Open AccessTGF-β orchestrates fibrogenic and developmental EMTs via the RAS effector RREB1
Author(s) -
Jie Su,
Sophie M. Morgani,
Charles J. David,
Qiong Wang,
Ekrem Emrah Er,
Yun-Han Huang,
Harihar Basnet,
Yilong Zou,
Weiqun Shu,
Rajesh Kumar Soni,
Ronald C. Hendrickson,
AnnaKaterina Hadjantonakis,
Joan Massagué
Publication year - 2020
Publication title -
nature
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 15.993
H-Index - 1226
eISSN - 1476-4687
pISSN - 0028-0836
DOI - 10.1038/s41586-019-1897-5
Subject(s) - smad , biology , microbiology and biotechnology , cancer research , transforming growth factor , transcription factor , snail , epithelial–mesenchymal transition , mapk/erk pathway , snai1 , signal transduction , downregulation and upregulation , gene , genetics , ecology
Epithelial-to-mesenchymal transitions (EMTs) are phenotypic plasticity processes that confer migratory and invasive properties to epithelial cells during development, wound-healing, fibrosis and cancer 1-4 . EMTs are driven by SNAIL, ZEB and TWIST transcription factors 5,6 together with microRNAs that balance this regulatory network 7,8 . Transforming growth factor β (TGF-β) is a potent inducer of developmental and fibrogenic EMTs 4,9,10 . Aberrant TGF-β signalling and EMT are implicated in the pathogenesis of renal fibrosis, alcoholic liver disease, non-alcoholic steatohepatitis, pulmonary fibrosis and cancer 4,11 . TGF-β depends on RAS and mitogen-activated protein kinase (MAPK) pathway inputs for the induction of EMTs 12-19 . 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 effector 20,21 , 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.