title: Inhibition of 14-3-3 binding to Rictor of mTORC2 for Akt phosphorylation at Ser473 is regulated by selenoprotein W.
abstract: 14-3-3 reduces cell proliferation by inhibiting the activity of proteins involved in the signaling pathway that includes Akt kinase. Activation of Akt is enhanced by activating the mammalian target of rapamycin complex 2 (mTORC2). 14-3-3 is also a negative regulator of the mTORC2/Akt pathway, by interacting with a component of mTORC2. Recently, we reported that selenoprotein W (SelW) regulated the interaction between 14-3-3 and its target protein, CDC25B. Here, we show that the binding of Rictor, a component of mTORC2, to 14-3-3, is regulated by the interaction of 14-3-3 with SelW. When SelW was down-regulated, mTORC2-dependent phosphorylation of Akt at Ser473 was decreased. However, the phosphorylation of Thr308 was not affected. The interaction of Rictor with 14-3-3 was increased in SelW-knockdown cells, as compared to control cells. SelW-knockdown cells were also more sensitive to DNA damage induced by etoposide, than control cells. This phenomenon was due to the decreased phosphorylation of Akt at Ser473. We also found that ectopic expression of SelW(U13C) reduced the interaction between Rictor and 14-3-3, leading to Akt phosphorylation at Ser473. Taken together, these findings demonstrate that SelW activates the mTORC2/Akt pathway for Akt phosphorylation at Ser473, by interrupting the binding of Rictor to 14-3-3.
authors.affiliation: School of Life Sciences and Biotechnology, Korea University, Sungbuk-Ku, Seoul, Republic of Korea.
authors.forename: Yeong Ha
authors.initials: YH
authors.lastname: Jeon
authors.forename: Yong Hwan
authors.initials: YH
authors.lastname: Park
authors.forename: Joon Hyun
authors.initials: JH
authors.lastname: Kwon
authors.forename: Jea Hwang
authors.initials: JH
authors.lastname: Lee
authors.forename: Ick Young
authors.initials: IY
authors.lastname: Kim
mesh_terms: D048948:14-3-3 Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D005434:Flow Cytometry; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051151:Selenoprotein W / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D014945:Wound Healing
chemical_list: D048948:14-3-3 Proteins; D002352:Carrier Proteins; D046912:Multiprotein Complexes; C492571:RICTOR protein, human; D012333:RNA, Messenger; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D051151:Selenoprotein W; D012694:Serine; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: 14-3-3; Akt; GSH; NMR; Nuclear magnetic resonance spectroscopy; Rapamycin-insensitive companion of mTOR; Rictor; Sec, U; Selenocysteine; Selenoprotein W; Trx; glutathione; mTOR; mammalian target of rapamycin; s.d.; standard deviation; thioredoxin