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: UMLS:C0043167 (pertussis)
19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

RVGLVRGEKARKGK (peptide 14) from residues 2410-2423 of the human insulin-like growth factor II receptor (IGF-IIR) directly activates adenylylcyclase-inhibitory guanine nucleotide-binding proteins (Gi proteins) whereas RGEKARKGK (peptide 9) has no stimulatory action. However, peptide 9 inhibited the actions of peptide 14 on both GDP release from and guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) binding to Gi-2 in an aqueous system. Peptide 9 also inhibited peptide 14-induced Gi-1 activation with a similar profile. The peptide 9 action was competitive for peptide 14 action and determined by the first arginine residue and the C-terminal RKGK. In reconstituted IGF-IIR-Gi-2 vesicles, peptide 9 blocked the G protein stimulation by IGF-II with a potency similar to that observed in the action of peptide 9 on peptide 14; and peptide 9-induced inhibition was also observed in IGF-IIR-Gi-1 vesicles. In pertussis toxin-treated K562 cell membranes supplemented with Gi-2, peptide 9 inhibited IGF-II-induced reduction in pertussis toxin-catalyzed ADP-ribosylation of Gi-2 with an IC50 of 30 microM. This inhibitory effect of peptide 9 was competitive for the concentration of these IGF-IIR-positive/IGF-I receptor-negative cell membranes. Therefore, peptide 9 inhibits the Gi-activating function of IGF-IIR possibly by interacting with the putative peptide 14 recognition site of Gi proteins. The significance of this sequence is discussed.
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PMID:Guanine nucleotide-binding protein interacting but unstimulating sequence located in insulin-like growth factor II receptor. Its autoinhibitory characteristics and structural determinants. 164 3

Arg2410-Lys2423 (RVGLVRGEKARKGK, peptide 14) of the human insulin-like growth factor II receptor directly activates Gi and deletion of C-terminal 4 residues from peptide 14 nullifies this activity. A study was thus made of the effects of peptides modified in the C-terminal structure. RVGLVRGEKAAKGK and RVGLVRGEKARKGA scarcely activated Gi, whereas RVGLVRGEKARAGK (peptide A5) activated Gi as much as peptide 14 did. However, peptide A5 action did not depend on Mg2+ concentration and was little affected by pertussis toxin modification of Gi alpha. Peptide A5 may thus recognize the region on Gi alpha that is distinct from the extreme C-terminus. It is consequently considered that (i) the first and the last basic residues in the C-terminal motif of peptide 14 determine the capacity for recognition of Gi and (ii) there is a region different from the C-terminus of Gi alpha, through which the C-terminal second basic residue-altered peptide 14 activates Gi in a Mg(2+)-independent manner.
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PMID:Distinct mode of G protein activation due to single residue substitution of active IGF-II receptor peptide Arg2410-Lys2423: evidence for stimulation acceptor region other than C-terminus of Gi alpha. 165 44

We previously reported that insulin-like growth factor-II (IGF-II) stimulates both calcium influx and DNA synthesis by acting on the cell surface IGF-II receptor (IGF-IIR) in a manner sensitive to pertussis toxin, and recently demonstrated that IGF-II binding to the IGF-IIR gives rise to functional changes of purified Gi-2, a GTP-binding protein (G protein) in phospholipid vesicles as well as in broken cell membranes. On the other hand, a variety of evidence indicates that the IGF-IIR binds mannose 6-phosphate (man6P) with high affinity probably at a receptor extracellular region different from the IGF-II-binding site. In the present study, we examined whether man6P stimulation of the IGF-IIR evokes the activation of Gi-2 in phospholipid vesicles and in native cell membranes. In vesicles reconstituted with purified rat IGF-IIR and bovine Gi-2, man6P did not stimulate GDP dissociation from Gi-2 even in concentrations up to 10 mM, while IGF-II dose-dependently facilitated GDP release from Gi-2 with an EC50 of 6 nM. The stimulatory effect of IGF-II was not observed in vesicles reconstituted with Gi-2 alone. In addition, also in a native environment of cell membranes, man6P did not affect an endogenous 40-kDa protein or exogenously added purified Gi-2 as assessed with reduction of the pertussis toxin-catalyzed ADP-ribosylation. These results indicate that the IGF-IIR does not activate Gi-like proteins upon man6P binding in phospholipid vesicles and in native cellular membranes, whereas the receptor activates Gi-like proteins upon IGF-II binding in both environments. Thus, we postulate that the IGF-IIR dissimilarly responds to the two structurally unrelated ligands, IGF-II and man6P, in the linkage function with G proteins.
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PMID:Insulin-like growth factor-II/mannose 6-phosphate receptor is incapable of activating GTP-binding proteins in response to mannose 6-phosphate, but capable in response to insulin-like growth factor-II. 216 Dec 18

