Phosphoinositide 3-kinase: A new effector in signal transduction?

Downes, C P; Carter, A N

doi:10.1016/0898-6568(91)90027-r

Cited by 168 publications

(86 citation statements)

References 74 publications

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“…PI 3-kinase is involved in multiple signaling pathways (20), such as those activated by insulin and PDGF. Activation of this enzyme results from the association of the p85 subunit of the PI 3-kinase to tyrosine-phosphorylated IRS 1 in response to insulin (12)(13)(14)21) or directly to tyrosinephosphorylated PDGF receptor in response to PDGF (10, 11).…”

Section: Discussionmentioning

confidence: 99%

Cross-talk between the Platelet-derived Growth Factor and the Insulin Signaling Pathways in 3T3-L1 Adipocytes

Ricort

Tanti

Obberghen

et al. 1997

Journal of Biological Chemistry

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Phosphatidylinositol (PI) 3-kinase is activated by various growth factors such as PDGF (platelet-derived growth factor) and insulin. The aim of the present study was to determine whether PDGF could modulate insulin activation of PI 3-kinase in 3T3-L1 adipocytes. When cells were preincubated for 5-15 min with PDGF, PI 3-kinase activity associated to insulin receptor substrate 1 (IRS 1) in response to insulin was decreased, due to reduced association of the PI 3-kinase p85 subunit with IRS 1. In addition, following this PDGF pretreatment, the tyrosine phosphorylation of IRS 1 in response to insulin and its electrophoretic mobility were diminished. The change in the mobility of IRS 1 could be attributed to PDGF-induced serine/threonine phosphorylation of the protein which was partly inhibited by PI 3-kinase inhibitors. By contrast, epidermal growth factor, which does not stimulate PI 3-kinase, had no effect on the association of PI 3-kinase with IRS 1 in response to insulin. This series of results indicates that the PDGFinduced serine/threonine phosphorylation of IRS 1 could be due to activation of PI 3-kinase pathway. Furthermore, this phosphorylation of IRS 1 is associated with a decrease in its tyrosine phosphorylation by insulin and in its association with the p85 subunit of PI 3-kinase. This study suggests that a cross-talk exists between the different pathways stimulated by PDGF and insulin in intact cells. Phosphatidylinositol (PI) 3-kinase1 is a common element of the signaling pathway of a large number of tyrosine kinase receptors. PI 3-kinase is a heterodimer consisting of an 85-kDa regulatory subunit (p85) containing one Src homology 3 (SH3) domain and two Src homology 2 (SH2) domains (1-3) and an 110-kDa catalytic subunit (4). The catalytic subunit phosphorylates inositol lipids at the D-3 position of the inositol ring and has been shown to possess a serine kinase activity (5). By contrast, the p85 regulatory subunit functions as an adaptor which, via its SH2 domains, links PI 3-kinase to tyrosinephosphorylated proteins such as autophosphorylated tyrosine kinase receptors (6). This association leads to the stimulation of the kinase activities of the p110 subunit (6, 7). Since PI 3-kinase is activated by a large range of peptide growth factors, this enzyme activity appears to be implicated in various cellular responses including promotion of cell growth, regulation of cell differentiation, and metabolism (for review see Ref. 6). Despite this, each growth factor triggers distinct and specific biological responses in each particular cell type. In the present study, we looked at the effects of a prior stimulation by platelet-derived growth factor (PDGF) on the further ability of insulin to activate PI 3-kinase. We took advantage of the 3T3-L1 adipocytes where PI 3-kinase can be activated by both insulin and PDGF but not by EGF (8, 9). When PDGF stimulates tyrosine phosphorylation of its receptor, the p85 regulatory subunit of PI 3-kinase associates to phosphorylated Tyr-Xaa-Xaa-Met motifs of the PDGF recepto...

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Section: Discussionmentioning

confidence: 99%

Cross-talk between the Platelet-derived Growth Factor and the Insulin Signaling Pathways in 3T3-L1 Adipocytes

Ricort

Tanti

Obberghen

et al. 1997

Journal of Biological Chemistry

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“…1 The abbreviations used are: PtdIns-3,4,5-P 3 , phosphatidylinositol 3,4,5-trisphosphate; PtdIns-4,5-P 2 , phosphatidylinositol 4,5-bisphosphate; PKC, protein kinase C; PRK, PKC-related kinase; PtdSer, phosphatidylserine; TPA, 12-O-tetradecanoylphorbol 13-acetate; InsS 6 , inositol hexasulfate; InsP 6 , inositol hexaphosphate; InsP 4 , inositol tetraphosphate.…”

Section: Methodsmentioning

confidence: 99%

Activation of PRK1 by Phosphatidylinositol 4,5-Bisphosphate and Phosphatidylinositol 3,4,5-Trisphosphate

