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.

Rictor/mTORC2 Loss in the Myf5 Lineage Reprograms Brown Fat Metabolism and Protects Mice against Obesity and Metabolic Disease

“…However, FoxO1/3 phosphorylation is not affected in Rictor-deficient BAT; thus, if the metabolic shift is driven by FoxO1/3, it may be through an alterative mechanism such as acetylation (Banks et al, 2011; Masui et al, 2013). Another possibility is that FoxC2 mediates the metabolic shift (Cederberg et al, 2001; Yao et al, 2013); however, we do not observe any change in FoxC2 expression in Rictor-deficient preadipocytes (not shown), nor do we see effects on the FoxC2 targets C/ebpβ or Wnt10b during differentiation (Gerin et al, 2009). The shift could also bemediated through unidentified AKT substrates thatuniquelyrequirehydrophobic motif phosphorylation.…”

The Roles of mTOR Complexes in Lipid Metabolism

“…Consistently, loss of Rictor in adipose precursors cells or MEFs impairs adipogenesis in vitro (42, 138). Mechanistically, it was proposed that mTORC2 affects early adipogenesis by blocking the activity of the transcription factor forkhead-box C2 (FoxC2), downstream of Akt (138) (Figure 4b). The combination of results from all these studies suggests that mTORC2 is required for early adipogenesis but likely dispensable for the terminal differentiation and the maintenance of mature adipocytes.…”

Recent Advances in Adipose mTOR Signaling and Function: Therapeutic Prospects

“…However, in these studies the rictor gene was knocked out only in mature adipocytes or during the terminal phase of adipocyte differentiation, which may not be able to reveal the exact role of mTORC2 in early adipocyte differentiation. In fact, several recent studies demonstrated that mTORC2-mediated phosphorylation of Akt1 promoted adipogenesis by suppressing the expression of FoxC2, and Rictor-null mouse embryonic fibroblasts (MEFs) are incapable of differentiating into adipocytes [55-57]. In addition, Rictor-deficient brown adipocyte precursor cells are unable to differentiate and synthesize lipid droplets in vitro [58].…”