Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pleckstrin homology (PH) domains are 90-110 amino acid regions of protein sequence homology that are found in a variety of proteins involved in signal transduction and growth control. We have previously reported that the PH domains of several proteins, including beta ARK1, PLC gamma, IRS-1, Ras-GRF, and Ras-GAP, expressed as glutathione S-transferase fusion proteins, can reversibly bind purified bovine brain G beta gamma subunits in vitro with varying affinity. To determine whether PH domain peptides would behave as antagonists of G beta gamma subunit-mediated signal transduction in intact cells, plasmid minigene constructs encoding these PH domains were prepared, which permit transient cellular expression of the peptides. Pertussis toxin-sensitive, G beta gamma subunit-mediated inositol phosphate (IP) production was significantly inhibited in COS-7 cells transiently coexpressing the alpha 2-C10 adrenergic receptor (AR) and each of the PH domain peptides. Pertussis toxin-insensitive, Gq alpha subunit-mediated IP production via coexpressed M1 muscarinic acetylcholine receptor (M1 AChR) was attenuated only by the PLC gamma PH domain peptide, suggesting that the inhibitory effect of most of the PH domain peptides was G beta gamma subunit-specific. Stimulation of the mitogen-activated protein (MAP) kinase pathway by Gi-coupled receptors in COS-7 cells has been reported to require activation of p21ras and to be independent of protein kinase C. Since several proteins involved in activation contain PH domains, the effect of PH domain peptide expression on alpha 2-C10 AR-mediated p21ras-GTP exchange and MAP kinase activation as well as direct G beta gamma subunit-mediated activation of MAP kinase was determined. In each assay, coexpression of the PH domain peptides resulted in significant inhibition. Increasing G beta gamma subunit expression surmounted PH domain peptide-mediated inhibition of MAP kinase activation. These data suggest that the PH domain peptides behave as specific antagonists of G beta gamma-mediated signaling in intact cells and that interactions between PH domains and G beta gamma subunits or structurally related proteins may play a role in the activation of mitogenic signaling pathways by G protein-coupled receptors.
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PMID:Effect of cellular expression of pleckstrin homology domains on Gi-coupled receptor signaling. 776 89

The insulin receptor mediates a variety of cellular responses to insulin, including glucose transport, endocytosis, and cell proliferation. The role of the insulin receptor in mediating cellular motility has not, however, been extensively investigated. In this report, we demonstrate that chinese hamster ovary (CHO) cells that normally have low concentrations of insulin receptor display chemotaxis toward insulin after overexpression of the wild type human insulin receptor. Chemotaxis toward insulin proceeded through a pertussis toxin-sensitive pathway and required both tyrosine kinase activity and tyrosine autophosphorylation of the regulatory region of the beta-subunit. In contrast, the autophosphorylation sites in the carboxyl terminus of the receptor were not required for chemotactic activity. A mutation in the juxtamembrane region, which disabled tyrosine phosphorylation of the insulin receptor substrate-1 (IRS-1), also prevented the chemotactic response, suggesting a possible role for IRS-1 in chemotactic signaling. In the absence of insulin receptor, however, the presence of excess transfected IRS-1 was not sufficient to mediate chemotaxis toward insulin. These results demonstrate that the intact insulin receptor can stimulate a chemotactic signaling pathway and that this initial pathway more closely correlates with that for insulin-stimulated cell proliferation than for insulin-stimulated receptor endocytosis.
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PMID:Functional domains of the insulin receptor responsible for chemotactic signaling. 827 80

