title: Distinct roles for mammalian target of rapamycin complexes in the fibroblast response to transforming growth factor-beta.
abstract: Transforming growth factor-beta (TGF-beta) promotes a multitude of diverse biological processes, including growth arrest of epithelial cells and proliferation of fibroblasts. Although the TGF-beta signaling pathways that promote inhibition of epithelial cell growth are well characterized, less is known about the mechanisms mediating the positive response to this growth factor. Given that TGF-beta has been shown to promote fibrotic diseases and desmoplasia, identifying the fibroblast-specific TGF-beta signaling pathways is critical. Here, we investigate the role of mammalian target of rapamycin (mTOR), a known effector of phosphatidylinositol 3-kinase (PI3K) and promoter of cell growth, in the fibroblast response to TGF-beta. We show that TGF-beta activates mTOR complex 1 (mTORC1) in fibroblasts but not epithelial cells via a PI3K-Akt-TSC2-dependent pathway. Rapamycin, the pharmacologic inhibitor of mTOR, prevents TGF-beta-mediated anchorage-independent growth without affecting TGF-beta transcriptional responses or extracellular matrix protein induction. In addition to mTORC1, we also examined the role of mTORC2 in TGF-beta action. mTORC2 promotes TGF-beta-induced morphologic transformation and is required for TGF-beta-induced Akt S473 phosphorylation but not mTORC1 activation. Interestingly, both mTOR complexes are necessary for TGF-beta-mediated growth in soft agar. These results define distinct and overlapping roles for mTORC1 and mTORC2 in the fibroblast response to TGF-beta and suggest that inhibitors of mTOR signaling may be useful in treating fibrotic processes, such as desmoplasia.
authors.affiliation: Department of Biochemistry and Molecular Biology, Thoracic Diseases Research Unit, Mayo Clinic Cancer Center, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Rod A
authors.initials: RA
authors.lastname: Rahimi
authors.forename: Mahefatiana
authors.initials: M
authors.lastname: Andrianifahanana
authors.forename: Mark C
authors.initials: MC
authors.lastname: Wilkes
authors.forename: Maryanne
authors.initials: M
authors.lastname: Edens
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Kottom
authors.forename: John
authors.initials: J
authors.lastname: Blenis
authors.forename: Edward B
authors.initials: EB
authors.lastname: Leof
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D004285:Dogs; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes; D051058:Oncogene Protein v-akt / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D011506:Proteins; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D011506:Proteins; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C504923:Crtc2 protein, mouse; C000624653:TSC2 protein, human; C000624654:Tsc2 protein, mouse; C546842:MTOR protein, human; C546843:mTOR protein, mouse