Regulation of PTEN translation by PI3K signaling maintains pathway homeostasis

Mukherjee, Radha; Vanaja, Kiran G.; Boyer, Jacob A.; Gadal, Sunyana; Solomon, Hilla; Chandarlapaty, Sarat; Levchenko, Andre; Rosen, Neal

doi:10.1016/j.molcel.2021.01.033

Cited by 135PI3K/AKT/mTOR signaling in cancerMetabolism, Diabetes, and CancerProtein Kinase Regulation and GTPase Signaling

Regulation of PTEN translation by PI3K signaling maintains pathway homeostasis

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Mukherjee, Radha, Vanaja, Kiran G., Boyer, Jacob A., Gadal, Sunyana, Solomon, Hilla, Chandarlapaty, Sarat, Levchenko, Andre, Rosen, Neal·2021·Molecular Cell

DOI 10.1016/j.molcel.2021.01.033PMC PMC8384339

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Abstract

The PI3K pathway regulates cell metabolism, proliferation, and migration, and its dysregulation is common in cancer. We now show that both physiologic and oncogenic activation of PI3K signaling increase the expression of its negative regulator PTEN. This limits the duration of the signal and output of the pathway. Physiologic and pharmacologic inhibition of the pathway reduces PTEN and contributes to the rebound in pathway activity in tumors treated with PI3K inhibitors and limits their efficacy. Regulation of PTEN is due to mTOR/4E-BP1-dependent control of its translation and is lost when 4E-BP1 is deleted. Translational regulation of PTEN is therefore a major homeostatic regulator of physiologic PI3K signaling and plays a role in reducing the pathway activation by oncogenic PIK3CA mutants and the antitumor activity of PI3K pathway inhibitors. However, pathway output is hyperactivated in tumor cells with coexistent PI3K mutation and loss of PTEN function.