We have previously reported that pertussis toxin (PTX)-sensitive GTP binding protein (G-protein) and phosphatidylinositol 3-kinase (PI 3-K) are involved in adipocyte differentiation of 3T3-L1 cells induced by insulin/dexamethasone/methylisobutyl xanthine. The aim of this study was to examine the effect of PTX on the tyrosine kinase cascade stimulated by insulin acting through insulin-like growth factor-I (IGF-I) receptors in undifferentiated 3T3-L1 cells. A high level of mitogen-activated protein kinase (MAPK) activation was sustained for up to 4 h after insulin treatment, and mobility shifted and tyrosine phosphorylated MAPK was also detected. MAPK kinase activity measured by the incorporation of 32P into kinase-negative recombinant MAPK was enhanced by insulin treatment. We previously discovered that insulin activates Ras and that this is mediated by wortmannin-sensitive PI 3-K. Tyrosine-phosphorylation of IRS-1 and Shc also occurred in response to insulin. Subsequently, we investigated the effects of PTX on the activation of these proteins by insulin. Interestingly, treating 3T3-L1 cells with PTX attenuates the activation by insulin of both the Ras-MAPK cascade and PI 3-K. In contrast, neither tyrosine-phosphorylation of IRS-1 and Shc nor the interaction between IRS-1 and PI 3-K is sensitive to PTX. However, activation of the Ras-MAPK cascade and tyrosine-phosphorylation of Shc by epidermal growth factor are insensitive to PTX. These results indicate that there is another pathway which regulates PI 3-K and Ras-MAPK, independent of the pathway mediated by IGF-I receptor kinase. These findings suggest that in 3T3-L1 fibroblasts, PTX-sensitive G-proteins cross-talk with the Ras-MAPK pathway via PI 3-K by insulin acting via IGF-I receptors.
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PMID:Pertussis toxin-sensitive and insensitive intracellular signalling pathways in undifferentiated 3T3-L1 cells stimulated by insulin converge with phosphatidylinositol 3-kinase upstream of the Ras mitogen-activated protein kinase cascade. 1009 67

The present study demonstrates negative intracellular cross-talk between angiotensin II type 2 (AT2) and insulin receptors. AT2 receptor stimulation leads to inhibition of insulin-induced extracellular signal-regulated protein kinase (ERK2) activity and cell proliferation in transfected Chinese hamster ovary (CHO-hAT2) cells. We show that AT2 receptor interferes at the initial step of insulin signaling cascade, by impairing tyrosine phosphorylation of the insulin receptor (IR) beta-chain. AT2-mediated inhibition of IR phosphorylation is insensitive to pertussis toxin and is also detected in neuroblastoma N1E-115 and pancreatic acinar AR42J cells that express endogenous receptors. We present evidence that AT2 receptor inhibits the autophosphorylating tyrosine kinase activity of IR, with no significant effect on insulin binding properties. AT2-mediated inactivation of IR does not mainly involve tyrosine dephosphorylation by vanadate-sensitive tyrosine phosphatases nor serine/threonine phosphorylation by protein kinase C. As a consequence of IR inactivation, AT2 receptor inhibits tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and signal-regulatory protein (SIRPalpha1) and prevents subsequent association of both IRS-1 and SIRPalpha1 with Src homology 2 (SH2)-containing tyrosine phosphatase SHP-2. Our results thus demonstrate functional trans-inactivation of IR kinase by G protein-coupled AT2 receptor, illustrating a novel mode of negative communication between two families of membrane receptors.
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PMID:Functional trans-inactivation of insulin receptor kinase by growth-inhibitory angiotensin II AT2 receptor. 1084 82

Isolated rat pancreatic islets were incubated at 3.3 (low) and 16.7 (high) mM glucose with different concentrations of the phosphotyrosine phosphatase (PTP) inhibitor, peroxovanadate (pV). At low glucose, pV stimulated insulin secretion 2- to 4-fold, but it inhibited insulin secretion at 16.7 mM. The latter effect was not due to an inhibition of glucose metabolism, nor was it inhibited by pertussis toxin pretreatment. In addition, pV stimulated insulin secretion approximately 3-fold in depolarized cells at both low and high glucose. pV markedly increased the tyrosine phosphorylation of several proteins, including IRS-1 and -2, and also increased the phosphorylation of the downstream kinases PKB/Akt and MAPK. PKB/Akt, but not MAPK, was also phosphorylated in the absence of pV. Intracellular pV-stimulated tyrosine phosphorylation, including that of IRS-2, was generally increased by high glucose suggesting a further inhibition of PTP and/or enhanced tyrosine kinase activity. Thus, these data suggest that intracellular tyrosine and serine (PKB/Akt) phosphorylation are related to insulin secretion but they do not support a unique and direct link between IRS-2 tyrosine phosphorylation and glucose-stimulated insulin secretion.
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PMID:Effects of phosphotyrosine phosphatase inhibition on insulin secretion and intracellular signaling events in rat pancreatic islets. 1116 49

