Redox regulation of PI 3-kinase signalling via inactivation of PTEN

Leslie, Nicholas R.; Bennett, Deborah; Lindsay, Yvonne; Stewart, Hazel; Gray, Alexander; Downes, C P

doi:10.1093/emboj/cdg513

Cited by 559 publications

(473 citation statements)

References 64 publications

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“…Recent studies indicate that PTEN can be inactivated by H 2 O 2 , and this inactivation was correlated with a shift in the electrophoretic mobility of PTEN consistent with its oxidation both in vitro and in cultured cells (Lee et al, 2002). Moreover, either H 2 O 2 or endogenous ROS production in macrophages inactivates a fraction of PTEN (Leslie et al, 2003). Our results, along with these earlier observations suggest that the inactivation of PTEN by endogenously produced ROS is required to produce a net increase in PtdIns(3,4,5)P 3 levels in response to insulin stimulation.…”

supporting

confidence: 80%

The Major Target of the Endogenously Generated Reactive Oxygen Species in Response to Insulin Stimulation Is Phosphatase and Tensin Homolog and Not Phosphoinositide-3 Kinase (PI-3 Kinase) in the PI-3 Kinase/Akt Pathway

Seo

Ahn

Lee

et al. 2005

MBoC

159

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(2) human neuroblastoma cell lines. When cells were stimulated with insulin, PI-3 kinase was activated in both cell lines, whereas the translocation of PDK-1 to the membrane fraction and phosphorylated Akt were observed only in SK-N-SH cells. Analyses of the insulin-mediated reactive oxygen species (ROS) generation and Phosphatase and Tensin homolog (PTEN) oxidation indicate that PTEN oxidation occurred in SK-N-SH cells, which can produce ROS, but not in SK-N-BE(2) cells, which cannot increase ROS in response to insulin stimulation. When SK-N-SHcells were pretreated with the NADPH oxidase inhibitor diphenyleneiodonium chloride before insulin stimulation, insulin-mediated translocation of PDK-1 to the membrane fraction and phosphorylation of Akt were remarkably reduced, whereas PI-3 kinase activity was not changed significantly. These results indicate that not only PI-3 kinase activation but also inhibition of PTEN by ROS is needed to increase cellular level of phosphatidylinositol 3,4,5-trisphosphate for recruiting downstream signaling molecules such as PDK-1 and Akt in insulin-mediated signaling. Moreover, the ROS generated by insulin stimulation mainly contributes to the inactivation of PTEN and not to the activation of PI-3 kinase in the PI-3 kinase/Akt pathway. INTRODUCTIONReactive oxygen species (ROS), and especially H 2 O 2 , are rapidly and transiently increased by a variety of external signals that include cytokines, peptide growth factors, and agonists of seven-transmembrane domain, or G proteincoupled receptors (GPCRs) (Ohba et al., 1994;Kimura et al., 1995;Krieger-Brauer and Kather, 1995;Sundaresan et al., 1995;Bae et al., 1997;Patterson et al., 1999). Previous studies have demonstrated that the binding of peptide growth factors to their specific receptors induces a transient increase in the intracellular concentration of ROS (Krieger-Brauer and Kather, 1995;Lo and Cruz, 1995;Sundaresan et al., 1996;Bae et al., 1997;Sattler et al., 1999). This growth factor-mediated transient increase of ROS is an integral constituent of downstream signal transduction (Finkel, 1998). The ROS-mediated modulation of growth factor signaling was achieved via the inactivation of PTPases through oxidation of the cysteine residue in the active site sequence motif (Zhang, 1998).ROS generation in a variety of nonphagocytic cells is much lower than in phagocytes, although the ROS generation systems in nonphagocytic cells are considered similar (Babior, 1999;Bokoch and Diebold, 2002). ROS generation in phagocytes is catalyzed by NADPH oxidase, which consists of two transmembrane subunits, p22 phox and gp91 phox , and at least three cytosolic subunits, p47 phox , p67 phox , and Rac (Babior, 1999;Banfi et al., 2003). Recently, six gp91 phox homologues (NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2) have been identified in different mammalian tissue (Banfi et al., 2003). Although the mechanism of the growth factor-mediated ROS generation in nonphagocytotic cells has not been completely understood, several recent reports (Bae et al., 200...

