ArticleGastroenterology2012
The phosphatase PHLPP1 regulates Akt2, promotes pancreatic cancer cell death, and inhibits tumor formation.
Article in Gastroenterology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers.
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Who cites it
54 citing papers in PubMed, 92 citations in OpenAlex.
- Post-translational modification-centric base editor screens to assess phosphorylation site functionality in high throughput.Nature methods · 2024Article
- SKP2 Contributes to AKT Activation by Ubiquitination Degradation of PHLPP1, Impedes Autophagy, and Facilitates the Survival of Thyroid Carcinoma.Molecules and cells · 2023Article
- Emerging roles of PHLPP phosphatases in lung cancer.Frontiers in oncology · 2023Review
- PHLPP isoforms differentially regulate Akt isoforms and AS160 affecting neuronal insulin signaling and insulin resistance via Scribble.Cell communication and signaling : CCS · 2022Article
- Circular RNA ANAPC7 Inhibits Tumor Growth and Muscle Wasting via PHLPP2-AKT-TGF-β Signaling Axis in Pancreatic Cancer.Gastroenterology · 2022Article
- The Curcumin Analog Da0324 Inhibits the Proliferation of Gastric Cancer CellsJournal of Cancer · 2022Article
- Article
- The Multifaceted Role of CMA in Glioma: Enemy or Ally?International journal of molecular sciences · 2021Review
- Immune correlates of tuberculosis disease and risk translate across species.Science translational medicine · 2020Article
- PHLPP Sensitizes Multiple Myeloma Cells to Bortezomib Through Regulating LAMP2.OncoTargets and therapy · 2020Article
- PHLPP2 as a novel metastatic and prognostic biomarker in non-small cell lung cancer patients.Thoracic cancer · 2019Article
- Phlpp1 is associated with human intervertebral disc degeneration and its deficiency promotes healing after needle puncture injury in mice.Cell death & disease · 2019Article
- Expression of PHLPP2 correlates with clinicopathologic characteristics and prognosis in colorectal cancer.International journal of clinical and experimental pathology · 2019Article
- The impact of phosphatases on proliferative and survival signaling in cancer.Cellular and molecular life sciences : CMLS · 2018Review
- Article
- Differentially Expressed Genes in Osteomyelitis Induced byFrontiers in microbiology · 2018Article
- Roles of autophagy and metabolism in pancreatic cancer cell adaptation to environmental challenges.American journal of physiology. Gastrointestinal and liver physiology · 2017Article
- Expression, regulation and function of miR-495 in healthy and tumor tissues.Oncology letters · 2017Article
- MicroRNA-27a contributes to the malignant behavior of gastric cancer cells by directly targeting PH domain and leucine-rich repeat protein phosphatase 2.Journal of experimental & clinical cancer research : CR · 2017Article
- Regulation of PI3K effector signalling in cancer by the phosphoinositide phosphatases.Bioscience reports · 2017Review
Corrections and comments
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Authors and funding
10 authors at 4 institutions in 2 countries.
Funding
Abstract
BACKGROUND &
aimsThe kinase Akt mediates resistance of pancreatic cancer (PaCa) cells to death and is constitutively active (phosphorylated) in cancer cells. Whereas the kinases that activate Akt are well characterized, less is known about phosphatases that dephosporylate and thereby inactivate it. We investigated regulation of Akt activity and cell death by the phosphatases PHLPP1 and PHLPP2 in PaCa cells, mouse models of PaCa, and human pancreatic ductal adenocarcinoma (PDAC).
methodsWe measured the effects of PHLPP overexpression or knockdown with small interfering RNAs on Akt activation and cell death. We examined regulation of PHLPPs by growth factors and reactive oxygen species, as well as associations between PHLPPs and tumorigenesis.
resultsPHLPP overexpression inactivated Akt, whereas PHLPP knockdown increased phosphorylation of Akt in PaCa cells. Levels of PHLPPs were greatly reduced in human PDAC and in mouse genetic and xenograft models of PaCa. PHLPP activities in PaCa cells were down-regulated by growth factors and Nox4 reduced nicotinamide adenine dinucleotide phosphate oxidase. PHLPP1 selectively dephosphorylated Akt2, whereas PHLPP2 selectively dephosphorylated Akt1. Akt2, but not Akt1, was up-regulated in PDAC, and Akt2 levels correlated with mortality. Consistent with these results, high levels of PHLPP1, which dephosphorylates Akt2 (but not PHLPP2, which dephosphorylates Akt1), correlated with longer survival times of patients with PDAC. In mice, xenograft tumors derived from PaCa cells that overexpress PHLPP1 (but not PHLPP2) had inactivated Akt, greater extent of apoptosis, and smaller size.
conclusionsPHLPP1 has tumor suppressive activity and might represent a therapeutic or diagnostic tool for PDAC.
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Registered trials
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