into the serum of fetal, neonatal and adult rats. The biological role of this receptor in IGF-II function is yet to be determined.
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PMID:Multifunctional glycoprotein receptors for insulin and the insulin-like growth factors. 255 7

The ruminant corpus luteum synthesizes and secretes oxytocin, but little is known of the regulation of these processes in the ovary. In the present work we describe a method for the preparation of cells from the early bovine corpus luteum (1-5 days postovulation) and their maintenance in serum-free culture. The release of oxytocin and progesterone from these cells was increased by the addition of insulin or insulin-like growth factor I (IGF-I), but not by IGF-II. Hormone release (measured between 60 and 84 h of culture) was increased approximately 5-fold (oxytocin) and 2.5-fold (progesterone) by maximally effective concentrations of IGF-I (EC50, 0.27 nM) and insulin (EC50, 1.94 nM). Sustained exposure (0-84 h) to prostaglandins (PGs) caused a dose-dependent reduction in oxytocin release in the presence of IGF-I (PGF2 alpha EC50, 31 nM; rank order of potency, PGF2 alpha greater than PGE2 greater than PGE1), but did not markedly reduce progesterone release. The inhibitory effect of PG on oxytocin production was mimicked by sustained exposure to a protein kinase-C activator (phorbol 12,13-dibutyrate), supporting the proposed role for this enzyme as a mediator of PG action. These data provide the first demonstration that oxytocin release from early bovine corpus luteal cell cultures can be regulated by insulin, IGF-I, and PGs. Since granulosa and/or luteal cells produce and respond to IGF-I and PGF2 alpha, our data indicate functional interaction of these compounds in the regulation of luteal cell activity.
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PMID:Oxytocin and progesterone release from bovine corpus luteal cells in culture: effects of insulin-like growth factor I, insulin, and prostaglandins. 264 14

The synthesis of IGF-II mRNA in sheep foetal tissues is considerably higher than IGF-I. IGF-II probably has a paracrine role in the foetus; however it is likely that IGF-I originates mainly from the foetal liver and has an endocrine function. Although in the adult system IGF-I is tightly bound to serum carrier proteins it is potentially biologically active. Galactopoiesis in the goat mammary gland provides a useful model for demonstrating the importance of circulating IGF-I as a mediator of GH action. Ligand-receptor interactions involved in the stimulation of Swiss 3T3 fibroblasts by IGF-I, II and insulin were examined. It was found that the potency of binding to type I receptors was IGF-I greater than IGF-II much greater than insulin by competitive binding assays and chemical cross-linking studies, and that some cell lines secrete an IGF binding protein which is specific for IGF-I and II and which acts as an inhibitor in cellular binding assays. Maximal stimulation of DNA synthesis induced by IGF-I, II and insulin in the presence of synergising mitogens were similar. While the actions of the IGFs were consistent with type I receptor binding insulin appeared to act through its own receptor. The reduction of EGF receptor affinity following the addition of IGF-I and insulin to 3T3 cells may involve a protein kinase that is not sensitive to phorbol esters. 3T3 cell nuclei contain endogenous inositol phospholipids and their corresponding kinases and monoesterases.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:From animal to molecule: aspects of the biology of insulin-like growth factors. 285 64

