Unknown

Dataset Information

0

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.

SUBMITTER: Rahimi RA 

PROVIDER: S-EPMC2656374 | BioStudies | 2009-01-01

REPOSITORIES: biostudies

Similar Datasets

2014-01-01 | S-EPMC4146613 | BioStudies
2014-01-01 | S-EPMC4198127 | BioStudies
2018-01-01 | S-EPMC6239304 | BioStudies
1000-01-01 | S-EPMC4558569 | BioStudies
2016-01-01 | S-EPMC4823739 | BioStudies
1000-01-01 | S-EPMC5314913 | BioStudies
1000-01-01 | S-EPMC4140469 | BioStudies
2011-01-01 | S-EPMC3225010 | BioStudies
2011-01-01 | S-EPMC3750737 | BioStudies
2010-01-01 | S-EPMC2832937 | BioStudies