title: Cell size and invasion in TGF-beta-induced epithelial to mesenchymal transition is regulated by activation of the mTOR pathway.
abstract: Epithelial to mesenchymal transition (EMT) occurs during development and cancer progression to metastasis and results in enhanced cell motility and invasion. Transforming growth factor-beta (TGF-beta) induces EMT through Smads, leading to transcriptional regulation, and through non-Smad pathways. We observe that TGF-beta induces increased cell size and protein content during EMT. This translational regulation results from activation by TGF-beta of mammalian target of rapamycin (mTOR) through phosphatidylinositol 3-kinase and Akt, leading to the phosphorylation of S6 kinase 1 and eukaryotic initiation factor 4E-binding protein 1, which are direct regulators of translation initiation. Rapamycin, a specific inhibitor of mTOR complex 1, inhibits the TGF-beta-induced translation pathway and increase in cell size without affecting the EMT phenotype. Additionally, rapamycin decreases the migratory and invasive behavior of cells that accompany TGF-beta-induced EMT. The TGF-beta-induced translation pathway through mTOR complements the transcription pathway through Smads. Activation of mTOR by TGF-beta, which leads to increased cell size and invasion, adds to the role of TGF-beta-induced EMT in cancer progression and may represent a therapeutic opportunity for rapamycin analogues in cancer.
authors.affiliation: Department of Cell and Tissue Biology, Program in Cell Biology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Samy
authors.initials: S
authors.lastname: Lamouille
authors.forename: Rik
authors.initials: R
authors.lastname: Derynck
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology; D018797:Cell Cycle Proteins; D002465:Cell Movement / Q000502:physiology; D048429:Cell Size; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology; D004848:Epithelium / Q000502:physiology*; D039642:Eukaryotic Initiation Factors; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008321:Mammary Glands, Animal / Q000033:anatomy & histology; D008648:Mesoderm / Q000502:physiology*; D051379:Mice; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D020123:Sirolimus / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000903:Antibiotics, Antineoplastic; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C499527:Eif4ebp1 protein, mouse; D039642:Eukaryotic Initiation Factors; D010750:Phosphoproteins; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus