Protein Kinase B/Akt Binds and Phosphorylates PED/PEA-15, Stabilizing Its Antiapoptotic Action

Trencia, Alessandra; Perfetti, Anna; Cassese, Angela; Vigliottá, Giovanni; Miele, Claudia; Oriente, Francesco; Santopietro, Stefania; Giacco, Ferdinando; Condorelli, Gerolama; Formisano, Pietro; Béguinot, Francesco

doi:10.1128/mcb.23.13.4511-4521.2003

Cited by 137 publications

(166 citation statements)

References 30 publications

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“…In tumoral cells including glioma, AKT controls the stability and the antiapoptotic function of the protein PED/PEA-15 by its phosphorylation on ser116. 29,30 We explored the effect of K34c on PED/ PEA-15 expression and phosphorylation in U87MG-α5 high cells. Both were decreased by K34c but not affected by Nutlin3a (Figure 3c).…”

Section: Resultsmentioning

confidence: 99%

Integrin α5β1 and p53 convergent pathways in the control of anti-apoptotic proteins PEA-15 and survivin in high-grade glioma

et al. 2015

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Integrin α5β1 expression is correlated with a worse prognosis in high-grade glioma. We previously unraveled a negative crosstalk between integrin α5β1 and p53 pathway, which was proposed to be part of the resistance of glioblastoma to chemotherapies. The restoration of p53 tumor-suppressor function is under intensive investigations for cancer therapy. However, p53-dependent apoptosis is not always achieved by p53-reactivating compounds such as Nutlin-3a, although full transcriptional activity of p53 could be obtained. Here we investigated whether integrin α5β1 functional inhibition or repression could sensitize glioma cells to Nutlin-3a-induced p53-dependent apoptosis. We discovered that α5β1 integrin-specific blocking antibodies or small RGD-like antagonists in association with Nutlin-3a triggered a caspase (Casp) 8/Casp 3-dependent strong apoptosis in glioma cells expressing a functional p53. We deciphered the molecular mechanisms involved and we showed the crucial role of two anti-apoptotic proteins, phosphoprotein enriched in astrocytes 15 (PEA-15) and survivin in glioma cell apoptotic outcome. PEA-15 is under α5β1 integrin/AKT (protein kinase B) control and survivin is a p53-repressed target. Moreover, interconnections between integrin and p53 pathways were revealed. Indeed PEA-15 repression by specific small-interfering RNA (siRNA)-activated p53 pathway to repress survivin and conversely survivin repression by specific siRNA decreased α5β1 integrin expression. This pro-apoptotic loop could be generalized to several glioma cell lines, whatever their p53 status, inasmuch PEA-15 and survivin protein levels were decreased. Our findings identify a novel mechanism whereby inhibition of α5β1 integrin and activation of p53 modulates two anti-apoptotic proteins crucially involved in the apoptotic answer of glioma cells. Importantly, our results suggest that high-grade glioma expressing high level of α5β1 integrin may benefit from associated therapies including integrin antagonists and repressors of survivin expression.

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Section: Resultsmentioning

confidence: 99%

Integrin α5β1 and p53 convergent pathways in the control of anti-apoptotic proteins PEA-15 and survivin in high-grade glioma

et al. 2015

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“…Consistent with this possibility, recent studies by Data are presented as the means ± SEM or %. Statistical significance was assessed by comparing all three groups of subjects our own as well as other laboratories have shown that PEA15 is highly regulated at the post-translational level [1,2,7,12]. Previous studies in cultured cells and in transgenic mice have shown that overexpression of the gene encoding PEA15 determines resistance to insulin action and impairs glucose-induced insulin secretion.…”

Section: Discussionmentioning

confidence: 99%

“…It binds ERKs in the nucleus, exporting them into the cytoplasm, thus preventing cell cycle entry caused by sustained phospho-ERK nuclear accumulation [5,6]. PEA15 also interacts with protein kinase B (Akt/ PKB) and p90 ribosomal S6 kinase isozyme (RSK2), two key components of the phosphoinositide 3-kinase (PI3-K) and ERK signalling pathways, whose activation is central to control of cell survival [7,8]. In addition, PEA15 exerts a wide anti-apoptotic action.…”

