Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Both IGF-I and IGF-II peptides have been localized to specific brain regions. The distribution of IGF-I is homogeneous whereas IGF-II appears to be more local. Two species of IGF receptors are found in the CNS. The type II (m6P) is similar to that in the periphery, but the type I has nearly the same affinity for IGF-I and IGF-II. IGF-I has now been shown to provide cell growth and survival as well as stimulate neurite outgrowth. Dorsal root ganglia and sympathetic neurons are sensitive to IGF-II and the action may be additive with NGF. Cells other than neurites, such as oligodendrocytes respond to the IGFs as well as primary and transformed lines. The mechanism of action has not been resolved but IDG-II appears to act via G-protein coupled activation of protein kinase C. Interaction between various growth factors and the IGFs may be due to up or down-regulation of the receptor predicated by the non-homologous peptide.
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PMID:The effects of IGF-I and IGF-II on cell growth and differentiation in the central nervous system. 144 82

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

Phosphorylation of hormone receptors by protein kinase C (PKC) may be involved in the regulation of receptor recycling. We have studied the recycling and the phosphorylation state of the insulin growth factor (IGF) II/mannose 6-phosphate (Man-6-P) receptor in microvascular endothelial cells from rat adipose tissue. Scatchard analysis showed these cells have over 2 x 10(6) receptors/cell with an affinity constant of 1 x 10(9) M-1. In the presence of phorbol myristate acetate (PMA), an activator of PKC and analog of diacylglycerol, IGF-II receptor number increased in the plasma membrane by 60% without changes in the binding affinity. This increase in cell surface receptor number was confirmed by affinity cross-linking and 125I-surface labeling studies, occurred with a half-time of 20 min, and was reversible upon withdrawal of PMA. The redistribution of IGF-II/Man-6-P receptors was not due to an inhibition of internalization which was in fact stimulated by PMA. The effect of PMA on IGF-II receptor recycling correlated with its stimulation of PKC activity. Furthermore, after down-regulation of cellular PKC levels by preincubation with PMA, PMA was unable to activate residual PKC activity in the membranous pool or increase IGF-II receptor number at the cell surface. The phosphorylation state of the IGF-II/Man-6-P receptor was determined by 32P labeling of intact cells and immunoprecipitation with anti-receptor antibodies. In the basal state, the receptor was phosphorylated only on serine residues which was increased by 75% after treatment with PMA. In contrast, IGF-II decreased receptor phosphorylation and plasma membrane binding in a parallel and dose-dependent manner. Thus, PKC-stimulated serine phosphorylation of IGF-II/Man-6-P receptor may promote the translocation of the receptor to the cell surface, whereas IGF-II-stimulated dephosphorylation of the receptor may lead to a decrease in the number of cell surface receptors. These data suggest a role for PKC-mediated serine phosphorylation in the regulation of intracellular trafficking of receptors in endothelial cells.
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PMID:Modulation of the insulin growth factor II/mannose 6-phosphate receptor in microvascular endothelial cells by phorbol ester via protein kinase C. 216 43

Significant advances in our understanding of the regulation of fetal adrenal growth, differentiation, and steroidogenesis have been made in the past several years. In vitro studies employing molecular biological techniques have demonstrated that the placenta and several fetal tissues synthesize growth factors and/or oncogene-related products, which have the capacity to modulate growth and maturation of the fetal adrenal. Moreover, there is evidence that the fetal adrenal itself produces IGF-I and IGF-II and that the mRNAs for these growth factors are responsive to ACTH and perhaps other peptides originating in the fetal pituitary and/or the placenta. Most fascinating are the studies demonstrating that growth factors may also regulate the pattern of steroidogenesis elicited by the fetal adrenal. For example, TGF beta modulates binding, internalization, and degradation of LDL-cholesterol in adult adrenals while IGF-I increases fetal adrenal steroidogenesis by mechanisms that do not involve induction of P-450scc or enhanced metabolism of LDL. These studies, coupled with the observation that activation of protein kinase C by EGF or bFGF can block ACTH and/or other cAMP-induced increases in the activity of P-450(17 alpha), provide new insight into the subcellular mechanisms that underlie the regulation of fetal adrenal function. However, in vivo investigations must be aggressively pursued because the latter provide a major and perhaps exclusive means to elucidate the complex and multiple mechanisms that are apparently operative in utero in the regulation of fetal adrenal development. Moreover, in vivo studies remain the only valid means to delineate whether the factors that have been shown to modulate fetal adrenal function in vitro are indeed operable in vivo. Thus, in vivo investigations have shown that a multifactorial regulation of the fetal adrenal exists in utero in which PRL and perhaps other peptides as well as ACTH selectively stimulate fetal adrenal androgen production. Moreover, in vivo studies have demonstrated that a feedback mechanism operates in utero whereby estrogen produced in the placenta from androgen precursors of fetal adrenal origin feeds back to modulate the responsivity of the fetal adrenal to tropic peptides perhaps by regulating peptide binding to cell membrane receptors and/or other mechanisms. Evidence has also been provided from in vivo studies to support the concept that the placenta via metabolism of maternal cortisol and cortisone regulates fetal pituitary production of ACTH by modulating the extent to which maternal cortisol arrives at the fetus.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Regulation of the primate fetal adrenal cortex. 218 Jun 86