In mouse Balb/c3T3 fibroblasts, insulin-like growth factor (IGF)-II activates a calcium-permeable cation channel through a cell surface IGF-II receptor (Kojima, I., Nishimoto, I., Iiri, T., Ogata, E., and Rosenfeld, R. G. (1988) Biochem. Biophys. Res. Commun. 154, 9-19; Matsunaga, H., Nishimoto, I., Kojima, I., Yamashita, N., Kurokawa, K., and Ogata, E. (1988) Am. J. Physiol. 255, C442-C446). In the action of IGF-II, a pertussis toxin (or islet-activating protein; IAP)-sensitive GTP-binding protein (G protein) is inferred to be involved (Nishimoto, I., Hata, Y., Ogata, E., and Kojima, I. (1987) J. Biol. Chem. 262, 12120-12126). In the present study, we examined the direct coupling of the IGF-II receptor with G proteins. In broken Balb/c3T3 cell membranes, 10 nM IGF-II rapidly attenuated the IAP-catalyzed ADP-ribosylation of a 40-kDa protein in a manner requiring magnesium ion. The IGF-II-mediated attenuation in the IAP substrate activity was 80% recovered after washing off IGF-II and inhibited by coexisting guanosine 5'-O-(2-thiodiphosphate), while either aluminum fluoride solution (10 mM NaF plus 100 microM AlCl3) or 100 microM guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) reproduced the action of IGF-II. When purified IAP substrate G proteins (Gi1, Gi2, G0) were incubated with IGF-II in the presence of membranes from IAP-treated Balb/c3T3 cells, the attenuation in the IAP substrate activity was evident in Gi2, but not in Gi1 or G0. On the other hand, 10 nM insulin had no effect on the modification of the 40-kDa IAP substrate in Balb/c3T3 cell membranes, whereas 10 nM IGF-I elicited a slow onset of the IAP sensitivity attenuation from the 40-kDa protein. However, the specific involvement of the IGF-II receptor in the modification of the IAP substrate induced by low concentrations of IGF-II was suggested by the observations that (i) IGF-I receptor-lacking cell membranes were effective for the Gi2 modification by IGF-II, (ii) the ability of membranes to mediate the action of IGF-II was markedly attenuated in IGF-II receptor-lacking cell membranes, and (iii) agonistic anti-IGF-II receptor antibody mimicked the action of IGF-II on the 40-kDa protein in Balb/c3T3 cell membranes in a dose-dependent manner similar to that observed in the antibody-induced blocking of membrane IGF-II binding.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Possible direct linkage of insulin-like growth factor-II receptor with guanine nucleotide-binding proteins. 254 80

There is controversy as to whether or not a pertussis toxin sensitive G-protein is involved in the signaling pathway of insulin-like growth factor-I. We have used normal rat kidney epithelial (NRKE) cells to ask whether or not a pertussis toxin sensitive G-protein was involved in IGF-I stimulated DNA synthesis. NRKE cells express both IGF and IGF-II/M6P receptors and respond to IGF-I with increased thymidine incorporation into DNA. Under many circumstances incubation of cells/cell membranes with GTP analogues will inhibit binding of ligands that are linked to a G-protein-receptor pathway. However, when NRKE membrane preparations were incubated with 125I-IGF-I or 125I-IGF-II in the presence or absence of GTP gamma S, ATP and GTP, binding of the radioligands was not affected by the GTP-analogue. IGF-I and factors from serum of hypophysectomized rats (HRS) stimulated [3H]thymidine incorporation into DNA of NRKE cells. Under serum-free conditions in the presence of EGF (2 ng/ml) and PDGF (1 ng/ml) pertussis toxin over a wide range of doses had no effect upon IGF-I stimulated [3H]thymidine incorporation into DNA of NRKE cells. In addition, PT at a dose of 100 ng/ml had no effect on IGF-I(0.2-50 ng/ml) stimulated DNA synthesis of NRKE cells. However, PT at doses of 5, 50, 500, 5000 and 50,000 ng/ml was capable to ADP-ribosylate a 40 kDa protein in NRKE cell plasma membrane preparations corresponding to known PT-sensitive G-proteins. We conclude, that (1) PT-sensitive G-proteins and both IGF-I and IGF-II/M6P receptors are present in NRKE cell plasma membrane preparations, and most importantly, that (2) PT-sensitive G-proteins are not involved in the mitogenic signaling pathway of IGF-I in NRKE cells.
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PMID:Pertussis toxin sensitive G-proteins are not involved in the mitogenic signaling pathway of insulin-like growth factor-I in normal rat kidney epithelial (NRKE) cells. 879 68

