%0 Journal Article %A Woodcock, Hannah V %A Eley, Jessica D %A Guillotin, Delphine %A Platé, Manuela %A Nanthakumar, Carmel B %A Martufi, Matteo %A Peace, Simon %A Joberty, Gerard %A Poeckel, Daniel %A Good, Robert B %A Taylor, Adam R %A Zinn, Nico %A Redding, Matthew %A Forty, Ellen J %A Hynds, Robert E %A Swanton, Charles %A Karsdal, Morten %A Maher, Toby M %A Bergamini, Giovanna %A Marshall, Richard P %A Blanchard, Andy D %A Mercer, Paul F %A Chambers, Rachel C %D 2019 %T The mTORC1/4E-BP1 axis represents a critical signaling node during fibrogenesis %U https://crick.figshare.com/articles/journal_contribution/The_mTORC1_4E-BP1_axis_represents_a_critical_signaling_node_during_fibrogenesis/11410074 %2 https://crick.figshare.com/ndownloader/files/20297259 %K Adaptor Proteins, Signal Transducing %K Cell Line %K Collagen %K Fibroblasts %K Humans %K Idiopathic Pulmonary Fibrosis %K Mechanistic Target of Rapamycin Complex 1 %K Phosphatidylinositol 3-Kinases %K Phosphoproteins %K Signal Transduction %K Sirolimus %K TOR Serine-Threonine Kinases %K Transforming Growth Factor beta1 %K Swanton FC001169 %K GSK %X Myofibroblasts are the key effector cells responsible for excessive extracellular matrix deposition in multiple fibrotic conditions, including idiopathic pulmonary fibrosis (IPF). The PI3K/Akt/mTOR axis has been implicated in fibrosis, with pan-PI3K/mTOR inhibition currently under clinical evaluation in IPF. Here we demonstrate that rapamycin-insensitive mTORC1 signaling via 4E-BP1 is a critical pathway for TGF-β1 stimulated collagen synthesis in human lung fibroblasts, whereas canonical PI3K/Akt signaling is not required. The importance of mTORC1 signaling was confirmed by CRISPR-Cas9 gene editing in normal and IPF fibroblasts, as well as in lung cancer-associated fibroblasts, dermal fibroblasts and hepatic stellate cells. The inhibitory effect of ATP-competitive mTOR inhibition extended to other matrisome proteins implicated in the development of fibrosis and human disease relevance was demonstrated in live precision-cut IPF lung slices. Our data demonstrate that the mTORC1/4E-BP1 axis represents a critical signaling node during fibrogenesis with potential implications for the development of novel anti-fibrotic strategies. %I The Francis Crick Institute