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Cited by 19Tuberous Sclerosis Complex ResearchPI3K/AKT/mTOR signaling in cancerProtein Kinase Regulation and GTPase Signaling

Inhibition of ERK1/2 Restores GSK3β Activity and Protein Synthesis Levels in a Model of Tuberous Sclerosis

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Pal, Rituraj, Bondar, Vitaliy V., Adamski, Carolyn J., Rodney, George G., Sardiello, Marco·2017·Scientific Reports
DOI 10.1038/s41598-017-04528-5PMC PMC5482840
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Abstract

Tuberous sclerosis (TS) is a multi-organ autosomal dominant disorder that is best characterized by neurodevelopmental deficits and the presence of benign tumors. TS pathology is caused by mutations in tuberous sclerosis complex (TSC) genes and is associated with insulin resistance, decreased glycogen synthase kinase 3β (GSK3β) activity, activation of the mammalian target of rapamycin complex 1 (mTORC1), and subsequent increase in protein synthesis. Here, we show that extracellular signal–regulated kinases (ERK1/2) respond to insulin stimulation and integrate insulin signaling to phosphorylate and thus inactivate GSK3β, resulting in increased protein synthesis that is independent of Akt/mTORC1 activity. Inhibition of ERK1/2 in Tsc2−/− cells—a model of TS—rescues GSK3β activity and protein synthesis levels, thus highlighting ERK1/2 as a potential therapeutic target for the treatment of TS.

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  • A well-established mechanism for ERK/Wnt crosstalk involves direct regulation of GSK3β, the master kinase of the β-catenin destruction complex.

    “A well-established mechanism for this crosstalk involves the direct regulation of Glycogen Synthase Kinase 3β (GSK3β), the master kinase of the β-catenin destruction complex [46–51].”

    From PPP1R18-mediated activation of Wnt/β-catenin and EMT is dependent on ERK signaling in clear cell renal cell carcinoma (2026) · cites this paper as [49]

    The Results section reports that ERK regulates insulin-mediated GSK3β activity, supporting a connection between ERK and GSK3β. But the same section says ERK does not appear to phosphorylate GSK3β directly and reports no detectable interaction. The passages address insulin signaling and protein synthesis, not ERK/Wnt crosstalk or GSK3β’s role in the β-catenin destruction complex (page unavailable). (LLM, conf=0.88)

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Cited by

Sorted by citations

Authors
Pal, R., Bondar, V. V., Adamski, C. J., Rodney, G. G., & Sardiello, M.
Affiliations
Baylor College of Medicine (US)
Corresponding author
Sardiello, Marco
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2017-06-23
Volume
7
Issue
1
Pages
4174-4174
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-017-04528-5
PMC
PMC5482840
OpenAlex
W2717569083
Cited by
19
References
39
Citations by year
2026: 3 · 2025: 2 · 2024: 1 · 2023: 1 · 2022: 2 · 2021: 1 · 2020: 3 · 2019: 3 · 2018: 1 · 2017: 2
FWCI
1.82
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health (NS079618)
  • National Institute of Neurological Disorders and Stroke (R01NS079618)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR061370, R01AR061370)
Topics
  • Health Sciences › Medicine › Physiology › Tuberous Sclerosis Complex Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
tuberous sclerosis complex, ERK1/2, GSK3β, protein synthesis, insulin signaling, TSC2, mTORC1, Akt, therapeutic target
MeSH terms
Glycogen Synthase Kinase 3 beta, Mechanistic Target of Rapamycin Complex 1, Tuberous Sclerosis Complex 2 Protein, Animals, Humans, Insulin, Models, Biological, Protein Biosynthesis, Tuberous Sclerosis, Signal Transduction, Extracellular Signal-Regulated MAP Kinases, Proto-Oncogene Proteins c-akt, Mice, HEK293 Cells

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