Cross-talk between phospholipase C and phosphoinositide 3-kinase signalling pathways

Ih, Batty; Dm, Hickinson; Cp, Downes

doi:10.1042/bst0251132

Cited by 15 publications

(12 citation statements)

References 4 publications

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“…PI-3 kinase has many targets, including Akt, PDK1, and IL K , which can regulate PKC isoforms, p70S6 kinase, GSK-3, and PK A (Monfar et al, 1995;Batty et al, 1997;Delcommenne et al, 1998;Le Good et al, 1998;C ass et al, 1999;Wu, 1999). In addition to other kinases, GSK-3 is a critical downstream element of Akt (Pap and Cooper, 1998).…”

Section: Discussionmentioning

confidence: 99%

Activation of Phosphatidylinositol-3 Kinase (PI-3K) and Extracellular Regulated Kinases (Erk1/2) Is Involved in Muscarinic Receptor-Mediated DNA Synthesis in Neural Progenitor Cells

Li¹,

Zhang

et al. 2001

J. Neurosci.

104

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Muscarinic acetylcholine receptor (mAChR), a member of the G-protein-coupled receptors (GPCRs) gene superfamily, has been shown to mediate the effects of acetylcholine on differentiation and proliferation in the CNS. However, the mechanism or mechanisms whereby mAChRs regulate cell proliferation remain poorly understood. Here we show that in vitro bFGFexpanded neural progenitor cells dissociated from rat cortical neuroepithelium express muscarinic acetylcholine receptor subtype mRNAs. We demonstrate that stimulation of these mAChRs with carbachol, a muscarinic agonist, activated extracellularregulated kinases (Erk1/2) and phosphatidylinositol-3 kinase (PI-3K). This, in turn, stimulated DNA synthesis in neural progenitor cells. MEK inhibitor PD98059 and PI-3K inhibitors wortmannin and LY294002 inhibited a carbachol-induced increase in DNA synthesis. These findings indicate that the activation of both PI-3 kinase and MEK signaling pathways via muscarinic receptors is involved in stimulating DNA synthesis in the neural progenitor cells during early neurogenesis.

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Section: Discussionmentioning

confidence: 99%

Activation of Phosphatidylinositol-3 Kinase (PI-3K) and Extracellular Regulated Kinases (Erk1/2) Is Involved in Muscarinic Receptor-Mediated DNA Synthesis in Neural Progenitor Cells

Li¹,

Zhang

et al. 2001

J. Neurosci.

104

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“…This results both from prolonged inhibition of insulin-stimulated PI 3-kinase activity and from acute activation of an unidentified PtdIns (3,4,5)P 3 5-phosphatase (22,28). It was thus unexpected that PLC-coupled receptors would prove capable of stimulating PKB activity themselves.…”

Section: Muscarinicmentioning

confidence: 99%

Muscarinic Receptors Mediate Phospholipase C-dependent Activation of Protein Kinase B via Ca2+, ErbB3, and Phosphoinositide 3-Kinase in 1321N1 Astrocytoma Cells

Tang¹,

Batty²,

Downes

2002

Journal of Biological Chemistry

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In 1321N1 astrocytoma cells, heterotrimeric G-protein-coupled receptors that activate phosphoinositidespecific phospholipase C␤ (PLC␤) isoforms via G q , induced a prolonged activation of protein kinase B (PKB) after a short delay. For example, the effect of carbachol acting on M 3 muscarinic receptors is blocked by wortmannin, suggesting it is mediated via a phosphoinositide 3-kinase (PI 3-kinase). In support of this, carbachol increased PI 3-kinase activity in PI 3-kinase (p85) immunoprecipitates. The pathway linking PLC-coupled receptors to PI 3-kinase was deduced to involve phosphoinositide hydrolysis and Ca 2؉ -dependent ErbB3 transactivation but not protein kinase C on the basis of the following evidence: (i) inhibition of carbachol stimulated PLC by pretreatment with the phorbol ester phorbol 12-myristate 13-acetate concomitantly reduced PKB activity, whereas stimulation of other PLC-coupled receptors also activated PKB; (ii) Ca 2؉ ionophores and thapsigargin stimulated PKB activity in a wortmanninsensitive manner, whereas bis(2-aminophenoxy)ethane-N, N, N, N-tetraacetic acid blocked carbachol-stimulated PKB activity; (iii) phorbol 12-myristate 13-acetate alone did not activate PKB, whereas a protein kinase C inhibitor did not prevent the activation of PKB by carbachol; and (iv) carbachol stimulated ErbB3-tyrosine phosphorylation and association with p85, and both these and PKB activity were blocked by tyrphostin AG1478, an epidermal growth factor receptor-tyrosine kinase inhibitor. These experiments define a novel pathway linking G q -coupled G-protein-coupled receptors to the activation of PI 3-kinase and PKB. Protein kinase B (PKB),1 also known as c-Akt or Rac-PK, is a 60-kDa serine-threonine kinase that is the cellular homologue of the viral oncogene v-akt (1-3). PKB family members appear to be overexpressed in some human cancers, including those of the breast, pancreas, and ovaries (3, 4). Much of the interest in PKB stems from the discovery that this kinase is rapidly activated in response to a wide variety of receptortyrosine kinases and that such activation is prevented by strategies that inhibit or prevent the activation of phosphoinositide 3-kinases (PI 3-kinases; Refs. 2, 3, 5, 6). PKB is now established as one of several direct targets of the lipid products of PI 3-kinases, phosphatidylinositol 3,4,5-trisphosphate (PtdIns (3,4,5)P 3 ) and phosphatidylinositol 3,4-bisphosphate (7, 9) The current model for activation of PKB via receptor-tyrosine kinases involves phosphorylation at Thr 308 in the activation loop of the catalytic domain and Ser 473 in the carboxyl-terminal tail (5). The phosphorylation of both sites is required for maximum activation and requires an interaction between the amino-terminal pleckstrin homology domain of PKB with PtdIns (3,4,5)P 3 or phosphatidylinositol 3,4-bisphosphate (5, 10, 11). Lipid binding results in translocation of PKB to membranes and induces a conformational change in PKB, making it an efficient substrate for upstream kinase(s). Phosphorylation of Thr 308 ...

