ArticleThe Journal of biological chemistry2011
mTOR-dependent regulation of PHLPP expression controls the rapamycin sensitivity in cancer cells.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 71 citations in OpenAlex.
- PHLPP and LAMP2 predict favorable treatment response and survival in multiple myeloma patients who receive induction treatment with bortezomib.Irish journal of medical science · 2025Article
- MiR-25-3p regulates pulmonary arteriovenous malformation after Glenn procedure in patients with univentricular heart via the PHLPP2-HIF-1α axis.Scientific reports · 2025Article
- Phlpp1 alters the murine chondrocyte phospho-proteome during endochondral bone formation.Bone · 2024Article
- Ribosomal Protein S6: A Potential Therapeutic Target against Cancer?International journal of molecular sciences · 2021Review
- Downregulation of PHLPP induced by endoplasmic reticulum stress promotes eIF2α phosphorylation and chemoresistance in colon cancer.Cell death & disease · 2021Article
- Phosphatase PHLPP2 regulates the cellular response to metabolic stress through AMPK.Cell death & disease · 2021Article
- On the PHLPPside: Emerging roles of PHLPP phosphatases in the heart.Cellular signalling · 2021Review
- Inhibition of PHLPP1/2 phosphatases rescues pancreatic β-cells in diabetes.Cell reports · 2021Article
- Age-related expression of prominent regulatory elements in mouse brain: catastrophic decline of FOXO3a.GeroScience · 2021Article
- Feedback, Crosstalk and Competition: Ingredients for Emergent Non-Linear Behaviour in the PI3K/mTOR Signalling Network.International journal of molecular sciences · 2021Review
- PHLPPing the Script: Emerging Roles of PHLPP Phosphatases in Cell Signaling.Annual review of pharmacology and toxicology · 2021Review
- Reduced PHLPP Expression Leads to EGFR-TKI Resistance in Lung Cancer by Activating PI3K-AKT and MAPK-ERK Dual Signaling.Frontiers in oncology · 2021Article
- A Crosstalk Between Dual-Specific Phosphatases and Dual-Specific Protein Kinases Can Be A Potential Therapeutic Target for Anti-cancer Therapy.Advances in experimental medicine and biology · 2021Article
- Distinct Roles of mTOR Targets S6K1 and S6K2 in Breast Cancer.International journal of molecular sciences · 2020Review
- PHLPP2 as a novel metastatic and prognostic biomarker in non-small cell lung cancer patients.Thoracic cancer · 2019Article
- Expression of PHLPP2 correlates with clinicopathologic characteristics and prognosis in colorectal cancer.International journal of clinical and experimental pathology · 2019Article
- Dysregulated MicroRNA Fingerprints and Methylation Patterns in Hepatocellular Carcinoma, Cancer Stem Cells, and Mesenchymal Stem Cells.Frontiers in cell and developmental biology · 2019Review
- DNA methylation and FoxO3a regulate PHLPP1 expression in chondrocytes.Journal of cellular biochemistry · 2018Article
- The impact of phosphatases on proliferative and survival signaling in cancer.Cellular and molecular life sciences : CMLS · 2018Review
- Biochemical and cellular properties of insulin receptor signalling.Nature reviews. Molecular cell biology · 2018Review
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
PHLPP belongs to a novel family of protein phosphatases that serve as negative regulators of Akt. There are two isoforms, PHLPP1 and PHLPP2, identified in this family. Our previous studies indicated a tumor suppressor role of both PHLPP isoforms in colon cancer. Here we report that the expression of PHLPP is controlled by mTOR-dependent protein translation in colon and breast cancer cells. Treating cells with rapamycin or knockdown of mTOR using RNAi results in a marked decrease of PHLPP protein expression. In contrast, stable knockdown of TSC2, a negative regulator of mTOR activity, increases PHLPP expression. The rapamycin-mediated down-regulation of PHLPP is blocked by expression of a rapamycin-insensitive mutant of p70S6K. In addition, depletion of 4E-BP1 expression by RNAi results in an increase of PHLPP expression and resistance to rapamycin-induced down-regulation. Moreover, inhibition of mTOR activity by amino acid or glucose starvation reduces PHLPP expression in cells. Functionally, we show that rapamycin-mediated inhibition of PHLPP expression contributes to rapamycin resistance in colon cancer cells. Thus, our studies identify a compensatory feedback regulation in which the activation of Akt is inhibited by up-regulation of PHLPP through mTOR, and this mTOR-dependent expression of PHLPP subsequently determines the rapamycin sensitivity of cancer cells.
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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.