PEA-15 Binding to ERK1/2 MAPKs Is Required for Its Modulation of Integrin Activation

Chou, Fan-Li; Hill, Jennifer; Hsieh, Jui-Chien; Pouysségur, Jacques; Brunet, Anne; Glading, Angela; Überall, Florian; Ramos, Joe W.; Werner, M.D.; Ginsberg, Mark H.

doi:10.1074/jbc.m309322200

Cited by 53 publications

(76 citation statements)

References 37 publications

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“…PEA-15 is a multifunctional protein known (1) to modulate α5β1 integrin activity, 38 (2) to be included in the α5β1 adhesome 39 and (3) to bind to Fas-associated protein with death domain (FADD) and/or Casp 8 in the apoptotic death-inducing signaling complex. 32 PEA-15 can be phosphorylated on ser116 by AKT and on ser104 by protein kinase C leading to different functional implications.…”

Section: Discussionmentioning

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: Discussionmentioning

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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“…Moreover, these interactions are also regulated by protein phosphorylations and dephosphorylations (51,53). Because ERK protein requires complex formation with other proteins for its activities such as nuclear localizations and induced epithelial morphogenesis (54,55), p38␥ may promote Ras transformation through its C terminus-mediated ERK binding by a scaffoldlike mechanism.…”

Section: Discussionmentioning

confidence: 99%

Essential Role of p38γ in K-Ras Transformation Independent of Phosphorylation

Tang¹,

Qi²,

Mercola

et al. 2005

Journal of Biological Chemistry

111

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Here we report that K-Ras activated p38␥, a p38 MAPK family member, by inducing its expression without increasing its phosphorylation and that depletion of induced p38␥ suppressed Ras transformation in rat intestinal epithelial cells. This p38␥ activity contrasts with that of its family member, p38␣, which is activated by Ras through phosphorylation, leading to an inhibition of Ras transformation. Mechanistic analyses showed that unphosphorylated p38␥ may promote Ras transformation through an increased complex formation with ERK proteins. Significantly, functional p38␥ protein was expressed only in K-ras-mutated human colon cancer cells, and p38␥ transcripts were ubiquitously increased in a set of primary human colon cancer tissues. These studies thus demonstrate the essential role of p38␥ in K-Ras transformation independent of phosphorylation, and elevated p38␥ may serve as a novel diagnostic marker and therapeutic target for human colon cancer.

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“…Therefore, PEA-15 is a pivotal protein functionally linking Akt and ERK1/2. Although the molecular interactions between various motifs of ERK1/2 and PEA-15 have been investigated for their direct binding Chou et al, 2003), the mechanisms of molecular interactions between Akt and PEA-15 remain to be determined. An important issue will be to assess whether the phosphorylation state of Akt affects its binding to PEA-15 and/or the binding of PEA-15 to ERK1/2.…”

Section: Discussionmentioning

confidence: 99%

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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PEA-15 Binding to ERK1/2 MAPKs Is Required for Its Modulation of Integrin Activation

Cited by 53 publications

References 37 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

Essential Role of p38γ in K-Ras Transformation Independent of Phosphorylation

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

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