Section: Introductionmentioning

confidence: 99%

The PEA15 gene is overexpressed and related to insulin resistance in healthy first-degree relatives of patients with type 2 diabetes

et al. 2006

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Aims/hypothesis Overexpression of the gene encoding phosphoprotein enriched in astrocytes 15 (PEA15), also known as phosphoprotein enriched in diabetes (PED), causes insulin resistance and diabetes in transgenic mice and has been observed in type 2 diabetic individuals. The aim of this study was to investigate whether PEA15 overexpression occurs in individuals at high risk of diabetes and whether it is associated with specific type 2 diabetes subphenotypes. Subjects and methods We analysed PEA15 expression in euglycaemic first-degree relatives (FDR) of type 2 diabetic subjects.Results The expression of PEA15 in peripheral blood leucocytes (PBLs) paralleled that in fat and skeletal muscle tissues. In PBLs from the FDR, PEA15 expression was two-fold higher than in euglycaemic individuals with no family history of diabetes (control subjects), both at the protein and the mRNA level (p<0.001). The expression of PEA15 was comparable in FDR and type 2 diabetic subjects and in each group close to one-third of the subjects expressed PEA15 levels more than 2 SD higher than the mean of control subjects. Subjects with IFG with at least one type 2 diabetes-affected FDR also overexpressed PEA15 (p<0.05). In all the groups analysed, PEA15 expression was independent of sex and unrelated to age, BMI, waist circumference, systolic and diastolic BP, and fasting cholesterol, triacylglycerol and glucose levels. However, in euglycaemic FDR of type 2 diabetic subjects, PEA15 expression was inversely correlated with insulin sensitivity (r=−557, p=0.01). Conclusions/interpretation We conclude that PEA15 overexpression represents a common defect in FDR of patients with type 2 diabetes and is correlated with reduced insulin sensitivity in these individuals.

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“…Besides, we have already demonstrated that PEA-15 binds to ERK1/2 and prevents their nuclear translocation, which results in blockade of ERK-dependent transcription and cell proliferation in response to serum (Formstecher et al, 2001). More recently, PEA-15 has been identified as a novel Akt substrate (Trencia et al, 2003). These authors reported that phosphorylation by Akt of PEA-15 on Ser 116 determines resistance to apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand or serum deprivation.…”

Section: Introductionmentioning

confidence: 91%

Akt Down-Regulates ERK1/2 Nuclear Localization and Angiotensin II-induced Cell Proliferation through PEA-15

Gervais

Dugourd

Muller

et al. 2006

MBoC

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Angiotensin II (AngII) type 1 receptors (AT1) regulate cell growth through the extracellular signal-regulated kinase (ERK)1/2 and phosphatidylinositol 3-kinase (PI3K) pathways. ERK1/2 and Akt/protein kinase B, downstream of PI3K, are independently activated but both required for mediating AngII-induced proliferation when expressed at endogenous levels. We investigate the effect of an increase in the expression of wild-type Akt1 by using Chinese hamster ovary (CHO)-AT1 cells. Unexpectedly, Akt overexpression inhibits the AT1-mediated proliferation. This effect could be generated by a cross-talk between the PI3K and ERK1/2 pathways. A functional partner is the phosphoprotein enriched in astrocytes of 15 kDa (PEA-15), an Akt substrate known to bind ERK1/2 and to regulate their nuclear translocation. We report that Akt binds to PEA-15 and that Akt activation leads to PEA-15 stabilization, independently of PEA-15 interaction with ERK1/2. Akt cross-talk with PEA-15 does not affect ERK1/2 activation but decreases their nuclear activity as a result of the blockade of ERK1/2 nuclear accumulation. In response to AngII, PEA-15 overexpression displays the same functional consequences on ERK1/2 signaling as Akt overactivation. Thus, Akt overactivation prevents the nuclear translocation of ERK1/2 and the AngII-induced proliferation through interaction with and stabilization of endogenous PEA-15.

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Protein Kinase B/Akt Binds and Phosphorylates PED/PEA-15, Stabilizing Its Antiapoptotic Action

Cited by 137 publications

References 30 publications

Integrin α5β1 and p53 convergent pathways in the control of anti-apoptotic proteins PEA-15 and survivin in high-grade glioma

Integrin α5β1 and p53 convergent pathways in the control of anti-apoptotic proteins PEA-15 and survivin in high-grade glioma

The PEA15 gene is overexpressed and related to insulin resistance in healthy first-degree relatives of patients with type 2 diabetes

Akt Down-Regulates ERK1/2 Nuclear Localization and Angiotensin II-induced Cell Proliferation through PEA-15

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