We have characterized a plasma membrane phosphatidylinositol 4,5-bisphosphate (PIP2)-specific phospholipase C (PLC) and a cytosolic phosphatidylinositol (PI)-specific PLC in human liver. Epinephrine, 1 x 10(-5) M, and vasopressin, 1 x 10(-8) M, stimulated PIP2-PLC which was enhanced by guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S). PI-PLC stimulation was not observed by these agents. Insulin and insulin-like growth factors (IGF-I and IGF-II) in the presence and absence of GTP gamma S did not stimulate PIP2-PLC or PI-PLC in plasma membranes and cytosol preparations nor phosphoinositide breakdown in isolated human hepatocytes. Furthermore, serendipitly we found that PIP2-PLC activity was increased in liver membranes from obese patients with type II diabetes when compared to obese and lean controls. We conclude that in human liver, insulin and IGFs are not members of the family of hormones generating inositol trisphosphate (IP3) as a second messenger. Furthermore, the increased PIP2-PLC in diabetic liver may result in: (a) increased intracellular concentrations of IP3 and thus increased Ca2+, which has been postulated to induce insulin resistance; and (b) increased diacylglycerol and thus increased protein kinase C which phosphorylates the insulin receptor at serine residues inactivating the insulin receptor kinase. While the mechanism of increased PIP2-PLC activity in diabetes is unknown, it may initiate a cascade of events that result in insulin resistance.
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PMID:Effect of insulin and insulin-like growth factors I and II on phosphatidylinositol and phosphatidylinositol 4,5-bisphosphate breakdown in liver from humans with and without type II diabetes. 254 Jan 78

The effects of insulin, the tumour promotor tetradecanoyl phorbol acetate (TPA), TSH and combinations of these factors on growth and DNA synthesis have been examined in the FRTL-5 cell strain and in sheep thyroid cells. In addition the regulation of the production by sheep thyroid cells of the insulin-like growth factors (IGF) by TSH and their possible autocrine roles have been investigated. We found that insulin and the IGF's stimulated DNA synthesis in both rat FRTL-5 cells and sheep cells. TPA also stimulated growth in both cell types, and its effects were additive to those of insulin. In the FRTL-5 cells, TPA was a less potent stimulator of growth than TSH, but the effects of TPA and TSH were not additive which may imply growth stimulation through a common pathway. In sheep cells TSH was not mitogenic and did not appear to activate protein kinase C, the receptor for TPA. Sheep cells, unlike FRTL-5 cells, were found to produce IGF-I and IGF-II, and their syntheses were regulated by TSH. Sheep cells were also found to produce IGF-binding proteins which may modulate the biologic effects of the IGF's. Sheep thyroid IGF binding proteins were found to copurify with urokinase-like plasminogen activator on immunoaffinity chromatography. The production of this serine protease has also been shown to be regulated by TSH.
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PMID:Role of non-TSH factors in thyroid cell growth. 347 6

Isolated sheep thyroid follicles release insulin-like growth factors (IGF)-I and -II together with IGF-binding proteins (IGFBPs). We previously showed that TSH suppresses the biosynthesis and release of IGFBPs in vitro which may increase the tissue availability of IGFs, allowing a synergy with TSH which potentiates both thyroid growth and function. Many of the actions of TSH on thyroid cell function are dependent upon activation of adenylate cyclase, although increased synthesis of inositol trisphosphate and activation of protein kinase C (PKC) have also been implicated. We have now examined whether probable changes in intracellular cyclic adenosine monophosphate (cAMP) or PKC are involved in TSH-mediated suppression of IGFBP release. Confluent primary cultures of ovine thyroid cells were maintained in serum-free Ham's modified F-12M medium containing transferrin, somatostatin and glycyl-histidyl-lysine (designated 3H), and further supplemented with sodium iodide (10(-8)-10(-3) mol/l), dibutyryl cAMP (0.25-1 mmol/l), forskolin (5-20 mumol/l) or 12-O-tetradecanoylphorbol-13-acetate (TPA; 10(-11)-10(-6) mol/l), with or without exposure to TSH (200 microU/ml). The uptake and organification of Na [125I] by cells was examined after test incubations of up to 48 h, and IGFBPs in conditioned media were analysed by ligand blot using 125I-labelled IGF-II. The PKC activity in the cytosol and plasma membrane fractions of cells was measured by phosphorylation of histone using [gamma-32P]ATP, and PKC immunoreactivity was visualized by Western immunoblot analysis. While dibutyryl cAMP or forskolin largely reproduced the stimulatory effect of TSH on iodine organification, they did not mimic the inhibitory effect of TSH on the secretion of IGFBPs of 43, 34, 28 and 19 kDa. Incubation with physiological or pharmacological concentrations of iodide (10(-6)-10(-3) mol/l) for up to 48 h significantly decreased TSH action on iodide uptake and organification but did not alter the inhibitory action of TSH on IGFBP release. Incubation of cells with 10(-11)-10(-6) mol TPA/l for 24 h inhibited the subsequent ability of TSH both to potentiate iodine organification and to suppress IGFBP release. In 3H medium, PKC activity was predominantly recovered from the membrane fraction but, following incubation for 48 h with TSH, the enzyme was no longer translocated to the membrane and was recovered predominantly from the cytosol.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Role of 3', 5' cyclic adenosine monophosphate and protein kinase C in the regulation of insulin-like growth factor-binding protein secretion by thyroid-stimulating hormone in isolated ovine thyroid cells. 751 34