To investigate the mechanism of action of the placental angiogenic hormone proliferin (PLF), we analyzed the signaling components in endothelial cells that are required for PLF-induced chemotaxis. Pertussis toxin, which inactivates Gi proteins, inhibited PLF-induced chemotaxis of endothelial cells. Gi proteins can lead to activation of the mitogen-activated protein kinase (MAPK) pathway; PLF was found to stimulate MAPK activity, and this induction was blocked by both pertussis toxin and a specific inhibitor of MAPK kinase, PD 098059. Furthermore, a blockade of MAPK activation prevented endothelial cell movement in response to PLF. As PLF functionally interacts with the insulin-like growth factor II (IGF-II)/mannose 6-phosphate receptor, we also examined the effects of pertussis toxin and PD 098059 on another ligand for this receptor, a mutant form of IGF-II; both inhibitors also block the action of this factor on endothelial cells. These data suggest that chemotaxis initiated by PLF and mediated by the IGF-II/mannose 6-phosphate receptor occurs through a G protein-coupled pathway, and that MAPK activation is necessary for the chemotactic response.
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PMID:Proliferin induces endothelial cell chemotaxis through a G protein-coupled, mitogen-activated protein kinase-dependent pathway. 920 25

We have investigated the effect of IGF-II on glucose-induced insulin release in the pancreatic beta-cell. Introduction of IGF-II during perifusion of the cells with 20 mM glucose abolished glucose-induced insulin release. Concomitant addition of IGF-II with 20 mM glucose caused a complete inhibition of insulin release. In addition, IGF-II inhibited Ca(2+)-induced insulin release from electropermeabilized pancreatic beta-cells. IGF-II had no effect on K(+)-or tolbutamide-induced insulin release. However, IGF-II could suppress K(+)-stimulated insulin release when cells were pretreated with the protein phosphatase inhibitor okadaic acid. The inhibitory effect of IGF-II on insulin release was not associated with significant changes in membrane potential, activity of the voltage-gated L-type Ca(2+)-channel or cytoplasmic free Ca2+ concentration. Pretreatment of the cells with pertussis toxin or the phorbol ester TPA abolished the inhibitory action of IGF-II on insulin release. Hence, the molecular mechanism whereby activation of the IGF-II/M6P receptor by IGF-II inhibits glucose-stimulated insulin exocytosis in the pancreatic beta-cell involves pertussis toxin-sensitive G proteins and is dependent on PKC activity.
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PMID:Insulin-like growth factor II inhibits glucose-induced insulin exocytosis. 947 90

