ArticleOncogene2012
PEA-15 potentiates H-Ras-mediated epithelial cell transformation through phospholipase D.
Article in Oncogene, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 32 citations in OpenAlex.
- Phospholipase D1 promotes cervical cancer progression by activating the RAS pathway.Journal of cellular and molecular medicine · 2022Article
- Phosphoprotein enriched in astrocytes (PEA)-15 is a novel regulator of adipose tissue expansion.Scientific reports · 2021Article
- Identification of a Novel Protein-Based Signature to Improve Prognosis Prediction in Renal Clear Cell Carcinoma.Frontiers in molecular biosciences · 2021Article
- Mammalian phospholipase D: Function, and therapeutics.Progress in lipid research · 2020Review
- Cripto-1 overexpression in U87 glioblastoma cells activates MAPK, focal adhesion and ErbB pathways.Oncology letters · 2019Article
- PEA-15 C-Terminal Tail Allosterically Modulates Death-Effector Domain Conformation and Facilitates Protein-Protein Interactions.International journal of molecular sciences · 2019Article
- PLD1 promotes dendritic spine development by inhibiting ADAM10-mediated N-cadherin cleavage.Scientific reports · 2017Article
- MiR-206 suppresses epithelial mesenchymal transition by targeting TGF-β signaling in estrogen receptor positive breast cancer cells.Oncotarget · 2016Article
- PLD1 participates in BDNF-induced signalling in cortical neurons.Scientific reports · 2015Article
- On the Quest of Cellular Functions of PEA-15 and the Therapeutic Opportunities.Pharmaceuticals (Basel, Switzerland) · 2015Review
- Phospholipase D signaling pathways and phosphatidic acid as therapeutic targets in cancer.Pharmacological reviews · 2014Review
- Phosphoprotein enriched in astrocytes (PEA)-15: a potential therapeutic target in multiple disease states.Pharmacology & therapeutics · 2014Review
- Cellular and physiological roles for phospholipase D1 in cancer.The Journal of biological chemistry · 2014Review
- Functional regulation of phospholipase D expression in cancer and inflammation.The Journal of biological chemistry · 2014Review
- PEA15 regulates the DNA damage-induced cell cycle checkpoint and oncogene-directed transformation.Molecular and cellular biology · 2014Article
- The inflammatory cytokine TNFα cooperates with Ras in elevating metastasis and turns WT-Ras to a tumor-promoting entity in MCF-7 cells.BMC cancer · 2014Article
- Phosphatidic acid, phospholipase D and tumorigenesis.Advances in biological regulation · 2014Article
- FGFR2 signaling underlies p63 oncogenic function in squamous cell carcinoma.The Journal of clinical investigation · 2013Article
- Bisphosphorylated PEA-15 sensitizes ovarian cancer cells to paclitaxel by impairing the microtubule-destabilizing effect of SCLIP.Molecular cancer therapeutics · 2013Article
- Structure of ERK2 bound to PEA-15 reveals a mechanism for rapid release of activated MAPK.Nature communications · 2013Article
Corrections and comments
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Authors and funding
8 authors at 4 institutions in 2 countries.
Funding
Abstract
The small GTPase H-Ras is a proto-oncogene that activates a variety of different pathways including the extracellular-signal-regulated kinase (ERK)/mitogen-activated protein kinase pathway. H-Ras is mutated in many human malignancies, and these mutations cause the protein to be constitutively active. Phosphoprotein enriched in astrocytes, 15 kDa (PEA-15) blocks ERK-dependent gene transcription and inhibits proliferation by sequestering ERK in the cytoplasm. We therefore investigated whether PEA-15 influences H-Ras-mediated transformation. We found that PEA-15 does not block H-Ras-activated proliferation when H-Ras is constitutively active. We show instead that in H-Ras-transformed mouse kidney epithelial cells, co-expression of PEA-15 resulted in enhanced soft agar colony growth and increased tumor growth in vivo. Overexpression of both H-Ras and PEA-15 resulted in accelerated G1/S cell cycle transition and increased activation of the ERK signaling pathway. PEA-15 mediated these effects through activation of its binding partner phospholipase D1 (PLD1). Inhibition of PLD1 or interference with PEA-15/PLD1 binding blocked PEA-15's ability to increase ERK activation. Our findings reveal a novel mechanism by which PEA-15 positively regulates Ras/ERK signaling and increases the proliferation of H-Ras-transformed epithelial cells through enhanced PLD1 expression and activation. Thus, our work provides a surprising mechanism by which PEA-15 augments H-Ras-driven transformation. These data reveal that PEA-15 not only suppresses ERK signaling and tumorigenesis but also alternatively enhances tumorigenesis in the context of active Ras.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.