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supporting

confidence: 80%

The Major Target of the Endogenously Generated Reactive Oxygen Species in Response to Insulin Stimulation Is Phosphatase and Tensin Homolog and Not Phosphoinositide-3 Kinase (PI-3 Kinase) in the PI-3 Kinase/Akt Pathway

Seo

Ahn

Lee

et al. 2005

MBoC

159

111

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“…Recently, ROS have been shown to inactivate PTEN, a phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P 3 ) phosphatase, by oxidizing thiols of cysteine residues of PTEN (Leslie et al, 2003). This oxidative inactivation of PTEN causes an increase in cellular PtdIns(3,4,5)P 3 and thereby activates a downstream PtdIns(3,4,5)P 3 target, AKT.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of NADPH oxidase 4 activates apoptosis via the AKT/apoptosis signal-regulating kinase 1 pathway in pancreatic cancer PANC-1 cells

et al. 2006

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Pancreatic adenocarcinoma is an aggressive human malignancy and is characterized by resistance to apoptosis. Recently, NADPH oxidase (Nox) 4-mediated generation of intracellular reactive oxygen species (ROS) was proposed to confer antiapoptotic activity and thus a growth advantage to pancreatic cancer cells. The signaling mechanism by which Nox4 transmits cell survival signals remains unclear. Here, we show that both a flavoprotein inhibitor, diphenylene iodonium (DPI), and small interfering RNAs designed to target Nox4 mRNA (siNox4R-NAs) inhibited superoxide production in PANC-1 pancreatic cancer cells, and depletion of ROS by DPI or siNox4RNAs induced apoptosis. Parallely, DPI treatment and siNox4RNA transfection blocked activation of the cell survival kinase AKT by attenuating phosphorylation of AKT. Furthermore, AKT phosphorylation of apoptosis signal-regulating kinase 1 (ASK1) on Ser-83 was reduced by DPI and siNox4RNAs. When ASK1Ser83Ala (an AKT phosphorylation-defective ASK1 mutant) was introduced into PANC-1 cells, this mutant alone induced apoptosis. But, addition of DPI or co-transfection of siNox4RNA had no additive effect, indicating that the mutant can substitute for these reagents in apoptosis induction. Taken together, these findings suggest that ROS generated by Nox4, at least in part, transmit cell survival signals through the AKT-ASK1 pathway in pancreatic cancer cells and their depletion leads to apoptosis.

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“…Oxidation of PTEN by ROS/H 2 O 2 has been reported in macrophages stimulated with lipopolysaccharide and phorbol ester (Leslie et al, 2003), in HEK293 cells stimulated with insulin (Kwon et al, 2004), in HeLa cells stimulated with epidermal growth factor (EGF) (Kwon et al, 2004), and in fibroblasts stimulated with platelet-derived growth factor (PDGF) (Seo et al, 2005). Despite the limited degree of PTEN oxidation in these studies, there are ample functional consequences.…”

Section: Discussionmentioning

confidence: 99%

Akt activation by arachidonic acid metabolism occurs via oxidation and inactivation of PTEN tumor suppressor

2007

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Cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) enzymes are overexpressed during inflammation and multistage tumor progression in many neoplastic disorders including lung, breast and pancreatic cancers. Here we report that the tumor suppressor phosphatase and tensin homolog (PTEN) is oxidized and inactivated during arachidonic acid (AA) metabolism in pancreatic cancer cell lines expressing COX-2 or 5-LOX. Oxidation of PTEN decreases its phosphatase activity, favoring increased phosphatidylinositol 3,4,5-triphosphate production, activation of Akt and phosphorylation of downstream Akt targets including GSK-3b and S6K. These effects are recapitulated with pancreatic phospholipase A 2 , which hydrolyses the release of membrane-bound AA. Interference with PTEN's physiological antagonism of signals from growth factors, insulin and oncogenes may confer risk for hypertrophic or neoplastic diseases associated with chronic inflammation or unwarranted oxidative metabolism of essential fatty acids.

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Redox regulation of PI 3-kinase signalling via inactivation of PTEN

Cited by 559 publications

References 64 publications

The Major Target of the Endogenously Generated Reactive Oxygen Species in Response to Insulin Stimulation Is Phosphatase and Tensin Homolog and Not Phosphoinositide-3 Kinase (PI-3 Kinase) in the PI-3 Kinase/Akt Pathway

The Major Target of the Endogenously Generated Reactive Oxygen Species in Response to Insulin Stimulation Is Phosphatase and Tensin Homolog and Not Phosphoinositide-3 Kinase (PI-3 Kinase) in the PI-3 Kinase/Akt Pathway

Inhibition of NADPH oxidase 4 activates apoptosis via the AKT/apoptosis signal-regulating kinase 1 pathway in pancreatic cancer PANC-1 cells

Akt activation by arachidonic acid metabolism occurs via oxidation and inactivation of PTEN tumor suppressor

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