Palmer

Dekker

Woscholski

et al. 1995

Journal of Biological Chemistry

129

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As potential targets for polyphosphoinositides, activation of protein kinase C (PKC) isotypes (␤ 1 , ⑀, , ) and a member of the PKC-related kinase (PRK) family, PRK1, has been compared in vitro. PRK1 is shown to be activated by both phosphatidylinositol 4,5-bisphosphate (PtdIns 4,5-P 2 ) as well as phosphatidylinositol 3,4,5-trisphosphate (PtdIns-3,4,5-P 3 ) either as pure sonicated lipids or in detergent mixed micelles. When presented as sonicated lipids, PtdIns-4,5-P 2 and PtdIns-3,4,5-P 3 were equipotent in activating PRK1, and, furthermore, sonicated phosphatidylinositol (PtdIns) and phosphatidylserine (PtdSer) were equally effective. In detergent mixed micelles, PtdIns-4,5-P 2 and PtdIns-3,4,5-P 3 also showed a similar potency, but PtdIns and PtdSer were 10-fold less effective in this assay. Similarly, PKC-␤ 1 , -⑀, and -were all activated by PtdIns-4,5-P 2 and PtdIns-3,4,5-P 3 in detergent mixed micelles. The activation constants for PtdIns-4,5-P 2 and PtdIns-3,4,5-P 3 were essentially the same for all the kinases tested, implying no specificity in this in vitro analysis. Consistent with this conclusion, the effects of PtdIns-4,5-P 2 and PtdIns-3,4,5-P 3 were found to be inhibited at 10 mM Mg 2؉ and mimicked by high concentrations of inositol hexaphosphate and inositol hexasulfate. The similar responses of these two classes of lipid-activated protein kinase to these phosphoinositides are discussed in light of their potential roles as second messengers.The phosphatidylinositol 3-kinase family of lipid kinases are responsible for the phosphorylation of inositol lipids at the 3-OH position (reviewed in Ref. 1). In response to various agonists, phosphatidylinositol 3,4,5-trisphosphate (PtdIns-3,4,5-P 3 ) 1 accumulates and labeling studies suggest that this is the primary product and as such is the most likely second messenger candidate (2). While this remains an attractive hypothesis, in the absence of a defined intracellular target(s), the operation of the "PtdIns 3-kinase signaling pathway" will remain enigmatic.By their nature, lipid-dependent protein kinases are attractive candidates as targets for the postulated role of PtdIns-3,4,5-P 3 as a second messenger. Protein kinase C (PKC) isotypes constitute the major group of such enzymes, but several recent reports have indicated the existence of an additional class of lipid-activated protein kinases. These kinases, termed PKC-related kinases (PRKs) are closely homologous to PKC isotypes in the catalytic domain while retaining a distinct amino-terminal regulatory domain ((3, 4) see Fig. 6A). Unlike the PKCs which characteristically retain a cysteine-rich C1 domain responsible for effector binding, the PRKs do not encode a C1 domain but show two distinct conserved regulatory domains termed HR1 and HR2 (3). Consistent with the lack of a C1 domain, it has become clear that while the PRKs resemble PKCs in being activated by proteolysis, they differ from PKCs in not being activated by phorbol esters. However, like PKC, various fatty acids and phospholipids have bee...

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“…Inositol phospholipids, especially Ptdlns(4,5)P2, have critical roles in cellular control because they are substrates for receptorregulated enzymes, such as phospholipases C and phosphatidylinositol 3-kinase, which generate established or putative intracellular signals (Nishizuka, 1984;Berridge and Irvine, 1989;Cantley et al, 1991;Downes and Carter, 1991;Stephens et al, 1993). However, relatively little progress has been made towards elucidating the functions of inositol-phospholipid-derived second messengers in complex cellular events such as the control of cell division.…”

Section: Introdurtionmentioning

confidence: 99%

Inositol trisphosphate metabolism in Saccharomyces cerevisiae: identification, purification and properties of inositol 1,4,5-trisphosphate 6-kinase

Estévez

Pulford

Stark

et al. 1994

Biochemical Journal

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Ins(1,4,5)P3 metabolism was examined in Saccharomyces cerevisiae extracts. S. cerevisiae contains readily detectable Ins(1,4,5)P3 kinase activity that is predominantly soluble, but phosphomonoesterase activity acting on Ins(1,4,5)P3 was not detected in either soluble or particulate preparations from this organism. We have purified the kinase activity approximately 685-fold in a rapid four-step process, and obtained a stable preparation. The enzyme has an apparent native molecular mass of approximately 40 kDa, and displays Michaelis-Menten kinetics with respect to its two substrates, ATP and Ins(1,4,5)P3. The Km for ATP was 2.1 mM, and that for Ins(1,4,5)P3 was 7.1 microM. The enzyme appeared to be the first step in the conversion of Ins(1,4,5)P3 into an InsP5, and the partially purified preparation contained another activity that converted the InsP4 product into an InsP5. The InsP4 product of the partially purified kinase was not metabolized by human erythrocyte ghosts and co-chromatographed with an Ins(3,4,5,6)P4 [L-Ins(1,4,5,6)P4] standard, identifying it as D-Ins(1,4,5,6)P4. The yeast enzyme is thus an Ins(1,4,5)P3 6-kinase. This activity may be an important step in the production of inositol polyphosphates such as InsP5 and InsP6 in S. cerevisiae.

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Phosphoinositide 3-kinase: A new effector in signal transduction?

Cited by 168 publications

References 74 publications

Cross-talk between the Platelet-derived Growth Factor and the Insulin Signaling Pathways in 3T3-L1 Adipocytes

Cross-talk between the Platelet-derived Growth Factor and the Insulin Signaling Pathways in 3T3-L1 Adipocytes

Activation of PRK1 by Phosphatidylinositol 4,5-Bisphosphate and Phosphatidylinositol 3,4,5-Trisphosphate

Inositol trisphosphate metabolism in Saccharomyces cerevisiae: identification, purification and properties of inositol 1,4,5-trisphosphate 6-kinase

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