The regulation of synthesis and phosphorylation of osteopontin in relation to avian epiphyseal growth-plate chondrocyte differentiation was studied in situ and in culture. Osteopontin gene expression was evaluated in the tibia growth-plate of 3-week-old chickens by in situ hybridization. The gene was expressed mainly at the lower hypertrophic zone where cartilage matrix is calcified and endochondral bone formation is initiated. Within the hypertrophic region, a poorly labeled area separated the layer of osteopontin-positive hypertrophic chondrocytes from those associated with endochondral bone formation. In culture, proliferative chondrocytes show no alkaline phosphatase activity in contrast to ascorbic acid-treated chondrocytes which display the enzyme activity. Chondrocytes not treated with ascorbic acid, exhibited lower levels of osteopontin mRNA than the treated cells. The phorbol ester TPA--an activator of protein kinase C--and to a lesser extent FGF but not EGF, stimulated osteopontin gene expression. Chondrocytes secreted low levels of phosphorylated osteopontin to the medium. EGF treatment resulted in the appearance of phosphorylated osteopontin in the medium, without affecting the synthesis of other proteins. FGF and TGF beta, but not IGF-I or IGF-II, also caused phosphorylation of osteopontin. Ascorbic acid-treated chondrocytes secreted higher levels of phosphorylated osteopontin than the non-treated cells, but addition of FGF or TPA did not stimulate osteopontin phosphorylation any further. Parathyroid hormone caused a dose-dependent attenuation of osteopontin phosphorylation and inhibited the EGF-dependent osteopontin phosphorylation. The results suggest that osteopontin gene expression and phosphorylation in chondrocytes are regulated by separate mechanisms. The response to the various controlling agents varies with the state of differentiation. Both processes--the synthesis and phosphorylation of osteopontin--are under the control of local growth factors which are involved in bone growth and calcification.
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PMID:Synthesis and phosphorylation of osteopontin by avian epiphyseal growth-plate chondrocytes as affected by differentiation. 765 84

The data presented in this chapter are summarized in the schematic shown in Figure 9. Insulin binds to and stimulates autophosphorylation of neuronal insulin receptors, whereas, IGF-I and IGF-II binds to and stimulate autophosphorylation of neuronal IGF-I receptors. IGF-II is also capable of binding to the insulin receptor. Whether or not it activates the insulin receptor kinase remains to be clarified. Activated insulin and IGF-I receptor kinases phosphorylate a 70-kDa protein at early times in culture. This protein may mediate some actions of insulin, but we speculate that there are other intermediary proteins involved in the transduction pathway resulting in the activation of S6 kinase and PKC epsilon. The stimulation of S6 kinase by insulin and IGF-I may be associated with the translational activation of protein synthesis by these peptides. The stimulation of PKC epsilon appears to be a necessary step in the transcriptional regulation of the c-fos gene by insulin and IGF-I. The regulation of neuronal protein synthesis at a translational step and the initiation of transcriptional programs regulated by AP-1 represent two mechanisms by which insulin and IGFs alter neuronal growth and differentiation.
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PMID:Insulin and IGF-I receptor signaling in cultured neurons. 821 46

Treatment of normal primary human keratinocytes with phorbol 12-myristate 13-acetate (PMA) or phorbol 12-13 dibutyrate (PDBu) (100 ng/ml, 6-40 h) followed by two-dimensional (2-D) gel electrophoresis (isoelectric focusing) and microsequencing identified three polypeptides (phorbolin 1, M(r) = 19.9 kDa; phorbolin 2, M(r) = 19.7 kDa; and interleukin-1 (IL-1) receptor antagonist, IL-1ra, M(r) = 19.5 kDa) that are upregulated eight times or more by the phorbol esters and that are highly expressed in noncultured psoriatic keratinocytes. The response was not elicited by other effectors tested including second messengers (Bt2cAMP, Bt2cGMP), cytokines (basic fibroblast growth factor, transforming growth factor-alpha, IGF-II, tumor necrosis factor-alpha, and -beta, interleukin (IL)-1 alpha, IL-1 beta, IL-2, IL-3, IL-6, IL-7, IL-8, interferon-alpha, and -gamma), and other substances (Ca++, dexametasone, retinoic acid, lipopolysaccharides) and it was partially reversed by staurosporine, a strong inhibitor of protein kinase C. The results are taken to imply that the protein kinase C signaling pathway may be altered in psoriatic keratinocytes.
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PMID:Evidence for an altered protein kinase C (PKC) signaling pathway in psoriasis. 840 24


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