NCI-H295 is a recently described human adrenocortical carcinoma cell line that makes a variety of steroid hormones. We sought to determine if steroidogenesis in these cells employs the same enzymes as those used in normal adrenal steroidogenesis, and if the genes encoding those enzymes exhibit characteristic responsiveness to activators of the protein kinase-A and -C pathways of intracellular second messengers. Northern blots show that NCI-H295 cells contain abundant mRNAs for three key steroidogenic enzymes, cytochrome P450scc, cytochrome P450c17, and cytochrome P450c21. These mRNAs accumulated in a time- and dose-dependent fashion in response to 8-bromo-cAMP (8Br-cAMP), forskolin, cholera toxin, and 3-isobutyl-1-methylxanthine, all activators of the protein kinase-A pathway. Nuclear run-on assays and actinomycin-D transcriptional inhibition experiments show that cAMP regulates the expression of all three genes primarily at the transcriptional level. Inhibition of protein synthesis with cycloheximide did not prevent the cAMP-induced accumulation of P450scc or P450c17 mRNAs, but did inhibit accumulation of P450c21 mRNA, suggesting that cAMP is acting through a mechanism dependent on protein synthesis to promote accumulation of P450c21 mRNA. Stimulation of the protein kinase-C pathway with phorbol ester decreased P450scc and P450c17 mRNAs, but stimulated the accumulation of P450c21 mRNA. RNase protection experiments, Northern blot hybridizations, and reverse transcription-polymerase chain reaction show that NCI-H295 cells express both the 11 beta-hydroxylase (P450c11 beta) encoded by the P450c11B1 gene and the aldosterone synthetase (P450c11AS) encoded by the P450c11B2 gene. 8Br-cAMP increased the abundance of both of these mRNAs with similar kinetics, with maximal accumulation of both after about 24 h. NCI-H295 cells also contain the mRNAs for aromatase and insulin-like growth factor-II. 8Br-cAMP increased the abundance of aromatase mRNA and decreased the abundance of IGF-II mRNA. These studies show that NCI-H295 cells express most of the enzymes needed for human adrenal steroidogenesis, and that the genes encoding these enzymes respond to stimulation of second messenger pathways in a manner similar to that of human adrenals. NCI-H295 cells appear to be a good model for studying the molecular regulation of human adrenal steroidogenesis.
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PMID:Regulation of steroidogenesis in NCI-H295 cells: a cellular model of the human fetal adrenal. 838 59

The mRNA expressions of various growth regulatory molecules in single human anagen hair follicles were analysed by reverse transcription and polymerase chain reaction. Approximately 370 hair follicles were isolated from 20 normal individuals, and 0.90 +/- 0.34 microgram (mean +/- SD) total RNA was extracted per whole hair follicle. The mRNAs of fibroblast growth factor (FGF)-1, FGF-2, FGF-5, FGF-7, transforming growth factor (TGF)-alpha, TGF-beta 1, hepatocyte growth factor, insulin-like growth factor (IGF)-I, tumour suppressor gene p53 and high sulphur protein were detected in most or all of the examined hair follicles per target gene. In contrast, none of the mRNAs of FGF-3, FGF-4, FGF-6, FGF-9 and IGF-II was detected, and those of TGF-beta 2 and TGF-beta 3 were detected in only a limited number of the examined hair follicles. Among cyclin-dependent kinase inhibitors, the mRNAs of p21waf1/cip1 and p27kip1 were expressed in almost all the hair follicles, while those of p15INK4B and p16INK4A were not detected. These results suggest that both positive and negative factors for the proliferation and differentiation of follicular epithelial cells coexist in a human anagen hair follicle.
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PMID:Genes for a range of growth factors and cyclin-dependent kinase inhibitors are expressed by isolated human hair follicles. 941 26

Bone cells synthesize and respond to IGF-I and IGF-II which contribute to bone remodeling and linear growth. In osteoblasts, prostaglandin (PG)E2 stimulates IGF-I but not IGF-II synthesis through a cAMP-dependent protein kinase A (PKA)-related event. However, protein kinase C (PKC) activation by PGE2 enhances replication and protein synthesis by less differentiated periosteal cells more so than in osteoblast-enriched cultures from fetal rat bone. Using various PGs and other PKA and PKC pathway activators, the importance of these aspects of PGE2 activity has now been examined on IGF receptors in these bone cell culture models. PGE2 and other agents that activate PKA enhanced 125I-IGF-II binding to type 2 IGF receptors on both cell populations. In contrast, agents that activate PKC enhanced 125I-IGF-I binding to type 1 receptors on less differentiated bone cells, and of these, only phorbol myristate acetate (PMA), which activates PKC in a receptor-independent way, was effective in osteoblast-enriched cultures. No stimulator increased total type 1 receptor protein in either cell population. Consequently, ligand binding to type 1 and type 2 IGF receptors is differentially modulated by specific intracellular pathways in bone cells. Importantly, changes in apparent type 1 receptor number occur rapidly and may do so at least in part through post-translational effects. These results may help to predict new ways to manipulate autocrine or paracrine actions by IGFs in skeletal tissue.
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PMID:Alternate signaling pathways selectively regulate binding of insulin-like growth factor I and II on fetal rat bone cells. 949 8