The insulin-like growth factor-II/mannose-6-phosphate (IGF-II/M6P) receptor is a single-pass transmembrane glycoprotein that plays an important role in the intracellular trafficking of lysosomal enzymes and endocytosis-mediated degradation of IGF-II. However, its role in signal transduction after IGF-II binding remains unclear. In the present study, we report that IGF-II/M6P receptor in the rat brain is coupled to a G-protein and that its activation by Leu27IGF-II, an analog that binds rather selectively to the IGF-II/M6P receptor, potentiates endogenous acetylcholine release from the rat hippocampal formation. This effect is mediated by a pertussis toxin (PTX)-sensitive GTP-binding protein and is dependent on protein kinase Calpha (PKCalpha)-induced phosphorylation of downstream substrates, myristoylated alanine-rich C kinase substrate, and growth associated protein-43. Additionally, treatment with Leu27IGF-II causes a reduction in whole-cell currents and depolarization of cholinergic basal forebrain neurons. This effect, which is blocked by an antibody against the IGF-II/M6P receptor, is also sensitive to PTX and is mediated via activation of a PKC-dependent pathway. These results together revealed for the first time that the single transmembrane domain IGF-II/M6P receptor expressed in the brain is G-protein coupled and is involved in the regulation of central cholinergic function via the activation of specific intracellular signaling cascades.
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PMID:Single transmembrane domain insulin-like growth factor-II/mannose-6-phosphate receptor regulates central cholinergic function by activating a G-protein-sensitive, protein kinase C-dependent pathway. 1640 57

Insulin-like growth factor types 1 and 2 (IGF-1; IGF-2) and insulin-like peptides are all members of the insulin superfamily of peptide hormones but bind to several distinct classes of membrane receptor. Like the insulin receptor, the IGF-1 receptor is a heterotetrameric receptor tyrosine kinase, whereas the IGF-2/ mannose 6-phosphate receptor is a single transmembrane domain protein that is thought to function primarily as clearance receptors. We recently reported that IGF-1 and IGF-2 stimulate the ERK1/2 cascade by triggering sphingosine kinase-dependent "transactivation" of G protein-coupled sphingosine-1-phosphate receptors. To determine which IGF receptors mediate this effect, we tested seven insulin family peptides, IGF-1, IGF-2, insulin, and insulin-like peptides 3, 4, 6, and 7, for the ability to activate ERK1/2 in HEK293 cells. Only IGF-1 and IGF-2 potently activated ERK1/2. Although IGF-2 was predictably less potent than IGF-1 in activating the IGF-1 receptor, they were equipotent stimulators of ERK1/2. Knockdown of IGF-1 receptor expression by RNA interference reduced the IGF-1 response to a greater extent than the IGF-2 response, suggesting that IGF-2 did not signal exclusively via the IGF-1 receptor. In contrast, IGF-2 receptor knockdown markedly reduced IGF-2-stimulated ERK1/2 phosphorylation, with no effect on the IGF-1 response. As observed previously, both the IGF-1 and the IGF-2 responses were sensitive to pertussis toxin and the sphingosine kinase inhibitor, dimethylsphingosine. These data indicate that endogenous IGF-1 and IGF-2 receptors can independently initiate ERK1/2 signaling and point to a potential physiologic role for IGF-2 receptors in the cellular response to IGF-2.
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PMID:The insulin-like growth factor type 1 and insulin-like growth factor type 2/mannose-6-phosphate receptors independently regulate ERK1/2 activity in HEK293 cells. 1762 Mar 36

Accumulated evidence suggests that the single transmembrane domain insulin-like growth factor-II/mannose 6-phosphate receptor (IGF-II/M6P or IGF-II receptor) plays an important role in the intracellular trafficking of lysosomal enzymes and endocytosis-mediated degradation of insulin like growth factor (IGF-II). However, the role of this receptor in signal transduction following IGF-II binding remains controversial. In the present study, we revealed that Leu(27)IGF-II, an analog which binds preferentially to the IGF-II receptor, can attenuate K(+)-as well as veratridine-evoked GABA release from the adult rat hippocampal formation. Tetrodotoxin failed to alter the effects of Leu(27)IGF-II on GABA release, thus suggesting the lack of involvement of voltage-dependent Na(+) channels. Interestingly, the effect is found to be sensitive to pertussis toxin (PTX), indicating the possible involvement of a Gi/o protein-dependent pathway in mediating the release of GABA from the hippocampal slices. Additionally, Leu(27)IGF-II was found to attenuate GABA release from frontal cortex but not from striatum. These results, together with the evidence that IGF-II receptors are localized on GABAergic neurons, raised the possibility that this receptor, apart from mediating intracellular trafficking, may also be involved in the regulation of endogenous GABA release by acting directly on GABAergic terminals.
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PMID:Leu27 insulin-like growth factor-II, an insulin-like growth factor-II analog, attenuates depolarization-evoked GABA release from adult rat hippocampal and cortical slices. 2065 30


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