The evolutionarily conserved serine-threonine kinase mammalian target of rapamycin (mTOR) plays a critical role in regulating many pathophysiological processes. Functional characterization of the mTOR signaling pathways, however, has been hampered by the paucity of known substrates. We used large-scale quantitative phosphoproteomics experiments to define the signaling networks downstream of mTORC1 and mTORC2. Characterization of one mTORC1 substrate, the growth factor receptor-bound protein 10 (Grb10), showed that mTORC1-mediated phosphorylation stabilized Grb10, leading to feedback inhibition of the phosphatidylinositol 3-kinase (PI3K) and extracellular signal-regulated, mitogen-activated protein kinase (ERK-MAPK) pathways. Grb10 expression is frequently down-regulated in various cancers, and loss of Grb10 and loss of the well-established tumor suppressor phosphatase PTEN appear to be mutually exclusive events, suggesting that Grb10 might be a tumor suppressor regulated by mTORC1.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3195509 | PMC |
| http://dx.doi.org/10.1126/science.1199484 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
mTOR Ser1261 is an AMPK-dependent phosphosite in mouse and human skeletal muscle not required for mTORC2 activity.
FASEB J
January 2025
August Krogh Section for Human and Molecular Physiology, Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark.
The kinases AMPK, and mTOR as part of either mTORC1 or mTORC2, are major orchestrators of cellular growth and metabolism. Phosphorylation of mTOR Ser1261 is reportedly stimulated by both insulin and AMPK activation and a regulator of both mTORC1 and mTORC2 activity. Intrigued by the possibilities that Ser1261 might be a convergence point between insulin and AMPK signaling in skeletal muscle, we investigated the regulation and function of this site using a combination of human exercise, transgenic mouse, and cell culture models.
View Article and Find Full Text PDFCo-expression of the RPS6KB1 and PDPK1 genes for production of activated p70S6K1 using bac-to-bac baculovirus expression system.
Mol Biol Rep
January 2025
Department of Structural and Molecular Biology, University College London, London, WC1E 6BT, UK.
Background: Ribosomal protein S6 kinase 1 (p70S6K1) is a member of the AGC family of serine/threonine kinases which plays a role in various cellular processes, including protein synthesis, cell growth, and survival. Dysregulation of p70S6K1, characterized by its overexpression and/or hyperactivation, has been implicated in numerous human pathologies, particularly in several types of cancer. Therefore, generating active, recombinant p70S6K1 is critical for investigating its role in cancer biology and for developing novel diagnostic or therapeutic approaches.
View Article and Find Full Text PDFRHEB neddylation by the UBE2F-SAG axis enhances mTORC1 activity and aggravates liver tumorigenesis.
EMBO J
January 2025
Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, China.
Small GTPase RHEB is a well-known mTORC1 activator, whereas neddylation modifies cullins and non-cullin substrates to regulate their activity, subcellular localization and stability. Whether and how RHEB is subjected to neddylation modification remains unknown. Here, we report that RHEB is a substrate of NEDD8-conjugating E2 enzyme UBE2F.
View Article and Find Full Text PDFInositol phosphates dynamically enhance stability, solubility, and catalytic activity of mTOR.
J Biol Chem
December 2024
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, USA; Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Vanderbilt University Medical Center, Nashville, Tennessee, USA. Electronic address:
Mechanistic target of rapamycin (mTOR) binds the small metabolite inositol hexakisphosphate (IP) as shown in structures of mTOR; however, it remains unclear if IP, or any other inositol phosphate species, function as an integral structural element(s) or catalytic regulator(s) of mTOR. Here, we show that multiple, exogenously added inositol phosphate species can enhance the ability of mTOR and mechanistic target of rapmycin complex 1 (mTORC1) to phosphorylate itself and peptide substrates in in vitro kinase reactions, with the higher order phosphorylated species being more potent (IP = IP > IP >> IP). IP increased the V and decreased the apparent K of mTOR for ATP.
View Article and Find Full Text PDFIsothiocyanates induce autophagy and inhibit protein synthesis in primary cells via modulation of AMPK-mTORC1-S6K1 signaling pathway, and protect against mutant huntingtin aggregation.
Eur J Nutr
December 2024
Department of Medical Biology and Genetics, Faculty of Biology, University of Gdansk, Wita Stwosza 59, Gdansk, 80-308, Poland.
Purpose: Autophagy is a degradation process whose activation underlies beneficial effects of caloric restriction. Isothiocyanates (ITCs) induce autophagy in cancer cells, however, their impact on primary cells remains insufficiently explored, particularly in non-epithelial cells. The aim of this study was to investigate whether ITCs induce autophagy in primary (non-immortalized) mesenchymal cells and if so, to determine the molecular mechanism underlying its activation and consequences on cell functioning.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!