Suppression of the expression of the heterotrimeric G-protein Galpha(i2) in vivo has been shown to provoke insulin resistance, whereas enhanced insulin signaling is observed when Galpha(i2) is overexpressed in vivo. The basis for Galpha(i2) regulation of insulin signaling was explored in transgenic mice with targeted expression of the GTPase-deficient, constitutively active Q205L Galpha(i2) in fat and skeletal muscle. Phosphorylation of insulin receptor and IRS-1 in response to insulin challenge in vivo was markedly amplified in fat and skeletal muscle expressing Q205L Galpha(i2). The expression and activity of the protein-tyrosine phosphatase 1B (PTP1B), but not protein-tyrosine phosphatases SHP-1, SHP-2, and LAR, were constitutively decreased in tissues expressing the Q205L Galpha(i2), providing a direct linkage between insulin signaling and Galpha(i2). The loss of PTP1B expression may explain, in part, the loss of PTP1B activity in the iQ205L transgenic mice. Activation of Galpha(i2) in mouse adipocytes with lysophosphatidic acid was shown to decrease PTP1B activity, whereas pertussis toxin inactivates Galpha(i2), blocks lysophosphatidic acid-stimulated inhibition of PTP1B activity, and blocks tonic suppression of PTP1B activity by Galpha(i2). Elevation of intracellular cAMP in fat cells is shown to increase PTP1B activity, whereas either depression of cAMP levels or direct activation of Galpha(i2) suppresses PTP1B. These data provide the first molecular basis for the interplay between Galpha(i2) and insulin signaling, i.e. activation of Galpha(i2) can suppress both the expression and activity of PTP1B in insulin-sensitive tissues.
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PMID:Galpha(i2) enhances insulin signaling via suppression of protein-tyrosine phosphatase 1B. 1150 May 6

Insulin-like growth factor binding protein-3 (IGFBP-3) is the most abundant IGFBP in serum and other biological fluids. Apart from its capacity for specific and high-affinity binding to IGFs, it also has so-called "IGF-independent" activities that modulate cell proliferation and survival/apoptosis. However, the molecular elements of the IGFBP-3 signalling pathway remain obscure. In this study, we investigated the possible implication of phosphatidylinositol 3-kinase (PI 3-kinase) activity in MCF-7 breast carcinoma cells. In cells incubated with IGFBP-3, both total and insulin receptor substrate-1 (IRS-1)-associated PI 3-kinase activities were rapidly stimulated, with maximal effects after 3 and 10min of incubation, respectively. IGFBP-3-induced PI 3-kinase activity was unaffected by the state of IRS-1 tyrosine phosphorylation. Since IGFBP-3 failed to stimulate PI 3-kinase activity in MDA-MB 231 breast carcinoma cells, its effects in MCF-7 cells could be considered as cell-type-specific. Pertussis toxin abolished IGFBP-3-stimulation of PI 3-kinase activity, suggesting that this IGFBP-3 signalling pathway depends upon a pertussis toxin-sensitive G protein. Our results provide further evidence that IGFBP-3 directly triggers a specific intracellular signal in MCF-7 cells.
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PMID:Insulin-like growth factor binding protein-3 stimulates phosphatidylinositol 3-kinase in MCF-7 breast carcinoma cells. 1475 Dec 38

