title: TGF-β-induced activation of mTOR complex 2 drives epithelial-mesenchymal transition and cell invasion.
abstract: 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.
authors.affiliation: Department of Cell and Tissue Biology, University of California at San Francisco, San Francisco, CA 94143-0512,  USA.
authors.forename: Samy
authors.initials: S
authors.lastname: Lamouille
authors.forename: Erin
authors.initials: E
authors.lastname: Connolly
authors.forename: James W
authors.initials: JW
authors.lastname: Smyth
authors.forename: Rosemary J
authors.initials: RJ
authors.lastname: Akhurst
authors.forename: Rik
authors.initials: R
authors.lastname: Derynck
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D018450:Disease Progression; D004847:Epithelial Cells / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D051379:Mice; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D015398:Signal Transduction / Q000502:physiology; D000071250:Snail Family Transcription Factors; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing
chemical_list: D002352:Carrier Proteins; D020780:Matrix Metalloproteinase 9; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D000071250:Snail Family Transcription Factors; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D020742:rhoA GTP-Binding Protein; C525637:rictor protein, mouse; C561937:Mapkap1 protein, mouse; D048868:Adaptor Proteins, Signal Transducing; C546843:mTOR protein, mouse