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“…4 Both PtdIns(3,4)P 2 andPtdIns(3,4,5) P 3 bind to Akt (protein kinase B) and its activator phosphoinositidedependent kinase-1. 5,6 Activated Akt is required for the subsequent inactivation of glycogen synthase kinase 3β, which eventually leads to the stimulation of glycogen synthesis and fatty acid synthesis. 7 Activated Akt also stimulates the mTor /P70S6-kinase pathway, the activation of which is required for the initiation of protein synthesis.…”

Section: Introductionmentioning

confidence: 99%

Loss of Pten, a tumor suppressor, causes the strong inhibition of autophagy without affecting LC3 lipidation

Ueno

Sato²,

Horie³

et al. 2008

Autophagy

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1 Pten (phosphatase and tensin homolog deleted on chromosome ten), a tumor suppressor, is a phosphatase with a variety of substrate specificities. Its function as a negative regulator of the class I phosphatidyl-inositol 3-kinase/Akt pathway antagonizes insulin-dependent cell signaling. The targeted deletion of Pten in mouse liver leads to insulin hypersensitivity and the upregulation of the phosphatidyl-inositol 3-kinase/Akt signaling pathway. In this study, we investigated the effects of Pten deficiency on autophagy, a major cellular degradative system responsible for the turnover of cell constituents. The autophagic degradation of [ 14 C]-leucinelabeled proteins of hepatocytes isolated from Pten-deficient livers was strongly inhibited, compared with that of control hepatocytes. However, no significant difference was found in the levels of the Atg12-Atg5 conjugate and LC3-II, the lipidated form of LC3, an intrinsic autophagosomal membrane marker, between control and Pten-deficient livers. Electron microsopic analyses showed that numerous autophagic vacuoles (autophagosomes plus autolysosomes) were present in the livers of control mice that had been starved for 48 hours, whereas they were markedly reduced in Ptendeficient livers under the same conditions. In vivo administration of leupeptin to control livers caused the inhibition of autophagic proteolysis, resulting in the accumulation of autolysosomes. These autolysosomes could be separated as a denser autolysosomal fraction from other cell membranes by Percoll density gradient centrifugation. In leupeptin-administered mutant livers, however, the accumulation of denser autolysosomes was reduced substantially. Collectively, we conclude that enhanced insulin signaling in Pten deficiency suppresses autophagy at the formation and maturation steps of autophagosomes, without inhibiting ATG conjugation reactions.

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Cross-talk between phospholipase C and phosphoinositide 3-kinase signalling pathways

Cited by 15 publications

References 4 publications

Activation of Phosphatidylinositol-3 Kinase (PI-3K) and Extracellular Regulated Kinases (Erk1/2) Is Involved in Muscarinic Receptor-Mediated DNA Synthesis in Neural Progenitor Cells

Activation of Phosphatidylinositol-3 Kinase (PI-3K) and Extracellular Regulated Kinases (Erk1/2) Is Involved in Muscarinic Receptor-Mediated DNA Synthesis in Neural Progenitor Cells

Muscarinic Receptors Mediate Phospholipase C-dependent Activation of Protein Kinase B via Ca2+, ErbB3, and Phosphoinositide 3-Kinase in 1321N1 Astrocytoma Cells

Loss of Pten, a tumor suppressor, causes the strong inhibition of autophagy without affecting LC3 lipidation

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