Previous studies from this and other laboratories have shown that insulin-like growth factor-1 (IGF-I) and insulin-like growth factor-2 (IGF-II) support erythroid colony formation in cultures supplemented with serum substitute and recombinant erythropoietin. Subpopulations of IGF-I- and IGF-II-dependent, erythropoietin-independent colony-forming unit-erythroid (CFU-E)-derived colonies and BFU-E-derived colonies were identified under serum-substituted conditions for adult bone-marrow-derived erythroid progenitors which proliferate in the absence and presence of exogenous anti-erythropoietin receptor monoclonal antibody and in serum-substituted medium that was preadsorbed with anti-erythropoietin IgG. To assess whether Raf-1 is required for the formation of IGF-dependent, erythropoietin-independent human erythroid colonies, 5-15 microM sense or antisense oligomer to raf-1 were added to serum-substituted cultures containing either 2 U/ml recombinant human erythropoietin (rHuEpo) alone or 0-1,000 ng/ml IGF-I or IGF-II with/without 2 U/ml rHuEpo. Both erythropoietin-induced and IGF-induced erythroid colony formation were completely blocked by antisense (but not sense) oligomers to raf-1. Purified human CFU-Es were examined for Raf-1 message and protein. Total RNA was extracted, and raf-1 mRNA was detected on Northern blots. Furthermore, a 74 kD protein, corresponding to Raf-1, was also detected in CFU-Es purified from human adult sources. Together, these studies support the hypothesis that the Raf-1 protein mediates both erythropoietin-induced and IGF-induced signal transduction in human erythroid progenitor cells.
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PMID:The Raf-1 protein mediates insulin-like growth factor-induced proliferation of erythroid progenitor cells. 961 95

Insulin-like growth factor (IGF)-I and IGF-II are expressed at biologically effective levels by bone cells. Their stability and activity are modulated by coexpression of IGF binding proteins (IGFBPs). Secreted IGFBPs may partition to soluble, cell-associated, and matrix-bound compartments. Extracellular localization may sequester, store, or present IGFs to appropriate receptors. Of the six IGFBPs known, rat osteoblasts synthesize all but IGFBP-1. Of these, IGFBP-3, -4, and -5 mRNAs are induced by an increase in cAMP. Little is known about extracellular IGFBP localization in bone and nothing about IGFBP expression by nonosteoblastic periosteal bone cells. We compared basal IGFBP expression in periosteal and osteoblast bone cell cultures and assessed the effects of changes in cAMP-dependent protein kinase A or protein kinase C. Basal IGFBP gene expression differed principally in that more IGFBP-2 and -5 occurred in osteoblast cultures, and more IGFBP-3 and -6 occurred in periosteal cultures. An increase in cAMP enhanced IGFBP-3, -4, and -5 mRNAand accordingly increased soluble IGFBP-3, -4, and -5 and matrix-bound IGFBP-3 and -5 in both bone cell populations. In contrast, protein kinase C activators suppressed IGFBP-5 mRNA, and its basal protein levels remained very low. We also detected low Mr bands reactive with antisera to IGFBP-2, -3, and -5, suggesting proteolytic processing or degradation. Our studies reveal that various bone cell populations secrete and bind IGFBPs in selective ways. Importantly, inhibitory IGFBP-4 does not significantly accumulate in cell-associated compartments, even though its secretion is enhanced by cAMP. Because IGFBPs bind IGFs less tightly in cell-bound compartments, they may prolong anabolic effects by agents that increase bone cell cAMP.
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PMID:Insulin-like growth factor binding proteins localize to discrete cell culture compartments in periosteal and osteoblast cultures from fetal rat bone. 983 Oct 72


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