Distinct roles for mammalian target of rapamycin complexes in the fibroblast response to transforming growth factor-β

Rod A. Rahimi, Mahefatiana Andrianifahanana, Mark C. Wilkes, Maryanne Edens, Theodore J. Kottom, John Blenis, Edward B. Leof

Research output: Contribution to journalArticle

70 Scopus citations

Abstract

Transforming growth factor-β (TGF-β) promotes a multitude of diverse biological processes, including growth arrest of epithelial cells and proliferation of fibroblasts. Although the TGF-β 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-β has been shown to promote fibrotic diseases and desmoplasia, identifying the fibroblast-specific TGF-β 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-β. We show that TGF-β 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-β-mediated anchorage-independent growth without affecting TGF-β transcriptional responses or extracellular matrix protein induction. In addition to mTORC1, we also examined the role of mTORC2 in TGF-β action. mTORC2 promotes TGF-β-induced morphologic transformation and is required for TGF-β-induced Akt S473 phosphorylation but not mTORC1 activation. Interestingly, both mTOR complexes are necessary for TGF-β-mediated growth in soft agar. These results define distinct and overlapping roles for mTORC1 and mTORC2 in the fibroblast response to TGF-β and suggest that inhibitors of mTOR signaling may be useful in treating fibrotic processes, such as desmoplasia.

Original languageEnglish (US)
Pages (from-to)84-93
Number of pages10
JournalCancer research
Volume69
Issue number1
DOIs
StatePublished - Jan 1 2009

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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