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TGF-β-induced activation of mTOR complex 2 drives epithelial–mesenchymal transition and cell invasion
Samy Lamouille, Erin Connolly, James W. Smyth, Rosemary J. Akhurst, Rik Derynck


In cancer progression, carcinoma cells gain invasive behavior through a loss of epithelial characteristics and acquisition of mesenchymal properties, a process that can lead to epithelial–mesenchymal transition (EMT). TGF-β is a potent inducer of EMT, and increased TGF-β signaling in cancer cells is thought to drive cancer-associated EMT. Here, we examine the physiological requirement for mTOR complex 2 (mTORC2) in cells undergoing EMT. TGF-β rapidly induces mTORC2 kinase activity in cells undergoing EMT, and controls epithelial cell progression through EMT. By regulating EMT-associated cytoskeletal changes and gene expression, mTORC2 is required for cell migration and invasion. Furthermore, inactivation of mTORC2 prevents cancer cell dissemination in vivo. Our results suggest that the mTORC2 pathway is an essential downstream branch of TGF-β signaling, and represents a responsive target to inhibit EMT and prevent cancer cell invasion and metastasis.


  • Funding

    This research was supported by the National Institutes of Health [grant numbers RO1-CA136690 and PO1-HL60231 (project III) to R.D.; RO1-CA116019, RO1-HL078564 and RO1-GM60514 to R.J.A.]; a Leukemia and Lymphoma Society postdoctoral fellowship [grant number 5566-07] and an American Heart Association scientist development award [grant number SDG2280008] to S.L.; a postdoctoral support from the National Cancer Institute [grant number T32 CA108462] to E.C.; a postdoctoral fellowship from the American Federation for Aging Research [grant number A112457] and an American Heart Association scientist development award [grant number SDG3420042] to J.W.S. Deposited in PMC for release after 12 months.

  • Supplementary material available online at

  • Accepted October 16, 2011.
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