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Dephosphorylation of PTEN, which inhibits cap-dependent translation, is necessary for combined therapy to work.
“Similarly, cap-dependent translation is necessary for the transformed phenotype and we have shown previously that dephosphorylation of PTEN, which inhibits cap-dependent translation, is necessary for combined therapy to work48.”
From Combined inhibition of KRASG12C and mTORC1 kinase is synergistic in non-small cell lung cancer (2024) · cites this paper as [48]
In Results (‘mTOR controls PTEN expression’; page not available), the paper says dephosphorylated 4E-BP1—not PTEN—inhibits cap-dependent translation and reduces PTEN expression. In Results (‘Inhibition of PTEN translation by PI3K inhibitors’; page not available), it reports that reduced PTEN translation makes tumor cells less sensitive to combined PI3K-inhibitor treatment, contrary to the claim that this process is necessary for treatment to work. (LLM, conf=0.90)
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Cap-dependent translation is necessary for the transformed phenotype.
“Similarly, cap-dependent translation is necessary for the transformed phenotype and we have shown previously that dephosphorylation of PTEN, which inhibits cap-dependent translation, is necessary for combined therapy to work48.”
From Combined inhibition of KRASG12C and mTORC1 kinase is synergistic in non-small cell lung cancer (2024) · cites this paper as [48]
The Results section on mTOR-dependent PTEN expression shows that PTEN undergoes cap-dependent translation, and the section on 4E-BP1-dependent regulation links this mechanism to PI3K-inhibitor responses and tumor growth (page numbers unavailable). The paper does not establish that cap-dependent translation is necessary for the transformed phenotype. (LLM, conf=0.78)
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“Similarly, cap-dependent translation is necessary for the transformed phenotype and we have shown pre-viouslythatdephosphorylationofPTEN,whichinhibitscap-dependent translation, is necessary for combined therapy to work 48 .”
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METTL3-m6A methylation inhibits the proliferation and viability of type II alveolar epithelial cells in acute lung injury by enhancing the stability and translation efficiency of Pten mRNA
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PLEKHS1 drives PI3Ks and remodels pathway homeostasis in PTEN-null prostate
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Transcriptome‐wide high‐throughput m 6 A sequencing of differential m 6 A methylation patterns in the decidual tissues from RSA patients
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Discovery of 2-Methyl-2-(4-(2-methyl-8-(1H-pyrrolo[2,3-b]pyridin-6-yl)-1H-naphtho[1,2-d]imidazol-1-yl)phenyl)propanenitrile as a Novel PI3K/mTOR Inhibitor with Enhanced Antitumor Efficacy In Vitro and In Vivo
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Smurf1 Suppression Enhances Temozolomide Chemosensitivity in Glioblastoma by Facilitating PTEN Nuclear Translocation
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Uncovering novel therapeutic targets in glucose, nucleotides and lipids metabolism during cancer and neurological diseases
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Functional Assessments of Gynecologic Cancer Models Highlight Differences Between Single-Node Inhibitors of the PI3K/AKT/mTOR Pathway and a Pan-PI3K/mTOR Inhibitor, Gedatolisib
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PI3K/mTOR Dual Inhibitor GSK458 and Arsenic Trioxide Exert Synergistic Antitumor Effects against Ovarian Clear-Cell Carcinoma
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Progressive Alcohol-Related Brain Atrophy and White Matter Pathology Are Linked to Long-Term Inhibitory Effects on mTOR Signaling
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ABHD6 suppresses colorectal cancer progression via AKT signaling pathway
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PI3K regulates TAZ/YAP and mTORC1 axes that can be synergistically targeted
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Colorectal Cancer Cells–Derived Exosomal PIK3CA Mutation DNA Promotes Tumor Metastasis by Activating Fibroblast and Affecting Tumor Metastatic Microenvironment
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Exploring Phosphatase and Tensin Homologue Deleted on Chromosome Ten (PTEN) as a Potential Therapeutic Target for Cardiac Hypertrophy
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CDK4/6 Inhibitor Resistance in ER+ Breast Cancer
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The spectrum of cell death in sarcoma
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PIK3CA mutation fortifies molecular determinants for immune signaling in vascular cancers
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PTEN: a new dawn in Parkinson’s disease treatment
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The mTOR pathway genes mTOR , Rheb , Depdc5 , Pten , and Tsc1 have convergent and divergent impacts on cortical neuron development and functionPreprint
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Multi‐Modal Therapy for Diabetic Ulcers: A Hydrogel Platform Combining Antibacterial, Oxygenating, ROS‐Scavenging, and Pro‐Healing Functions
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BMP-7 Treatment Ameliorates PTEN-Akt Mediated Apoptosis and Adverse Cardiac Remodeling in Ponatinib-Induced Cardiotoxicity
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Therapeutic advances in HR+/HER2- advanced breast cancer after failure of CDK4/6 inhibitor therapy
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Preliminary investigation on the effect of extracorporeal shock wave combined with traction on joint contracture based on PTEN‐PI3K/AKT pathway
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Hyaluronic Acid Prevents Fusion of Brain Tumor-Derived Spheroids and Selectively Alters Their Gene Expression Profile
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Potentiation by Protein Synthesis Inducers of Translational Readthrough of Pathogenic Premature Termination Codons in PTEN Isoforms
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Identification of Prognostic Genes Related to Cell Senescence and Lipid Metabolism in Glioblastoma Based on Transcriptome and Single-Cell RNA-Seq Data
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Chikungunya virus infection under high glucose environment reverts insulin unresponsiveness and promotes cellular metabolic shift to increase anaplerosis and virion production
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Abstract 1090: Regulation of PTEN translation by PI3K signaling maintains pathway homeostasis
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Authors: Mukherjee, R., Vanaja, K. G., Boyer, J. A., Gadal, S., Solomon, H., Chandarlapaty, S., Levchenko, A., & Rosen, N.
Affiliations: Memorial Sloan Kettering Cancer Center (US)
Yale University (US)
Corresponding author: Levchenko, Andre
Rosen, Neal
ORCID: Mukherjee, Radha
Vanaja, Kiran G.
Boyer, Jacob A.
Gadal, Sunyana
Solomon, Hilla
Chandarlapaty, Sarat
Levchenko, Andre
Rosen, Neal
Venue: Molecular Cell
Publisher: Elsevier BV
Published: 2021-02
Volume: 81
Issue: 4
Pages: 708-723.e5
ISSN: 1097-2765 (ISSN-L)
DOI: 10.1016/j.molcel.2021.01.033
PMC: PMC8384339
OpenAlex: W3127889439
Cited by: 135
References: 62
Citations by year: 2026: 18 · 2025: 31 · 2024: 36 · 2023: 23 · 2022: 19 · 2021: 8
FWCI: 6.82
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 382 d)
doi.org/10.15223/policy-017 (stm-asf)
doi.org/10.15223/policy-037 (stm-asf)
doi.org/10.15223/policy-012 (stm-asf)
doi.org/10.15223/policy-029 (stm-asf)
doi.org/10.15223/policy-004 (stm-asf)
Locations: Molecular Cell (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: Breast Cancer Research Foundation (BCRF-20-141)
National Institutes of Health (P01 CA094060, R35 CA210085)
AstraZeneca
National Cancer Institute (R01 GM072024, P30 CA008748, U54 CA209992)
Boehringer Ingelheim
Eli Lilly and Company
Daiichi-Sankyo
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords: PTEN, PI3K signaling, translational regulation, PI3K inhibitors, PIK3CA mutation, PTEN loss
MeSH terms: Animals, Cricetulus, Homeostasis, Humans, Mutation, Neoplasms, Protein Biosynthesis, Signal Transduction, CHO Cells, Cell Cycle Proteins, Adaptor Proteins, Signal Transducing, PTEN Phosphohydrolase, Class I Phosphatidylinositol 3-Kinases, TOR Serine-Threonine Kinases

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Regulation of PTEN translation by PI3K signaling maintains pathway homeostasis

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