BSTA promotes mTORC2-mediated phosphorylation of Akt1 to suppress expression of FoxC2 and stimulate adipocyte differentiation.
BSTA promotes mTORC2-mediated phosphorylation of Akt1 to suppress expression of FoxC2 and stimulate adipocyte differentiation.
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DOI：
10.1126/scisignal.2003295
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发表时间：
2013-01-08
影响因子：
7.3
通讯作者：
Reddy SA
中科院分区：
文献类型：
--
作者：
Yao Y;Suraokar M;Darnay BG;Hollier BG;Shaiken TE;Asano T;Chen CH;Chang BH;Lu Y;Mills GB;Sarbassov D;Mani SA;Abbruzzese JL;Reddy SA
Akt1的磷酸化和激活是促进脂肪生成的关键信号事件。然而，通过苏氨酸308和丝氨酸473位点磷酸化导致Akt1激活的复杂多步骤过程，以及Akt1刺激脂肪生成的机制都尚未完全清楚。我们发现含BSD结构域的信号转导子和Akt相互作用蛋白（BSTA）在多种人和鼠细胞中促进Akt1在丝氨酸473位点的磷酸化，并且我们揭示了BSD结构域在BSTA - Akt1复合物形成中的作用。雷帕霉素靶蛋白复合物2（mTORC2）促进BSTA的磷酸化及其与Akt1的结合，并且BSTA - Akt1相互作用促进mTORC2与Akt1的结合以及在生长因子刺激下Akt1在丝氨酸473位点的磷酸化。此外，对bsta基因捕获小鼠胚胎干细胞的分析揭示了BSTA以及Akt1在丝氨酸473位点磷酸化在促进脂肪细胞分化中的关键作用，这需要抑制编码转录因子FoxC2的基因的表达。这些发现表明BSTA是促进Akt1在丝氨酸473位点磷酸化的分子开关，并揭示了一种对脂肪细胞分化至关重要的mTORC2 - BSTA - Akt1 - FoxC2介导的信号机制。
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.
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影响因子：
56.9
作者：
Franke, TF;Kaplan, DR;Toker, A
通讯作者：
Toker, A
影响因子：
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Franke, Thomas F.
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Newton, Alexandra C.
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