title: BSTA promotes mTORC2-mediated phosphorylation of Akt1 to suppress expression of FoxC2 and stimulate adipocyte differentiation.
abstract: Phosphorylation and activation of Akt1 is a crucial signaling event that promotes adipogenesis. However, neither the complex multistep process that leads to activation of Akt1 through phosphorylation at Thr³⁰⁸ and Ser⁴⁷³ nor the mechanism by which Akt1 stimulates adipogenesis is fully understood. We found that the BSD domain-containing signal transducer and Akt interactor (BSTA) promoted phosphorylation of Akt1 at Ser⁴⁷³ in various human and murine cells, and we uncovered a function for the BSD domain in BSTA-Akt1 complex formation. The mammalian target of rapamycin complex 2 (mTORC2) facilitated the phosphorylation of BSTA and its association with Akt1, and the BSTA-Akt1 interaction promoted the association of mTORC2 with Akt1 and phosphorylation of Akt1 at Ser⁴⁷³ in response to growth factor stimulation. Furthermore, analyses of bsta gene-trap murine embryonic stem cells revealed an essential function for BSTA and phosphorylation of Akt1 at Ser⁴⁷³ in promoting adipocyte differentiation, which required suppression of the expression of the gene encoding the transcription factor FoxC2. These findings indicate that BSTA is a molecular switch that promotes phosphorylation of Akt1 at Ser⁴⁷³ and reveal an mTORC2-BSTA-Akt1-FoxC2-mediated signaling mechanism that is critical for adipocyte differentiation.
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Yixin
authors.initials: Y
authors.lastname: Yao
authors.forename: Milind
authors.initials: M
authors.lastname: Suraokar
authors.forename: Bryant G
authors.initials: BG
authors.lastname: Darnay
authors.forename: Brett G
authors.initials: BG
authors.lastname: Hollier
authors.forename: Tattym E
authors.initials: TE
authors.lastname: Shaiken
authors.forename: Takayuki
authors.initials: T
authors.lastname: Asano
authors.forename: Chien-Hung
authors.initials: CH
authors.lastname: Chen
authors.forename: Benny H-J
authors.initials: BH
authors.lastname: Chang
authors.forename: Yiling
authors.initials: Y
authors.lastname: Lu
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.forename: Dos
authors.initials: D
authors.lastname: Sarbassov
authors.forename: Sendurai A
authors.initials: SA
authors.lastname: Mani
authors.forename: James L
authors.initials: JL
authors.lastname: Abbruzzese
authors.forename: Shrikanth A G
authors.initials: SA
authors.lastname: Reddy
mesh_terms: D017667:Adipocytes / Q000502:physiology*; D050156:Adipogenesis / Q000502:physiology*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology*; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D017434:Protein Structure, Tertiary / Q000235:genetics; D011506:Proteins; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
chemical_list: D002352:Carrier Proteins; D051858:Forkhead Transcription Factors; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D011506:Proteins; C581680:Syap1 protein, human; C082078:mesenchyme fork head 1 protein; C494918:AKT1 protein, human; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases