Cited by 7414-3-3 protein interactionsTuberous Sclerosis Complex ResearchPI3K/AKT/mTOR signaling in cancer

14-3-3β Binds to and Negatively Regulates the Tuberous Sclerosis Complex 2 (TSC2) Tumor Suppressor Gene Product, Tuberin

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Shumway, Stuart D., Li, Yong, Xiong, Yue·2003·Journal of Biological Chemistry

Abstract

TSC2, or tuberin, is the product of the tuberous sclerosis tumor suppressor gene TSC2 and acts downstream of the phosphatidylinositol 3-kinase-Akt signaling pathway to negatively regulate cellular growth. One mechanism underlying its function is to assemble into a heterodimer with the TSC1 gene product TSC1, or hamartin, resulting in a reduction in phosphorylation, and hence activation, of the ribosomal subunit S6 kinase (S6K). We identified a novel interaction between TSC2 and 14-3-3beta. We found that 14-3-3beta does not interfere with TSC1-TSC2 binding and can form a ternary complex with these two proteins. Association between 14-3-3beta and TSC2 requires phosphorylation of TSC2 at a unique residue that is not a known Akt phosphorylation site. The overexpression of 14-3-3beta compromises the ability of the TSC1-TSC2 complex to reduce S6K phosphorylation. The antagonistic activity of 14-3-3beta toward TSC is dependent on the 14-3-3beta-TSC2 interaction, since a mutant of TSC2 that is not recognized by 14-3-3beta is refractory to 14-3-3beta. We suggest that 14-3-3 proteins interact with the TSC1-TSC2 complex and negatively regulate the function of the TSC proteins.

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Crossref · 10.1074/jbc.c200499200

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  • TSC2 has been shown to interact with 14-3-3 proteins when phosphorylated, and this interaction disrupts the function of the TSC1-TSC2 complex.

    “Notably, TSC2 has already been shown to interact with 143-3 proteins when phosphorylated, and that this interaction disrupts the function of the TSC1-TSC2 complex (Nellist et al., 2003;Shumway et al., 2003).”

    From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Shumway et al., 2003

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Authors
Shumway, S. D., Li, Y., & Xiong, Y.
Affiliations
  • University of North Carolina at Chapel Hill (US)
  • University of Michigan (US)
Corresponding author
Xiong, Yue
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2003-01
Volume
278
Issue
4
Pages
2089-2092
ISSN
0021-9258 (ISSN-L)
OpenAlex
W2085381292
Cited by
74
References
18
Citations by year
2023: 1 · 2022: 3 · 2021: 3 · 2020: 2 · 2018: 2 · 2017: 2 · 2016: 3 · 2014: 5 · 2012: 3
FWCI
3.33
Type
journal article
Language
en
Open access
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
National Cancer Institute (R01CA065572, CA 65572)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › 14-3-3 protein interactions
  • Health Sciences › Medicine › Physiology › Tuberous Sclerosis Complex Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Keywords
14-3-3β, tuberin, TSC2, TSC1, hamartin, tuberous sclerosis complex, protein-protein interaction, ternary complex, Akt signaling, phosphatidylinositol 3-kinase, RSK, S6K phosphorylation, tumor suppressor regulation, protein phosphorylation
MeSH terms
Tuberous Sclerosis Complex 1 Protein, Tuberous Sclerosis Complex 2 Protein, Binding Sites, Cell Line, Gene Expression Regulation, Glutathione Transferase, Humans, Phosphorylation, Plasmids, Precipitin Tests, Protein Binding, Proteins, Recombinant Fusion Proteins, Repressor Proteins, Tumor Cells, Cultured, Tyrosine 3-Monooxygenase, Blotting, Western, Signal Transduction, Genes, Tumor Suppressor, Ribosomal Protein S6 Kinases, Two-Hybrid System Techniques, Tumor Suppressor Proteins, 14-3-3 Proteins

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