Melatonin is the pineal hormone that acts via a pertussis toxin-sensitive G-protein to inhibit adenylate cyclase. However, the intracellular signalling effects of melatonin are not completely understood. Melatonin receptors are mainly present in the suprachiasmatic nucleus (SCN) and pars tuberalis of both humans and rats. The SCN directly controls, amongst other mechanisms, the circadian rhythm of plasma glucose concentration. In this study, using immunoprecipitation and immunoblotting, we show that melatonin induces rapid tyrosine phosphorylation and activation of the insulin receptor beta-subunit tyrosine kinase (IR) in the rat hypothalamic suprachiasmatic region. Upon IR activation, tyrosine phosphorylation of IRS-1 was detected. In addition, melatonin induced IRS-1/PI3-kinase and IRS-1/SHP-2 associations and downstream AKT serine phosphorylation and MAPK (mitogen-activated protein kinase) phosphorylation, respectively. These results not only indicate a new signal transduction pathway for melatonin, but also a potential cross-talk between melatonin and insulin.
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PMID:In vivo activation of insulin receptor tyrosine kinase by melatonin in the rat hypothalamus. 1525 33

Since inhibition of protein tyrosine phosphatase (PTPase) activity by peroxovanadate (pV) affects insulin release and phosphorylation of pancreatic islet proteins in the insulin signaling pathway, we studied whether pV also modulates glucagon release. At 3.3mM glucose, pV (0.1-1mM) enhanced glucagon release in a dose-dependent manner in islets of normal Wistar and diabetic GK rats. Arginine-stimulated glucagon responses were higher in GK than in Wistar islets. These responses were inhibited by pV (0.01-0.1mM), also after islet exposure to pertussis toxin (PTX), but were abolished by 1 microM wortmannin. Moreover, in GK but not Wistar islets, wortmannin significantly stimulated basal glucagon secretion (p<0.05) and inhibited arginine-induced glucagon secretion (p<0.001). In In-R1-G9 glucagonoma cells, the inhibitory effect of pV (0.01 mM) on glucagon response to arginine was also observed and paralleled by increased IRS-1 and IRS-2 associated PI3-kinase activity. In conclusion, inhibition of PTPase activity by pV stimulates basal and inhibits arginine-induced glucagon release. The inhibitory effect of 0.01-0.1mM pV seems not to be accounted for by islet peptides acting on PTX sensitive G(i)-proteins. PI3-kinase activity seems to play an important role in pV-induced inhibition of glucagon release.
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PMID:Glucagon release is regulated by tyrosine phosphatase and PI3-kinase activity. 1553 Apr 28

Lysophosphatidic acid (LPA) is known to have diverse cellular effects, but although LPA is present in many biological fluids, including blood, its effects on glucose metabolism have not been elucidated. In this study, we investigated whether LPA stimulation is related to glucose regulation. LPA was found to enhance glucose uptake in a dose-dependent manner both in L6 GLUT4myc myotubes and 3T3-L1 adipocytes by triggering GLUT4 translocation to the plasma membrane. Moreover, the effect of LPA on glucose uptake was completely inhibited by pretreating both cells with LPA receptor antagonist Ki16425 and Gi inhibitor pertussis toxin. In addition, LPA increased the phosphorylation of AKT-1 with no effects on IRS-1, and LPA-induced glucose uptake was abrogated by pretreatment with the PI 3-kinase inhibitor LY294002. When low concentration of insulin and LPA were treated simultaneously, an additive effect on glucose uptake was observed in both cell types. In line with its cellular functions, LPA significantly lowered blood glucose levels in normal mice but did not affect insulin secretion. LPA also had a glucose-lowering effect in streptozotocin-treated type 1 diabetic mice. In combination, these results suggest that LPA is involved in the regulation of glucose homeostasis in muscle and adipose tissues.
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PMID:Lysophosphatidic acid regulates blood glucose by stimulating myotube and adipocyte glucose uptake. 1792 84


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