Phosphorylation is the switch that turns PEA-15 from tumor suppressor to tumor promoter

Sulzmaier, Florian J.; Opoku-Ansah, John; Ramos, Joe W.

doi:10.4161/sgtp.20021

Cited by 39 publications

(40 citation statements)

References 36 publications

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“…We showed that levels of PKC-ζ and S104-phosphorylated PEA-15 increased following G129R treatment, suggesting that S104-phosphorylated PEA-15 is tumor suppressive by contributing to G129R-induced growth inhibition. This finding diverges from a recent report that S104 phosphorylation is a switch to turn PEA-15 from tumor suppressor to tumor promoter (Sulzmaier et al, 2012). Further studies are needed to define the role of S104-PEA-15 in the tumor-inhibitory effect of blockade of PRL/PRLR.…”

Section: Discussioncontrasting

confidence: 99%

Antagonism of Tumoral Prolactin Receptor Promotes Autophagy-Related Cell Death

et al. 2014

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Summary Therapeutic upregulation of macroautophagy in cancer cells provides an alternative mechanism for cell death. Prolactin (PRL) and its receptor (PRLR) are considered attractive therapeutic targets because of their roles as growth factors in tumor growth and progression. We utilized a novel antagonist peptide of PRL, G129R, to block activity of the tumoral PRL/PRLR axis, which resulted in inhibition of tumor growth in orthotopic models of human ovarian cancer. Prolonged treatment with G129R induced accumulation of redundant autolysosomes in three-dimensional cancer spheroids, leading to a type II programmed cell death. This inducible autophagy was a non-canonical beclin-1–independent pathway and was sustained by an astrocytic phosphoprotein (PEA-15) and protein kinase C zeta interactome. Lower levels of tumoral PRL/PRLR in clinical samples were associated with longer patient survival. Our findings provide a new understanding of the mechanisms of tumor growth inhibition through targeting PRL/PRLR and may have clinical implications.

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Section: Discussioncontrasting

confidence: 99%

Antagonism of Tumoral Prolactin Receptor Promotes Autophagy-Related Cell Death

et al. 2014

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“…32 PEA-15 can be phosphorylated on ser116 by AKT and on ser104 by protein kinase C leading to different functional implications. 40 In fact, unphosphorylated PEA-15 acts as a tumor suppressor by sequestering extracellular signal-regulated kinase in the cytoplasm and thus inhibits proliferation. In tumoral cells with an exacerbated AKT signaling, phosphorylated-PEA-15 switches from tumor suppressor to tumor promoter by interfering with FADD/Casp 8 and apoptosis.…”

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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“…PEA15 is a multi-functional protein that has been implicated in the regulation of major intracellular processes including proliferation and apoptosis, and its function is tightly regulated by its phosphorylation at two serine residues, Ser104 and Ser116 [27]. Both CaMKII and AKT phosphorylate PEA15 at Ser116 [47][48][49] and, more recently, AMPK was reported to act as an upstream kinase of PEA15 in both normal and cancerous breast epithelial cells [36]. Phosphatases play an equally important role as kinases in regulating the phosphorylation state of PEA15.…”

Section: Discussionmentioning

confidence: 99%

“…Consistent with these observations, others have reported that the non-phosphorylated form of PEA15 binds to the extracellular signal-regulated kinase 1/2 (ERK1/2), preventing its nuclear accumulation, leading to the inhibition of cell proliferation [30,31]. On the other hand, phosphorylation of PEA15 on Ser116 promotes its binding to Fas-associated death domain protein (FADD) via its DED domain, preventing FADD-mediated activation of caspases and the formation of the death inducing signalling complex (DISC), leading to the inhibition of the extrinsic apoptotic pathway [30,33,47].…”

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confidence: 99%