TGF-β-induced activation of mTOR complex 2 drives epithelial–mesenchymal transition and cell invasion

• DOI: 10.1242/jcs.095299
• Publication Date: 2012-03-08T03:39:14Z
• Authors: Samy Lamouille; Erin Connolly; James W. Smyth; Rosemary J. Akhurst; Rik Derynck
• Keywords: 0301 basic medicine; 0303 health sciences; Epithelial-Mesenchymal Transition; Epithelial Cells; 3. Good health; Mice; 03 medical and health sciences; Rapamycin-Insensitive Companion of mTOR Protein; Matrix Metalloproteinase 9; Cell Movement; Cell Line, Tumor; Neoplasms; Carcinoma, Squamous Cell; Disease Progression; Animals; Neoplasm Invasiveness; RNA Interference; RNA, Messenger; Snail Family Transcription Factors; Phosphorylation; RNA, Small Interfering; Carrier Proteins; Proto-Oncogene Proteins c-akt; Signal Transduction

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.