Yin Yang 1 promotes mTORC2-mediated AKT phosphorylation

J Mol Cell Biol. 2016 Jun;8(3):232-43. doi: 10.1093/jmcb/mjw002. Epub 2016 Jan 13.


Yin Yang 1 (YY1) regulates both gene expression and protein modifications, and has shown a proliferative role in cancers. In this study, we demonstrate that YY1 promotes AKT phosphorylation at S473, a marker of AKT activation. YY1 expression positively correlated with AKT(S473) phosphorylation in a tissue microarray and cultured cells of breast cancer, but negatively associated with the distant metastasis-free survival of 166 breast cancer patients. YY1 promotes AKT phosphorylation at S473 through direct interaction with AKT, and the AKT-binding site is mapped to the residues G201-S226 on YY1. These residues are also involved in YY1 interaction with Mdm2, Ezh2, and E1A, and thus are designated as the oncogene protein binding (OPB) domain. YY1-promoted AKT phosphorylation relies on the OPB domain but is independent of either transcriptional activity of YY1 or the activity of phosphoinositide-3-kinases. We also determine that YY1-promoted mTORC2 access to AKT leads to its phosphorylation at S473. Importantly, a peptide based on the OPB domain blocks YY1 interaction with AKT and reduces AKT phosphorylation and cell proliferation. Thus, we demonstrate for the first time that YY1 promotes mTORC2-mediated AKT activation and disrupting YY1-AKT interaction by OPB domain-based peptide may represent a potential strategy for cancer therapy.

Keywords: AKT; OPB domain; Yin Yang 1; breast cancer; oncoproteins; phosphorylation.

MeSH terms

  • Animals
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Female
  • Humans
  • Mechanistic Target of Rapamycin Complex 2
  • Mice
  • Models, Biological
  • Multiprotein Complexes / metabolism*
  • Peptides / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation / drug effects
  • Protein Binding
  • Protein Domains
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Structure-Activity Relationship
  • TOR Serine-Threonine Kinases / metabolism*
  • YY1 Transcription Factor / chemistry
  • YY1 Transcription Factor / metabolism*


  • Multiprotein Complexes
  • Peptides
  • YY1 Transcription Factor
  • Mechanistic Target of Rapamycin Complex 2
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases