title: Yin Yang 1 promotes mTORC2-mediated AKT phosphorylation.
abstract: 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.
authors.affiliation: College of Life Science, Northeast Forestry University, Harbin, China Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA Present address: Department of Radiation Oncology, University of Michigan Health System, Ann Arbor, MI 48109, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Meimei
authors.initials: M
authors.lastname: Wan
authors.affiliation: College of Life Science, Northeast Forestry University, Harbin, China.
authors.forename: Jinming
authors.initials: J
authors.lastname: Shi
authors.affiliation: Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Horita
authors.affiliation: Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Lance D
authors.initials: LD
authors.lastname: Miller
authors.affiliation: Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Timothy E
authors.initials: TE
authors.lastname: Kute
authors.affiliation: Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Kridel
authors.affiliation: Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA Life Sciences Program, College of Science & General Studies, Alfaisal University, Riyadh 11533, Saudi Arabia.
authors.forename: George
authors.initials: G
authors.lastname: Kulik
authors.affiliation: College of Life Science, Northeast Forestry University, Harbin, China Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA gcsui@nefu.edu.cn gsui@wakehealth.edu.
authors.forename: Guangchao
authors.initials: G
authors.lastname: Sui
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D000072417:Protein Domains; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D050986:YY1 Transcription Factor / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes; D010455:Peptides; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D050986:YY1 Transcription Factor
keywords: AKT; OPB domain; Yin Yang 1; breast cancer; oncoproteins; phosphorylation