TGF-β orchestrates fibrogenic and developmental EMTs via the RAS effector RREB1 Journal Article

Authors: Su, J.; Morgani, S. M.; David, C. J.; Wang, Q.; Er, E. E.; Huang, Y. H.; Basnet, H.; Zou, Y.; Shu, W.; Soni, R. K.; Hendrickson, R. C.; Hadjantonakis, A. K.; Massagué, J.
Article Title: TGF-β orchestrates fibrogenic and developmental EMTs via the RAS effector RREB1
Abstract: Epithelial-to-mesenchymal transitions (EMTs) are phenotypic plasticity processes that confer migratory and invasive properties to epithelial cells during development, wound-healing, fibrosis and cancer1–4. EMTs are driven by SNAIL, ZEB and TWIST transcription factors5,6 together with microRNAs that balance this regulatory network7,8. Transforming growth factor β (TGF-β) is a potent inducer of developmental and fibrogenic EMTs4,9,10. Aberrant TGF-β signalling and EMT are implicated in the pathogenesis of renal fibrosis, alcoholic liver disease, non-alcoholic steatohepatitis, pulmonary fibrosis and cancer4,11. TGF-β depends on RAS and mitogen-activated protein kinase (MAPK) pathway inputs for the induction of EMTs12–19. Here we show how these signals coordinately trigger EMTs and integrate them with broader pathophysiological processes. We identify RAS-responsive element binding protein 1 (RREB1), a RAS transcriptional effector20,21, as a key partner of TGF-β-activated SMAD transcription factors in EMT. MAPK-activated RREB1 recruits TGF-β-activated SMAD factors to SNAIL. Context-dependent chromatin accessibility dictates the ability of RREB1 and SMAD to activate additional genes that determine the nature of the resulting EMT. In carcinoma cells, TGF-β–SMAD and RREB1 directly drive expression of SNAIL and fibrogenic factors stimulating myofibroblasts, promoting intratumoral fibrosis and supporting tumour growth. In mouse epiblast progenitors, Nodal–SMAD and RREB1 combine to induce expression of SNAIL and mesendoderm-differentiation genes that drive gastrulation. Thus, RREB1 provides a molecular link between RAS and TGF-β pathways for coordinated induction of developmental and fibrogenic EMTs. These insights increase our understanding of the regulation of epithelial plasticity and its pathophysiological consequences in development, fibrosis and cancer. © 2020, The Author(s), under exclusive licence to Springer Nature Limited.
Keywords: signal transduction; mitogen activated protein kinase; controlled study; protein expression; unclassified drug; human cell; nonhuman; pathophysiology; animal cell; mouse; smad protein; transforming growth factor beta; embryo; protein; protein binding; cell differentiation; carcinogenesis; fibrosis; gene activation; pluripotent stem cell; myofibroblast; tumor growth; tumor; transcription factor snail; physiological response; gastrulation; cell; ectoderm; epithelial mesenchymal transition; nucleic acid binding protein; phenotypic plasticity; cell plasticity; ras responsive element binding protein 1; cancer; human; female; priority journal; article; fibrogenesis; a-549 cell line; 393t3 cell line; lung cell line
Journal Title: Nature
Volume: 577
Issue: 7791
ISSN: 0028-0836
Publisher: Nature Publishing Group  
Date Published: 2020-01-23
Start Page: 566
End Page: 571
Language: English
DOI: 10.1038/s41586-019-1897-5
PUBMED: 31915377
PROVIDER: scopus
Notes: Article -- Export Date: 2 March 2020 -- Erratum issued, see DOI: 10.1038/s41586-020-1956-y -- Source: Scopus
Citation Impact
MSK Authors
  1. Joan Massague
    361 Massague
  2. Weiping Shu
    18 Shu
  3. Rajesh Kumar Soni
    15 Soni
  4. Charles Joseph David
    6 David
  5. Yilong Zou
    15 Zou
  6. Yun-Han Huang
    6 Huang
  7. Jie   Su
    10 Su
  8. Harihar   Basnet
    7 Basnet
  9. Ekrem Emrah   Er
    7 Er
  10. Qiong   Wang
    6 Wang