ArticleCancer research2009
RIP1 activates PI3K-Akt via a dual mechanism involving NF-kappaB-mediated inhibition of the mTOR-S6K-IRS1 negative feedback loop and down-regulation of PTEN.
Article in Cancer research, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 64 citations in OpenAlex.
- The protein kinase C inhibitor sotrastaurin allows regulatory T cell function.Clinical and experimental immunology · 2014Trial
- A multi-omics landscape of programmed cell death in acetaminophen-induced acute kidney injury.Renal failure · 2025Article
- Polymorphisms in Necroptosis Pathway Genes: Novel Prognostic Markers for Multiple Myeloma Treatment Outcomes.International journal of molecular sciences · 2025Article
- Signaling Pathways Involved in Acute Pancreatitis.Journal of inflammation research · 2025Review
- The PI3K/Akt/mTOR Pathway: Immuno-Metabolic Orchestration in IR/MASH-Associated Hepatocellular Carcinoma.International journal of biological sciences · 2025Review
- Article
- Role of Receptor Interacting Protein (RIP) kinases in cancer.Genes & diseases · 2022Review
- RIP1-dependent Apoptosis and Differentiation Regulated by Skp2 and Akt/GSK3β in Acute Myeloid Leukemia.International journal of medical sciences · 2022Article
- Review
- Receptor-interacting protein kinase 1 is a key mediator in TLR3 ligand and Smac mimetic-induced cell death and suppresses TLR3 ligand-promoted invasion in cholangiocarcinoma.Cell communication and signaling : CCS · 2020Article
- IL-33 suppresses GSK-3β activation through an ST2-independent MyD88/TRAF6/RIP/PI3K/Akt pathway.Heliyon · 2018Article
- RIPK1 Inhibition Enhances Pirarubicin Cytotoxic Efficacy through AKT-P21-dependent Pathway in Hepatocellular Carcinoma.International journal of medical sciences · 2018Article
- The crossroads of breast cancer progression: insights into the modulation of major signaling pathways.OncoTargets and therapy · 2017Review
- Microbial Degradation of Cellular Kinases Impairs Innate Immune Signaling and Paracrine TNFα Responses.Scientific reports · 2016Article
- Tubular epithelial cells in renal clear cell carcinoma express high RIPK1/3 and show increased susceptibility to TNF receptor 1-induced necroptosis.Cell death & disease · 2016Article
- Effects of TORC1 Inhibition during the Early and Established Phases of Polycystic Kidney Disease.PloS one · 2016Article
- The Neuroprotective Effect of Rapamycin as a Modulator of the mTOR-NF-κB Axis during Retinal Inflammation.PloS one · 2016Article
- Targeting the PI3K/Akt signaling pathway in gastric carcinoma: A reality for personalized medicine?World journal of gastroenterology · 2015Review
- Tanshinones suppress AURKA through up-regulation of miR-32 expression in non-small cell lung cancer.Oncotarget · 2015Article
- Lentiviral-Mediated Short Hairpin RNA Knockdown of MTDH Inhibits Cell Growth and Induces Apoptosis by Regulating the PTEN/AKT Pathway in Hepatocellular Carcinoma.International journal of molecular sciences · 2015Article
Corrections and comments
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Authors and funding
13 authors at 7 institutions in 1 country.
Funding
Abstract
Therapeutic inhibition of mammalian target of rapamycin (mTOR) in cancer is complicated by the existence of a negative feedback loop linking mTOR to the phosphatidylinositol 3-kinase (PI3K)-Akt pathway. Thus, mTOR inhibition by rapamycin or TSC1/2 results in increased PI3K-Akt activation. The death domain kinase receptor interacting protein 1 (RIP1) plays a key role in nuclear factor-kappaB (NF-kappaB) activation and also activates the PI3K-Akt pathway through unknown mechanisms. RIP1 has recently been found to be overexpressed in glioblastoma multiforme, the most common adult primary malignant brain tumor, but not in grade II to III glioma. Our data suggest that RIP1 activates PI3K-Akt using dual mechanisms by removing the two major brakes on PI3K-Akt activity. First, increased expression of RIP1 activates PI3K-Akt by interrupting the mTOR negative feedback loop. However, unlike other signals that regulate mTOR activity without affecting its level, RIP1 negatively regulates mTOR transcription via a NF-kappaB-dependent mechanism. The second mechanism used by RIP1 to activate PI3K-Akt is down-regulation of cellular PTEN levels, which appears to be independent of NF-kappaB activation. The clinical relevance of these findings is highlighted by the demonstration that RIP1 levels correlate with activation of Akt in glioblastoma multiforme. Thus, our study shows that RIP1 regulates key components of the PTEN-PI3K-Akt-mTOR pathway and elucidates a novel negative regulation of mTOR signaling at the transcriptional level by the NF-kappaB pathway. Our data suggest that the RIP1-NF-kappaB status of tumors may influence response to treatments targeting the PTEN-PI3K-mTOR signaling axis.
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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.