ArticleMolecular and cellular biology1997
The insulin-induced signalling pathway leading to S6 and initiation factor 4E binding protein 1 phosphorylation bifurcates at a rapamycin-sensitive point immediately upstream of p70s6k.
Article in Molecular and cellular biology, 1997. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 80 papers.
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Who cites it
80 citing papers in PubMed, 237 citations in OpenAlex.
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- Phosphatidic acid-mediated binding and mammalian cell internalization of the Vibrio cholerae cytotoxin MakA.PLoS pathogens · 2021Article
- A novel social fear conditioning procedure alters social behavior and mTOR signaling in differentially housed adolescent rats.Developmental psychobiology · 2021Article
- LIN28B/Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Fibro-adipose vascular anomaly (FAVA): three case reports with an emphasis on the mammalian target of rapamycin (mTOR) pathway.Diagnostic pathology · 2020Article
- Cryo-EM insight into the structure of MTOR complex 1 and its interactions with Rheb and substrates.F1000Research · 2019Review
- AKT signalling selectively regulates PINK1 mitophagy in SHSY5Y cells and human iPSC-derived neurons.Scientific reports · 2018Article
- Neoadjuvant therapy for localized prostate cancer: Examining mechanism of action and efficacy within the tumor.Urologic oncology · 2016Review
- Drosophila S6 Kinase like inhibits neuromuscular junction growth by downregulating the BMP receptor thickveins.PLoS genetics · 2015Article
- Gene expression profiling in pachyonychia congenita skin.Journal of dermatological science · 2015Article
- TORC1 promotes phosphorylation of ribosomal protein S6 via the AGC kinase Ypk3 in Saccharomyces cerevisiae.PloS one · 2015Article
- Predictive value of phosphorylated mammalian target of rapamycin for disease-free survival in breast cancer patients receiving neoadjuvant chemotherapy.Oncology letters · 2014Article
20 more citing papers are in PubMed but not listed here.
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Employing specific inhibitors and docking-site mutants of growth factor receptors, recent studies have indicated that the insulin-induced increase in 40S ribosomal protein S6 and initiation factor 4E binding protein 1 (4E-BP1) phosphorylation is mediated by the mTOR/FRAP-p70s6k signal transduction pathway. However, it has not been resolved whether the phosphorylation of both proteins is mediated by p70s6k or whether they reside on parallel pathways which bifurcate upstream of p70s6k. Here we have used either rapamycin-resistant, kinase-dead, or wild-type p70s6k variants to distinguish between these possibilities. The rapamycin-resistant p70s6k, which has high constitutive activity, was able to signal to S6 in the absence of insulin and to prevent the rapamycin-induced block of S6 phosphorylation. This same construct did not increase the basal state of 4E-BP1 phosphorylation or protect it from the rapamycin-induced block in phosphorylation. Unexpectedly, the rapamycin-resistant p70s6k inhibited insulin-induced 4E-BP1 phosphorylation in a dose-dependent manner. This effect was mimicked by the kinase-dead and wild-type p70s6k constructs, which also blocked insulin-induced dissociation of 4E-BP1 from initiation factor 4E. Both the kinase-dead and wild-type constructs also blocked reporter p70s6k activation, although only the kinase-dead p70s6k had a dominant-interfering effect on S6 phosphorylation. Analysis of phosphopeptides from reporter 4E-BP1 and p70s6k revealed that the kinase-dead p70s6k affected the same subset of sites as rapamycin in both proteins. The results demonstrate, for the first time, that activated p70s6k mediates increased S6 phosphorylation in vivo. Furthermore, they show that increased 4E-BP1 phosphorylation is controlled by a parallel signalling pathway that bifurcates immediately upstream of p70s6k, with the two pathways sharing a common rapamycin-sensitive activator.
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