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)

The type V transforming growth factor beta (TGF-beta) receptor (TbetaR-V) is a ligand-stimulated acidotropic Ser-specific protein kinase that recognizes a motif of SXE/S(P)/D. This motif is present in the cytoplasmic domain of the mannose 6-phosphate/insulin-like growth factor-II (Man-6-P/IGF-II) receptor. We have explored the possibility that the Man-6-P/IGF-II receptor is a substrate of TbetaR-V. Purified bovine Man-6-P/IGF-II receptor was phosphorylated by purified bovine TbetaR-V in the presence of [gamma-32P]ATP and MnCl2 with an apparent Km of 130 nM. TGF-beta stimulated the phosphorylation of the Man-6-P/IGF-II receptor at 0 degrees C in mouse L cells overexpressing the Man-6-P/IGF-II receptor and in wild-type mink lung epithelial (Mv1Lu cells) metabolically labeled with [32P]orthophosphate. The in vitro and in vivo phosphorylation of the Man-6-P/IGF-II receptor occurred at the putative phosphorylation sites as revealed by phosphopeptide mapping and amino acid sequence analysis. TGF-beta stimulated Man-6-P/IGF-II receptor-mediated uptake (approximately 2-fold after 12 h treatment) of exogenous beta-glucuronidase in Mv1Lu cells and type II TGF-beta receptor (TbetaR-II)-defective mutant cells (DR26 cells) but not in type I TGF-beta receptor (TbetaR-I)-defective mutant cells (R-1B cells) and human colorectal carcinoma cells (RII-37 cells) expressing TbetaR-I and TbetaR-II but lacking TbetaR-V. These results suggest the Man-6-P/IGF-II receptor serves as an in vitro and in vivo substrate of TbetaR-V and that both TbetaR-V and TbetaR-I may play a role in mediating the TGF-beta-stimulated uptake of exogenous beta-glucuronidase.
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PMID:The mannose 6-phosphate/insulin-like growth factor-II receptor is a substrate of type V transforming growth factor-beta receptor. 1039 50

The expression of the neuropeptide Y (NPY) gene varies considerably in human pheochromocytomas, but the mechanisms for this variation have not been clarified. To investigate the regulation pattern of the NPY gene in human pheochromocytomas, we screened 16 pheochromocytomas and 9 normal adrenal tissues with Northern blots. The expression level of NPY mRNA in normal adrenal medulla was low and relatively constant, while the pheochromocytomas showed a very wide variation in NPY mRNA levels in both malignant and benign tumors. This indicates that NPY gene expression is not correlated with malignancy in pheochromocytomas. In primary cultures of human pheochromocytoma cells, nerve growth factor treatment (causing neuronal differentiation) increased NPY mRNA accumulation 2- to 5-fold (P < 0.05). NPY mRNA levels were also induced by protein kinase modulators (Bu)(2)cAMP and staurosporine in the cultures (P < 0.05). In contrast, treatment with dexamethasone and IGF-II (causing or linked with chromaffin differentiation) reduced NPY mRNA accumulation (P < 0.05). These data show that the regulation pattern of NPY mRNA expression in cultured human pheochromocytoma cells is different from that previously described in rat pheochromocytoma PC12 cells. Regulation of NPY mRNA expression in primary cultures by these differentiating factors suggests that the expression of NPY mRNA in pheochromocytoma tissues may be associated with the neuronal differentiation of the tumor cells affected by multiple factors.
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PMID:Regulation of neuropeptide Y mRNA expression in cultured human pheochromocytoma cells. 1052 60

Maternal loss of heterozygosity (LOH) of the 11p15 region and overexpression of the insulin-like growth factor (IGF)-II gene are associated with the malignant phenotype in sporadic adrenocortical tumors. In the imprinted 11p15 region, the p57KIP2 gene is maternally expressed and encodes a cyclin-dependent kinase (CDK) inhibitor involved in G1/S phase of the cell cycle. We hypothesized that maternal LOH in malignant adrenocortical tumors could be responsible for loss of p57KIP2 gene expression and, thus, could favor progression through the cell cycle. We investigated 3 normal adrenals, 31 adrenocortical tumors [11 tumors with normal expression of the IGF-II gene (mainly benign) and 20 with IGF-II gene overexpression (mainly malignant)], and the human adrenocortical tumor cell line NCI H295R for expression of the p57KIP2 gene, G1 cyclins (cyclin D2 and E) and G1 CDK (CDK2, CDK3 and CDK4) protein contents and for kinase activity of G1 cyclin-CDK complexes. The expression of p57KIP2, G1 cyclins, and G1 CDKs in benign tumors was similar to that in normal adrenal tissues, as were kinase activities of G1 cyclin-CDK complexes. By contrast, abrogation of the p57KIP2 gene expression and increased expression of G1 cyclins (cyclin E) and G1 CDKs (CDK2 and CDK4) were associated with high activity of G1 cyclin-CDK complexes in malignant tumors and in the H295R cell line. These data suggest that the p57KIP2 gene might act as a tumor suppressor gene in adrenocortical tumors. Maternal LOH with duplication of the paternal allele or pathological functional imprinting of the 11p15 region are responsible for loss of expression of the p57KIP2 gene and increased expression of the IGF-II gene. Consequently, both events favor cell proliferation in malignant adrenocortical tumors.
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PMID:High expression of cyclin E and G1 CDK and loss of function of p57KIP2 are involved in proliferation of malignant sporadic adrenocortical tumors. 1063 6

Insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) is known to be secreted as a phosphoprotein, constitutively phosphorylated at casein kinase 2 (CK2) sites. To examine the effect of phosphorylation by CK2 on the properties of glycosylated human IGFBP-3, we phosphorylated plasma-derived IGFBP-3, containing less than 1 mol/mol phosphoserine, in vitro. As judged by incorporated 32P, enzymatic deglycosylation did not decrease the phosphate content of phospho-IGFBP-3. Phosphorylation had no effect on IGF-I or IGF-II binding, but was inhibitory to acid-labile subunit binding in the presence of either IGF. Determined in simian virus 40-transformed human fibroblasts, cell association by phospho-IGFBP-3 was inhibited approximately 50% compared with that of the nonphosphorylated preparation. Phospho-IGFBP-3 showed significant resistance to proteolysis by plasmin and a cysteine protease secreted by MCF-7 cells. However, no difference was seen between the two preparations in their inhibition of IGF-I-stimulated DNA synthesis when coincubated with IGF-I in neonatal skin fibroblasts or MCF-7 breast cancer cells, and little difference was found in their ability to potentiate IGF-I-stimulated DNA synthesis when preincubated with fibroblasts. These results indicate that IGFBP-3 interaction with acid-labile subunit and with the cell surface, both of which involve basic carboxyl-terminal residues, may be modulated by phosphorylation. Relative resistance to proteolysis and poor binding to cells suggest that CK2-phospho-IGFBP-3 may be a significant inhibitor of IGF activity in the extracellular environment.
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PMID:The effect of phosphorylation by casein kinase 2 on the activity of insulin-like growth factor-binding protein-3. 1065 Sep 37

The insulin-like growth factor (IGF)-binding proteins (IGFBPs) are a family of six homologous proteins with high binding affinity for IGF-I and IGF-II. Information from NMR and mutagenesis studies is advancing knowledge of the key residues involved in these interactions. IGF binding may be modulated by IGFBP modifications, such as phosphorylation and proteolysis, and by cell or matrix association of the IGFBPs. All six IGFBPs have been shown to inhibit IGF action, but stimulatory effects have also been established for IGFBP-1, -3, and -5. These generally involve a decrease in IGFBP affinity and may require cell association of the IGFBP, but precise mechanisms are unknown. The same three IGFBPs have well established effects that are independent of type I IGF receptor signaling. IGFBP-1 exerts these effects by signaling through alpha(5)beta(1)-integrin, whereas IGFBP-3 and -5 may have specific cell-surface receptors with serine kinase activity. The regulation of cell sensitivity to inhibitory IGFBP signaling may play a role in the growth control of malignant cells.
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PMID:Insulin-like growth factor (IGF)-binding proteins: interactions with IGFs and intrinsic bioactivities. 1082 97

