A summary of selected common stimuli, signalling pathways and transcription factors (TFs) associated with epithelial–mesenchymal transition [37, 38]

Selected stimuliSignalling pathwaysTFTF type
TGF-βSmad2, Smad3 and Smad4#Snail1 (Snail)Zinc finger
EGFMAPK/ERK1Snail2 (Slug)Zinc finger
VEGFWnt/β-catenin+ZEB1Zinc finger
HGFNotch§ZEB2 (SIP1)Zinc finger
Bile acidsHedgehogƒTwist1Basic helix–loop helix

The Snail, Twist and ZEB TF families control cell–cell adhesion, cell migration and extracellular matrix (ECM) degradation. They have been shown to have evolutionarily conserved roles in epithelial–mesenchymal transition (EMT) in different biological settings and in a range of organisms. TGF-β: transforming growth factor-β; EGF: epidermal growth factor; VEGF: vascular endothelial growth factor; HGF: hepatocyte growth factor; MAPK: mitogen-activated protein kinase; ERK: extracellular signal-regulated kinase; ZEB: zinc finger E-box-binding homeobox; SIP: Smad interacting protein. #: TGF-β (the classic, positive control in in vitro EMT experiments) activates Smad2 and Smad3 and complexes with Smad4, which then interacts with DNA-binding TFs inducing EMT; an alternative pathway operates via β-catenin released when intercellular adhesion breaks down; : activated by EGF-receptor stimulation for example; +: the Wnt pathway causes cytoplasmic β-catenin accumulation and nuclear translocation to act as a TF co-activator; §: Notch signalling activation occurs via cell to cell contact with ligand expression in signal-providing cells (dysregulated in the epithelium of COPD patients); ƒ: EMT/lung cancer are linked to the Hedgehog signalling pathway, which is modulated by cigarette smoke.