ArticleThe Journal of biological chemistry2011
Mechanical regulation of glycogen synthase kinase 3β (GSK3β) in mesenchymal stem cells is dependent on Akt protein serine 473 phosphorylation via mTORC2 protein.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers, 2 of them syntheses that pooled it.
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Who cites it
54 citing papers in PubMed, 2 syntheses or guidelines pooled it, 93 citations in OpenAlex.
- Protective role of irisin on bone in osteoporosis: a systematic review of rodent studies.Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA · 2025Pooled it
- Exercise training modalities in prediabetes: a systematic review and network meta-analysis.Frontiers in endocrinology · 2024Pooled it
- Effect of Baduanjin Exercise and Resistance Band Training on Sarcopenia in the Elderly: A Randomized Controlled Trial.Medical science monitor : international medical journal of experimental and clinical research · 2026Trial
- Biological mechanisms underlying the effects of low-magnitude mechanical stress in osteoporosis (Review).Experimental and therapeutic medicine · 2026Review
- PI3K/AKT signaling pathway: molecular crossroads in tumorigenesis and therapeutic innovation.Signal transduction and targeted therapy · 2026Review
- Peroxisome proliferator-activated receptor gamma (PPARγ) as a mechano-metabolic transducer: coordinating lipid homeostasis through mechanical cues.Molecular biomedicine · 2026Review
- Metabolic and Signaling Dysregulation in a Cellular Model of Hepatic Insulin Resistance.Current issues in molecular biology · 2026Article
- Article
- Integrated strategies for type 2 diabetes prevention: The role of diet and exercise.AIMS public health · 2025Review
- Dynamic strain and β-catenin mediated suppression of interferon responsive genes in quiescent mesenchymal stromal/stem cells.Biochemistry and biophysics reports · 2024Article
- Low intensity mechanical signals promote proliferation in a cell-specific manner: Tailoring a non-drug strategy to enhance biomanufacturing yields.Mechanobiology in medicine · 2024Article
- Mechanical loading and hyperosmolarity as a daily resetting cue for skeletal circadian clocks.Nature communications · 2023Article
- The skeleton in a physical world.Experimental biology and medicine (Maywood, N.J.) · 2022Review
- Gq Signaling in Autophagy Control: Between Chemical and Mechanical Cues.Antioxidants (Basel, Switzerland) · 2022Review
- Inhibition of focal adhesion turnover prevents osteoblastic differentiation through β-catenin mediated transduction of pro-osteogenic substrate.Journal of biomedical materials research. Part B, Applied biomaterials · 2022Article
- Mechanically Induced Nuclear Shuttling of β-Catenin Requires Co-transfer of Actin.Stem cells (Dayton, Ohio) · 2022Article
- The female syndecan-4Frontiers in cell and developmental biology · 2022Article
- The LINC Complex Assists the Nuclear Import of Mechanosensitive Transcriptional Regulators.Results and problems in cell differentiation · 2022Article
- Mechanoautophagy: Synergies Between Autophagy and Cell Mechanotransduction at Adhesive Complexes.Frontiers in cell and developmental biology · 2022Review
- Nuclear envelope mechanobiology: linking the nuclear structure and function.Nucleus (Austin, Tex.) · 2021Review
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Mechanical signals can inactivate glycogen synthase kinase 3β (GSK3β), resulting in stabilization of β-catenin. This signaling cascade is necessary for the inhibition of adipogenesis in mesenchymal stem cells (MSC) that is produced by a daily strain regimen. We investigated whether Akt is the mechanically activated kinase responsible for phosphorylation and inactivation of GSK3β in MSC. Mechanical strain (2% magnitude, 0.17 Hz) induced phosphorylation of Akt at Ser-473 and Thr-308 in parallel with phosphorylation of GSK3β at Ser-9. Inhibiting Akt (Akt1/2 kinase inhibitor treatment or Akt knockdown) prevented strain-induced phosphorylation of GSK3β at Ser-9. Inhibition of PI3K prevented Thr-308 phosphorylation, but strain-induced Ser-473 phosphorylation was measurable and induced phosphorylation of GSK3β, suggesting that Ser-473 phosphorylation is sufficient for the downstream mechanoresponse. As Rictor/mTORC2 (mammalian target of rapamycin complex 2) is known to transduce phosphorylation of Akt at Ser-473 by insulin, we investigated whether it contributes to strain-induced Ser-473 phosphorylation. Phosphorylation of Ser-473 by both mechanical and insulin treatment in MSC was prevented by the mTOR inhibitor KU0063794. When mTORC2 was blocked, mechanical GSK3β inactivation was prevented, whereas insulin inhibition of GSK3β was still measured in the absence of Ser-473 phosphorylation, presumably through phosphorylation of Akt at Thr-308. In sum, mechanical input initiates a signaling cascade that is uniquely dependent on mTORC2 activation and phosphorylation of Akt at Ser-473, an effect sufficient to cause inactivation of GSK3β. Thus, mechanical regulation of GSK3β downstream of Akt is dependent on phosphorylation of Akt at Ser-473 in a manner distinct from that of growth factors. As such, Akt reveals itself to be a pleiotropic signaling molecule whose downstream targets are differentially regulated depending upon the nature of the activating input.
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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.