Insulin-like growth factor (IGF) binding protein-1 (IGFBP-1) is a 28-kDa plasma protein that binds to IGF-I and IGF-II with high affinity. IGFBP-1 is elevated in the blood as a result of sepsis, AIDS, excessive alcohol consumption, and diabetes and may, in part, be responsible for the wasting observed during these pathophysiological conditions. The liver is the principal site of IGFBP-1 synthesis, and we have previously shown that proinflammatory cytokines can directly stimulate IGFBP-1 secretion in a human hepatoma cell line (HepG2). The purpose of the present study was to investigate the role of the MAP kinase pathway in regulating IGFBP-1 synthesis by IL-1beta. We show that IL-1beta stimulates the phosphorylation of ERK-1 and -2 in a time- and dose-dependent manner. In addition, the MAP kinase-kinase MEK-1 and the ribosomal S6-kinase RSK-1 are also phosphorylated in response to IL-1beta. The transcription factor CREB, a potential substrate of both protein kinase A (PKA) and RSK-1, is phosphorylated in response to IL-1beta and cAMP in HepG2 cells. The ability of IL-1beta to stimulate the expression of IGFBP-1 and the phosphorylation of the above kinases was specifically inhibited by PD98059, a MEK-1 inhibitor. cAMP also stimulated IGFBP-1 synthesis, but PD98059 failed to block the cAMP effect. Conversely, a PKA inhibitor (H-89) inhibited the ability of cAMP, but not IL-1beta to stimulate IGFBP-1 synthesis. The effect of IL-1beta and cAMP on IGFBP-1 messenger RNA (mRNA) accumulation was additive. IL-1beta, cAMP, PD98059, and H-89 had similar effects on the accumulation of IGFBP-1 protein and mRNA. IL-1beta and cAMP did not change the half-life of IGFBP-1 mRNA, but PD98059 and SB202190, a p38 MAP kinase inhibitor, destabilized IGFBP-1 mRNA and blocked the phosphorylation of RSK-1 in response to IL-1beta. Our data demonstrate that the MAP kinase signal transduction pathway plays an important role in the regulation of IGFBP-1 synthesis by IL-1beta.
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PMID:Stimulation of insulin-like growth factor binding protein-1 synthesis by interleukin-1beta: requirement of the mitogen-activated protein kinase pathway. 1096 86

Results of the present study demonstrate that activation of the adenylyl cyclase/protein kinase A (PKA) pathway leads to increased levels of insulin-like growth factor I (IGF-I) in cultured embryonic mouse mandibular mesenchymal cells. Treatment of serum-free cultures with 10(-8) M 8-OH-DPAT (DPAT) or with 10(-5) M forskolin in the presence of the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX; 10(-5) M) increased levels of IGF-I (but not IGF-II), as measured by [(125)I]protein A immunobinding. In a previous study, we showed that DPAT, forskolin, IBMX and the 5-HT(4) receptor agonist SC53116 all increased the synthesis of cyclic adenosine monophosphate (cAMP) in these cultures. Taken together, these results provide evidence that stimulation of the adenylyl cyclase/PKA pathway in embryonic mandibular mesenchymal cells positively regulates IGF-I. This is supported by the ability of the PKA inhibitor Rp-cAMPS to block increases in IGF-I caused by both DPAT and forskolin. Consistent with these results, DPAT and forskolin increased phosphorylation of the cAMP response element binding protein (CREB), which was also blocked by Rp-cAMPS. These results suggest that activation of 5-HT receptors positively coupled to the adenylyl cyclase/PKA pathway may promote transcription of IGF-I through a cAMP response element (CRE) in the IGF-I promoter. This may represent one mechanism whereby 5-HT positively regulates IGF-I expression in developing craniofacial mesenchymal cells.
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PMID:Activation of 5-HT receptors that stimulate the adenylyl cyclase pathway positively regulates IGF-I in cultured craniofacial mesenchymal cells. 1117 28

The aim of our in vitro experiments was to study the role of growth factors and protein kinase A (PKA)-dependent intracellular mechanisms in the control of nuclear maturation of porcine oocytes. Oocytes were cultured with or without growth factors (IGF-I, IGF-II, EGF; 10 ng x mL(-1) medium) and inhibitors of PKA (Rp-cAMPS or KT5720; 100 ng x mL(-1)). Stages of meiosis were determined from the structure of chromosomes after staining with Giemza. Intracellular levels of PKA were evaluated immunocytochemically using primary antisera against the PKA regulatory and catalytic subunits and by Western immunoblotting using primary antiserum against the PKA catalytic subunit. It was found that after 24 h culture the majority of oocytes had resumed nuclear maturation (they were at a stage of meiosis after diplotene) and that after 48 h culture the majority of cells had completed maturation (they had reached metaphase II of meiosis). Addition of IGF-I, IGF-II or EGF, or a combination of IGF-I and EGF, significantly increased the proportion of oocytes which resumed and completed meiosis. Immunocytochemistry demonstrated a significant increase in the proportion of cells containing catalytic and, in some cases, the regulatory subunits of PKA after addition of IGF-I, IGF-II and EGF. Immunoblotting showed the presence of 2 forms of the PKA catalytic subunit within the oocytes (MW approximately 52 and 40 kD). EGF, but not IGF-I or IGF-II, increased the content of both isoforms. Inhibitors of PKA, when given alone, did not substantially influence the proportion of oocytes which resumed or completed meiosis. However, Rp-cAMPS and KT5720 both prevented the stimulatory effects of IGF-I, IGF-II and EGF on the resumption and completion of oocyte maturation. The present observations suggest (1) that IGF-I, IGF-II and EGF are potent stimulators of both resumption and completion of porcine oocyte nuclear maturation, (2) that PKA is present in oocytes, and (3) that PKA-dependent intracellular mechanisms can mediate the action of growth factors on porcine oocytes.
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PMID:Evidence that growth factors IGF-I, IGF-II and EGF can stimulate nuclear maturation of porcine oocytes via intracellular protein kinase A. 1128 85

Insulin-like growth factor (IGF)-stimulated lung fibroblast proliferation may be regulated by locally produced IGF-binding proteins (IGFBPs) during lung development. Recent evidence has shown that many growth factors participate in the regulation of cell proliferation by regulating IGFBPs. Because platelet-derived growth factor-BB (PDGF-BB) is highly expressed during lung development and is known to regulate IGFBP-4 production by lung cells, we examined the mechanisms by which PDGF-BB regulates ICFBP-4 production using primary cultures of 19-day gestation rat lung fibroblasts. Exposure of fetal rat lung fibroblasts to PDGF-BB increased IGFBP-4 mRNA transcript abundance by 3.6- and 2.4-fold at 18 and 40 hours, respectively. Addition of Rp-adenosine-3'-5'-cyclic monophosphothioate triethylamine (rp-cAMPS), a competitive inhibitor of protein kinase A, blunted the PDGF-BB-stimulated increase in conditioned medium (CM) IGFBP-4 and the increase in IGFBP-4 mRNA. Proteolysis of IGFBP-4 was detected in aliquots of cell-free CM from cells exposed to SFM for 48 hours. IGFBP-4 proteolysis was inhibited by EDTA and 1,10-phenanthroline and was accentuated by the addition of IGF-I and IGF-II and, to a lesser extent, by des(1-3)IGF-I. Exposure of cells to PDGF-BB for 48 hours resulted in an inhibition of IGFBP-4 proteolysis that was associated with a decrease in the concentration of IGF-I in CM. These studies demonstrate that PDGF-BB increases the accumulation of ICFBP-4 in fetal rat lung fibroblasts CM through increased production and by inhibiting IGF-mediated IGFBP-4 proteolysis.
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PMID:PDGF-BB regulates IGF-mediated IGFBP-4 proteolysis in fetal lung fibroblasts. 1176 17

Inflammatory bladder disorders such as interstitial cystitis (IC) deserve attention since a major problem of the disease is diagnosis. IC affects millions of women and is characterized by severe pain, increased frequency of micturition, and chronic inflammation. Characterizing the molecular fingerprint (gene profile) of IC will help elucidate the mechanisms involved and suggest further approaches for therapeutic intervention. Therefore, in the present study we used established animal models of cystitis to determine the time course of bladder inflammatory responses to antigen, Escherichia coli lipopolysaccharide (LPS), and substance P (SP) by morphological analysis and cDNA microarrays. The specific aim of the present study was to compare bladder inflammatory responses to antigen, LPS, and SP by morphological analysis and cDNA microarray profiling to determine whether bladder responses to inflammation elicit a specific universal gene expression response regardless of the stimulating agent. During acute bladder inflammation, there was a predominant infiltrate of polymorphonuclear neutrophils into the bladder. Time-course studies identified early, intermediate, and late genes that were commonly up-regulated by all three stimuli. These genes included: phosphodiesterase 1C, cAMP-dependent protein kinase, iNOS, beta-NGF, proenkephalin B and orphanin, corticotrophin-releasing factor (CRF) R, estrogen R, PAI2, and protease inhibitor 17, NFkB p105, c-fos, fos-B, basic transcription factors, and cytoskeleton and motility proteins. Another cluster indicated genes that were commonly down-regulated by all three stimuli and included HSF2, NF-kappa B p65, ICE, IGF-II and FGF-7, MMP2, MMP14, and presenilin 2. Furthermore, we determined gene profiles that identify the transition between acute and chronic inflammation. During chronic inflammation, the urinary bladder presented a predominance of monocyte/macrophage infiltrate and a concomitant increase in the expression of the following genes: 5-HT 1c, 5-HTR7, beta 2 adrenergic receptor, c-Fgr, collagen 10 alpha 1, mast cell factor, melanocyte-specific gene 2, neural cell adhesion molecule 2, potassium inwardly-rectifying channel, prostaglandin F receptor, and RXR-beta cis-11-retinoic acid receptor. We conclude that microarray analysis of genes expressed in the bladder during experimental inflammation may be predictive of outcome. Further characterization of the inflammation-induced gene expression profiles obtained here may identify novel biomarkers and shed light into the etiology of cystitis.
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PMID:Gene expression profiling of mouse bladder inflammatory responses to LPS, substance P, and antigen-stimulation. 1205 14


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