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Sci. Signal., 8 January 2013
Vol. 6, Issue 257, p. ra2
[DOI: 10.1126/scisignal.2003295]

RESEARCH ARTICLES

BSTA Promotes mTORC2-Mediated Phosphorylation of Akt1 to Suppress Expression of FoxC2 and Stimulate Adipocyte Differentiation

Yixin Yao1, Milind Suraokar2, Bryant G. Darnay3, Brett G. Hollier4*, Tattym E. Shaiken5, Takayuki Asano1{dagger}, Chien-Hung Chen5, Benny H.-J. Chang6, Yiling Lu7, Gordon B. Mills7, Dos Sarbassov5, Sendurai A. Mani4, James L. Abbruzzese1, and Shrikanth A. G. Reddy1{ddagger}

1 Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
2 Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
3 Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
4 Department of Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
5 Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
6 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
7 Department of Systems Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.

* Present address: Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland 4059, Australia.

{dagger} Present address: Department of Gastrointestinal Surgery, St. Marianna University School of Medicine, Kanagawa 216-8511, Japan.

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.

{ddagger} To whom correspondence should be addressed. E-mail: sareddy{at}mdanderson.org

Citation: Y. Yao, M. Suraokar, B. G. Darnay, B. G. Hollier, T. E. Shaiken, T. Asano, C.-H. Chen, B. H.- J. Chang, Y. Lu, G. B. Mills, D. Sarbassov, S. A. Mani, J. L. Abbruzzese, S. A. G. Reddy, BSTA Promotes mTORC2-Mediated Phosphorylation of Akt1 to Suppress Expression of FoxC2 and Stimulate Adipocyte Differentiation. Sci. Signal. 6, ra2 (2013).

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