ArticleThe Biochemical journal2003
Activation of S6K1 (p70 ribosomal protein S6 kinase 1) requires an initial calcium-dependent priming event involving formation of a high-molecular-mass signalling complex.
Article in The Biochemical journal, 2003. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 80 citations in OpenAlex.
- TSC-associated microglial hyperactivity: enhanced calcium signaling, metabolism, and phagocytosis.Acta neuropathologica · 2026Article
- Possible involvement of p60-S6K1 in accelerating RPS6 phosphorylation for rapid recovery from skeletal muscle disuse atrophy.Laboratory animal research · 2025Article
- Piezo1 channels enhance anabolic signaling activation induced by electrical stimulation of cultured myotubes.FEBS open bio · 2025Article
- mTOR mutation disrupts larval zebrafish tail fin regeneration via regulating proliferation of blastema cells and mitochondrial functions.Journal of orthopaedic surgery and research · 2024Article
- Regulation of autophagy by perilysosomal calcium: a new player in β-cell lipotoxicity.Experimental & molecular medicine · 2024Review
- New Insights into the Regulation of mTOR Signaling via CaInternational journal of molecular sciences · 2023Review
- A compound directed against S6K1 hampers fat mass expansion and mitigates diet-induced hepatosteatosis.JCI insight · 2022Article
- The Gut Microbiome and Type 2 Diabetes Mellitus: Discussing a Complex Relationship.Biomedicines · 2020Review
- An Anabolic Signaling Response of Rat Soleus Muscle to Eccentric Contractions Following Hindlimb Unloading: A Potential Role of Stretch-Activated Ion Channels.International journal of molecular sciences · 2019Article
- Inhibition of store-operated channels by carboxyamidotriazole sensitizes ovarian carcinoma cells to anti-BclxOncotarget · 2018Article
- Activation of the Stress Response Kinase JNK (c-Jun N-terminal Kinase) Attenuates Insulin Action in Retina through a p70S6K1-dependent Mechanism.The Journal of biological chemistry · 2017Article
- Article
- Methionine Regulates mTORC1 via the T1R1/T1R3-PLCβ-CaInternational journal of molecular sciences · 2016Article
- Ca(2+) permeation and/or binding to CaV1.1 fine-tunes skeletal muscle Ca(2+) signaling to sustain muscle function.Skeletal muscle · 2015Article
- Orexin/hypocretin activates mTOR complex 1 (mTORC1) via an Erk/Akt-independent and calcium-stimulated lysosome v-ATPase pathway.The Journal of biological chemistry · 2014Article
- Ligands for FKBP12 increase Ca2+ influx and protein synthesis to improve skeletal muscle function.The Journal of biological chemistry · 2014Article
- Molecular Characterization and Expression Analysis of S6K1 in Cashmere Goats (Capra hircus).Asian-Australasian journal of animal sciences · 2013Article
- Identification of protein interactions involved in cellular signaling.Molecular & cellular proteomics : MCP · 2013Review
- Novel role for SHP-2 in nutrient-responsive control of S6 kinase 1 signaling.Molecular and cellular biology · 2013Article
- Gemfibrozil, a lipid-lowering drug, induces suppressor of cytokine signaling 3 in glial cells: implications for neurodegenerative disorders.The Journal of biological chemistry · 2012Article
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The mitogen-stimulated protein kinase p70 ribosomal protein S6 kinase 1 (S6K1) is a key enzyme in the regulation of cell growth and proliferation. Activation of S6K1 requires a complex, ordered series of conformational changes and phosphorylation reactions. While the role of sequential, multi-site phosphorylation has been extensively detailed, characterization of the priming step required to initiate this cascade has remained elusive. In the present study we show for the first time that this priming process is dependent on calcium. Calcium-dependent regulation of S6K1 did not specifically target Thr-229 and Thr-389, the key regulatory phosphorylation sites; rather, calcium chelation resulted in a global inhibition of S6K1 phosphorylation. Mutation of individual phosphorylation sites in the auto-inhibitory and hydrophobic domains to acidic residues (to mimic phosphorylation) yields a kinase that remains sensitive to calcium chelation, while the combined mutations alleviate the requirement for calcium. Furthermore, deletion of the C-terminal residues (398-502) also renders the kinase insensitive to calcium. We hypothesize that the initial calcium-dependent process is required to release an inhibitory interaction between the C- and N-termini of S6K1, thus allowing phosphorylation of these key domains. The requirement for this priming step can only be overcome by mutations mimicking the phosphorylation of both the auto-inhibitory and hydrophobic domains. We further propose that the priming event involves formation of a calcium-dependent protein complex that releases the interaction between the N- and C-termini. S6K1 is then accessible for activation by the kinases that target the known regulatory phosphorylation sites. Consistent with this hypothesis, serum stimulation of S6K1 activity is associated with its incorporation into a calcium-dependent high-molecular-mass complex.
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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 Socratic graph.