Essential Role of TGF-β Signaling in Glucose-Induced Cell Hypertrophy
Open accessAbstract
In multicellular organisms, cell size is tightly controlled by nutrients and growth factors. Increasing ambient glucose induces enhanced protein synthesis and cell size. Continued exposure of cells to high glucose in vivo, as apparent under pathological conditions, results in cell hypertrophy and tissue damage. We demonstrate that activation of TGF-beta signaling has a central role in glucose-induced cell hypertrophy in fibroblasts and epithelial cells. Blocking the kinase activity of the TbetaRI receptor or loss of its expression prevented the effects of high glucose on protein synthesis and cell size. Exposure of cells to high glucose induced a rapid increase in cell surface levels of the TbetaRI and TbetaRII receptors and a rapid activation of TGF-beta ligand by matrix metalloproteinases, including MMP-2 and MMP-9. The consequent autocrine TGF-beta signaling in response to glucose led to Akt-TOR pathway activation. Accordingly, preventing MMP-2/MMP-9 or TGF-beta-induced TOR activation inhibited high glucose-induced cell hypertrophy.
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Cells can rapidly increase TGF-β responsiveness by moving intracellular receptors to the surface.
“Cells have a remarkable ability to rapidly upregulate TGF-β responsiveness by inducing receptor transport to the cell surface, thus enhancing the availability of receptors for TGF-β binding91,92.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [92]
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- Authors
- Wu, L., & Derynck, R.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Derynck, Rik
- ORCID
- Derynck, Rik
- Venue
- Developmental Cell
- Publisher
- Elsevier BV
- Published
- 2009-07
- Volume
- 17
- Issue
- 1
- Pages
- 35-48
- ISSN
- 1534-5807 (ISSN-L)
- PMC
- PMC2722039
- OpenAlex
- W2007634515
- Cited by
- 167
- References
- 57
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 9 · 2023: 13 · 2022: 12 · 2021: 16 · 2020: 12 · 2019: 10 · 2018: 6 · 2017: 11 · 2016: 7 · 2015: 11 · 2014: 7 · 2013: 10 · 2012: 10
- FWCI
- 4.16
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Developmental Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (P01HL060231, P01 HL60231)
- National Cancer Institute (R01CA063101, R01-CA63101)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- TGF-beta signaling, matrix metalloproteinases, MMP-2, MMP-9, protein synthesis, cell size control, fibroblasts, epithelial cells, hyperglycemia
- MeSH terms
- Receptor, Transforming Growth Factor-beta Type I, Receptor, Transforming Growth Factor-beta Type II, Animals, Cell Line, Diabetes Mellitus, Epithelial Cells, Fibroblasts, Glucose, Hyperglycemia, Hypertrophy, Neoplasms, Protein Kinases, Signal Transduction, Transforming Growth Factor beta, Protein Serine-Threonine Kinases, Receptors, Transforming Growth Factor beta, Mice, Knockout, Matrix Metalloproteinase 2, Matrix Metalloproteinase 9, Active Transport, Cell Nucleus, RNA Interference, Cell Size, Proto-Oncogene Proteins c-akt, Mice, Rats, Smad3 Protein, TOR Serine-Threonine Kinases
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