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14-3-3beta binds to and negatively regulates the tuberous sclerosis complex 2 (TSC2) tumor suppressor gene product, tuberin.

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.

Pubmed ID: 12468542


  • Shumway SD
  • Li Y
  • Xiong Y


The Journal of biological chemistry

Publication Data

January 24, 2003

Associated Grants

  • Agency: NCI NIH HHS, Id: CA65572

Mesh Terms

  • 14-3-3 Proteins
  • Binding Sites
  • Blotting, Western
  • Cell Line
  • Gene Expression Regulation
  • Genes, Tumor Suppressor
  • Glutathione Transferase
  • Humans
  • Phosphorylation
  • Plasmids
  • Precipitin Tests
  • Protein Binding
  • Proteins
  • Recombinant Fusion Proteins
  • Repressor Proteins
  • Ribosomal Protein S6 Kinases
  • Signal Transduction
  • Tumor Cells, Cultured
  • Tumor Suppressor Proteins
  • Two-Hybrid System Techniques
  • Tyrosine 3-Monooxygenase