The activation of protein kinase B by H2O2 or heat shock is mediated by phosphoinositide 3-kinase and not by mitogen-activated protein kinase-activated protein kinase-2

Shaw, M.; Cohen, Philip; Alessi, Dario R.

doi:10.1042/bj3360241

Cited by 250 publications

(214 citation statements)

References 31 publications

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“…Based on data showing that PI3K inhibitors do not prevent AKT1 activation by stress, these studies concluded that stressinduced AKT1 activation was PI3K-independent. Other studies, however, found that PI3K activity was required for AKT1 activation by heat shock or oxidative stress in Swiss 3T3 cells (19,20). It has been suggested that certain cellular stresses activate AKT1 and AKT3 but not AKT2 (19), a finding that is consistent with the different functions of the AKTs as revealed by studies of mice lacking AKT1 or AKT2 (21)(22)(23).…”

mentioning

confidence: 64%

Inhibition of JNK by Cellular Stress- and Tumor Necrosis Factor α-induced AKT2 through Activation of the NFκB Pathway in Human Epithelial Cells

Yuan¹,

Feldman²,

Sun³

et al. 2002

Journal of Biological Chemistry

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Previous studies have demonstrated that AKT1 and AKT3 are activated by heat shock and oxidative stress via both phosphatidylinositol 3-kinase-dependent and -independent pathways. However, the activation and role of AKT2 in the stress response have not been fully elucidated. In this study, we show that AKT2 in epithelial cells is activated by UV-C irradiation, heat shock, and hyperosmolarity as well as by tumor necrosis factor ␣ (TNF␣) through a phosphatidylinositol 3-kinase-dependent pathway. The activation of AKT2 inhibits UVand TNF␣-induced c-Jun N-terminal kinase (JNK) and p38 activities that have been shown to be required for stress-and TNF␣-induced programmed cell death. Moreover, AKT2 interacts with and phosphorylates I B kinase ␣. The phosphorylation of I B kinase ␣ and activation of NF B mediates AKT2 inhibition of JNK but not p38. Furthermore, phosphatidylinositol 3-kinase inhibitor or dominant negative AKT2 significantly enhances UV-and TNF␣-induced apoptosis, whereas expression of constitutively active AKT2 inhibits programmed cell death in response to UV and TNF␣ stimulation with an accompanying decreased JNK and p38 activity. These results indicate that activated AKT2 protects epithelial cells from stress-and TNF␣-induced apoptosis by inhibition of stress kinases and provide the first evidence that AKT inhibits stress kinase JNK through activation of the NF B pathway.

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mentioning

confidence: 64%

Inhibition of JNK by Cellular Stress- and Tumor Necrosis Factor α-induced AKT2 through Activation of the NFκB Pathway in Human Epithelial Cells

Yuan¹,

Feldman²,

Sun³

et al. 2002

Journal of Biological Chemistry

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“…Although cell-type differences may explain such discrepancy, the ability of sorbitol to increase PKB activity in fibroblasts has not been consistently observed. 25,27 This could be explained by the fact that sorbitol is a weak activator of PKB making this effect difficult to detect. Our results clearly show that PKB activity is increased by sorbitol in fibroblasts (Figure 4).…”

Section: Discussionmentioning

confidence: 99%

Activation of extracellular signal-regulated protein kinase 5 downregulates FasL upon osmotic stress

et al. 2006

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Extracellular signal-regulated protein kinase (ERK) 5 is a mitogen-activated protein kinase (MAPK) that is activated by dual phosphorylation via a unique MAPK/ERK kinase 5, MEK5. The physiological importance of this signaling cascade is underscored by the early embryonic death caused by the targeted deletion of the erk5 or the mek5 genes in mice. Here, we have found that ERK5 is required for mediating the survival of fibroblasts under basal conditions and in response to sorbitol treatment. Increased Fas ligand (FasL) expression acts as a positive feedback loop to enhance apoptosis of ERK5-or MEK5-deficient cells under conditions of osmotic stress. Compared to wild-type cells, erk5À/À and mek5À/À fibroblasts treated with sorbitol display a reduced protein kinase B (PKB) activity associated with increased Forkhead box O3a (Foxo3a) activity. Based on these results, we conclude that the ERK5 signaling pathway promotes cell survival by downregulating FasL expression via a mechanism that implicates PKB-dependent inhibition of Foxo3a downstream of phosphoinositide 3 kinase.

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“…It has been demonstrated that the activity of PI-3 kinase, the level of 3-phosphorylated PIs, and the activity of Akt are increased in cells exposed to H 2 O 2 (Konishi et al, 1997;Shaw et al, 1998;Sonoda et al, 1999;Tanaka et al, 1999;Qin et al, 2000). This H 2 O 2 -mediated activation of PI-3 kinase/Akt pathway is considered to be the result of reversible oxidation and inactivation of protein tyrosine phosphatase (PTP) family protein such as PTEN that have a critical cysteine residue in the active site (Denu and Tanner, 1998;Lee et al, 1998;Meng et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

“…Because PTEN has a critical role in antagonizing PI-3 kinase signaling pathways, it might be expected that PTEN would be the target of complex control mechanisms. Only limited studies have addressed this issue, but evidence is now emerging for functional regulation of PTEN at the level of protein stability and localization, as well as transcription of the PTEN gene (Adey et al, 2000;Vazquez et al, 2000Vazquez et al, , 2001Kurose et al, 2001;Bastola et al, 2002).It has been demonstrated that the activity of PI-3 kinase, the level of 3-phosphorylated PIs, and the activity of Akt are increased in cells exposed to H 2 O 2 (Konishi et al, 1997;Shaw et al, 1998;Sonoda et al, 1999;Tanaka et al, 1999;Qin et al, 2000). This H 2 O 2 -mediated activation of PI-3 kinase/Akt pathway is considered to be the result of reversible oxidation and inactivation of protein tyrosine phosphatase (PTP) family protein such as PTEN that have a critical cysteine residue in the active site (Denu and Tanner, 1998;Lee et al, 1998;Meng et al, 2002).…”

mentioning

confidence: 99%

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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(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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The activation of protein kinase B by H2O2 or heat shock is mediated by phosphoinositide 3-kinase and not by mitogen-activated protein kinase-activated protein kinase-2

Cited by 250 publications

References 31 publications

Inhibition of JNK by Cellular Stress- and Tumor Necrosis Factor α-induced AKT2 through Activation of the NFκB Pathway in Human Epithelial Cells

Inhibition of JNK by Cellular Stress- and Tumor Necrosis Factor α-induced AKT2 through Activation of the NFκB Pathway in Human Epithelial Cells

Activation of extracellular signal-regulated protein kinase 5 downregulates FasL upon osmotic stress

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

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