BSTA promotes mTORC2-mediated phosphorylation of Akt1 to suppress expression of FoxC2 and stimulate adipocyte differentiation

Sci Signal. 2013 Jan 8;6(257):ra2. doi: 10.1126/scisignal.2003295.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / physiology*
  • Adipogenesis / physiology*
  • Animals
  • Carrier Proteins / metabolism*
  • Cell Differentiation / physiology*
  • Forkhead Transcription Factors / metabolism
  • Humans
  • Immunoprecipitation
  • Intracellular Signaling Peptides and Proteins
  • Mechanistic Target of Rapamycin Complex 2
  • Mice
  • Multiprotein Complexes / metabolism*
  • Nerve Tissue Proteins / metabolism*
  • Phosphorylation / drug effects
  • Protein Structure, Tertiary / genetics
  • Proteins
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction / physiology*
  • TOR Serine-Threonine Kinases / metabolism*
  • Two-Hybrid System Techniques

Substances

  • Carrier Proteins
  • Forkhead Transcription Factors
  • Intracellular Signaling Peptides and Proteins
  • Multiprotein Complexes
  • Nerve Tissue Proteins
  • Proteins
  • Syap1 protein, human
  • mesenchyme fork head 1 protein
  • AKT1 protein, human
  • Mechanistic Target of Rapamycin Complex 2
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases