Mitogen inactivation of glycogen synthase kinase-3<i>β</i> in intact cells via serine 9 phosphorylation

Stambolic, Vuk; Woodgett, James R.

doi:10.1042/bj3030701

Cited by 549 publications

(418 citation statements)

References 21 publications

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“…LEF/TCF promoter activity was increased in SKOV-3/ shEcad cells and was abolished by LY294002 treatment. To further show a vital role for PI3K/Akt-mediated GSK3b inhibition in the activation of b-catenin/ TCF-dependent transcription in SKOV-3 cells, we used a dominant-negative Akt and a constitutively active form of GSK3b (GSK3b-S9A), in which Ser9 was replaced with alanine, thus preventing phosphorylation and inactivation of the kinase (Stambolic and Woodgett, 1994;Eldar-Finkelman et al, 1996). Forced expression of either dominant-negative Akt or GSK3b-S9A abolished the effects of E-cadherin loss on LEF/TCF promoter activity ( Figure 3E).…”

Section: Resultsmentioning

confidence: 99%

E-cadherin inhibits tumor cell growth by suppressing PI3K/Akt signaling via β-catenin-Egr1-mediated PTEN expression

2011

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E-cadherin is a cell-cell adhesion protein and tumor suppressor that is silenced in many malignancies. E-cadherin is thought to suppress tumor cell growth by antagonizing b-catenin signaling. However, the role of E-cadherin in ovarian cancer progression is still controversial. In this study, we showed that loss of E-cadherin induced ovarian cancer cell growth and constitutive activation of phosphoinositide 3-kinase (PI3K)/Akt signaling by the inhibition of phosphatase and tensin homolog (PTEN) transcription through the downregulation of early growth response gene 1 (Egr1). In addition, immunofluorescence microscopy and T-cell factor promoter/luciferase reporter assays showed that E-cadherin loss was associated with enhanced nuclear b-catenin signaling. Constitutive activation of PI3K/Akt signaling reinforced nuclear b-catenin signaling by inactivating glycogen synthase kinase-3b indicating cross-talk between the PI3K/Akt and b-catenin signaling pathways. Finally, we found that E-cadherin negatively regulates tumor cell growth, in part, by positively regulating PTEN expression via b-catenin-mediated Egr1 regulation, thus influencing PI3K/Akt signaling. In summary, endogenous E-cadherin inhibits PI3K/Akt signaling by antagonizing b-catenin-Egr1-mediated repression of PTEN expression. Thus, the loss of E-cadherin itself may contribute to dysregulated PI3K/Akt signaling through its effects on PTEN, or it may exacerbate the frequent activation of PI3K/Akt signaling that occurs as a result of overexpression, mutation and/or amplification.

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Section: Resultsmentioning

confidence: 99%

E-cadherin inhibits tumor cell growth by suppressing PI3K/Akt signaling via β-catenin-Egr1-mediated PTEN expression

2011

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“…The level of total GSK-3b was decreased and the serine-9 phosphorylated GSK-3b/total GSK-3b ratio was increased, especially in the muscles of DM cows. GSK-3b is a constitutively active component of the PI3K/Akt pathway that is inactivated upon serine-9 phosphorylation by Akt (Stambolic and Woodgett, 1994), and the GSK-3b ser9/total GSK-3b ratio is an accurate indicator of GSK3b inactivation (Grimes and Jope, 2001). Therefore, GSK-3b activity was inhibited in DM muscles, which was a pre-requisite for the induction of the PI3K/Akt downstream survival signalling pathway.…”

Section: Discussionmentioning

confidence: 99%

Myostatin inactivation induces a similar muscle molecular signature in double-muscled cattle as in mice

Chelh

Picard

Hocquette

et al. 2011

Animal

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Myostatin (MSTN), a member of the TGF-b superfamily, is a negative regulator of skeletal muscle mass. We have previously shown that the cell survival/apoptosis pathway is a downstream target of MSTN loss-of-function in mice through the regulation of the expression or abundance of many survival and apoptotic factors. In this study, we used western-blot and quantitative PCR (qPCR) analyses to validate these novel downstream targets of MSTN in double-muscled (DM) cattle v. their controls including 260-day-old foetuses and adult cows from the INRA95 strain. MSTN loss-of-function in DM foetuses and DM cows resulted in a glycolytic shift of the muscles (e.g. upregulation of H-MyBP, PGM1 and SNTA1 and downregulation of H-FABP), activation of cell survival pathway through regulation of some components of the PI3K/Akt pathway (e.g. upregulation of DJ-1 and Gsk-3bser9/ Gsk-3btotal ratio and downregulation of PTEN) and upregulation of cell survival factors translationally controlled tumour protein (14-3-3E, Pink1). We also found a lower abundance of pro-apoptotic transcripts and/or proteins (Caspase-3, caspase-8, caspase-9, BID, ID2 and Daxx) and a higher expression of anti-apoptotic transcripts (Traf2 and Bcl2l2) in DM muscles. All together, these results are in favour of activation of the cell survival pathway and loss of apoptosis pathway within the muscles of DM animals. Alteration of both pathways may increase myonuclear or satellite cell survival, which is crucial for protein synthesis. This could contribute to muscle hypertrophy in DM foetuses and DM cows.Keywords: myostatin, cattle, muscle hypertrophy, apoptosis, cell survival ImplicationsMuscle hypertrophy has been extensively studied in meatproducing animals. In double-muscled (DM) cattle, a loss-offunction mutation in the myostatin gene (MSTN ) is responsible for muscle hypertrophy. In order to get a thorough knowledge of the molecular mechanisms of MSTN action, we have examined the molecular phenotype of DM muscle based on our previous data in MSTN-null mice. The data bring new elements to the understanding of the DM muscle phenotype and of the regulation of muscle mass in farm animals.

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“…Erk1 and/or Erk2 may phosphorylate BAD directly or through activation of other kinases such as Rsk-2. Indeed in vitro, Rsk-2 is capable of phosphorylating serine 21 of glycogen synthase kinase3a (GSK-3a) and serine 9 of glycogen synthase kinase3b (GSK-3b) (Southerland et al, 1993;Stambolic and Woodgett, 1994). The amino acid sequence around these serine residues of GSK-3a and GSK-3b resembles the sequence surrounding Ser-112 of BAD (Zha et al, 1996;del Peso et al, 1997;Datta et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Regulation of BAD phosphorylation at serine 112 by the Ras-mitogen-activated protein kinase pathway

et al. 1999

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The function of the pro-apoptotic molecule BAD is regulated by phosphorylation of two sites, serine-112 (Ser-112) and . Phosphorylation at either site results in loss of the ability of BAD to heterodimerize with the survival proteins BCL-X L or BCL-2. Phosphorylated BAD binds to 14-3-3 and is sequestered in the cytoplasm. It has been shown that phosphorylation of BAD at Ser-136 is mediated by the serine/threonine protein kinase Akt-1/PKB which is downstream of phosphatidylinositol 3-kinase (PI3K). The signaling process leading to phosphorylation of BAD at Ser-112 has not been identi®ed. In this study, we show that phosphorylation of the two serine residues of BAD is di erentially regulated. While Ser-136 phosphorylation is concordant with activation of Akt, Ser-112 phosphorylation does not correlate with Akt activation. Instead, we demonstrate that activated Ras and Raf, which are upstream of mitogen-activated protein kinases (MAPK), stimulate selective phosphorylation of BAD at Ser-112. Furthermore, phosphorylation of Ser-112, but not Ser-136 requires activation of the MAPK pathway as the MEK inhibitor, PD 98059, blocks EGF-, as well as activated Ras-or Raf-mediated phosphorylation of BAD at Ser-112. Therefore, the PI3K-Akt and Ras-MAPK pathways converge at BAD by mediating phosphorylation of distinct serine residues.

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Mitogen inactivation of glycogen synthase kinase-3β in intact cells via serine 9 phosphorylation

Cited by 549 publications

References 21 publications

E-cadherin inhibits tumor cell growth by suppressing PI3K/Akt signaling via β-catenin-Egr1-mediated PTEN expression

E-cadherin inhibits tumor cell growth by suppressing PI3K/Akt signaling via β-catenin-Egr1-mediated PTEN expression

Myostatin inactivation induces a similar muscle molecular signature in double-muscled cattle as in mice

Regulation of BAD phosphorylation at serine 112 by the Ras-mitogen-activated protein kinase pathway

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