The TGF-β superfamily includes TGF-βs, bone morphogenic proteins (BMP), and activins.
59 These proteins are essential to fetal development, as they regulate genes related to developmental EMT and the reverse phenomenon, mesenchymal-to-epithelial transition (MET). They are also implicated postnatally in physiological and pathological EMT, such as in wound healing, pluripotent cell differentiation, fibrosis, and cancer (reviewed in Ref. 60). They transduce extracellular signals via transmembrane Ser/Thr kinase heterotetramer receptors and Tyr kinase receptors. The canonical pathway is activated by binding of a TGF-β protein to a type II TGF-β receptor (TβRII), a Ser/Thr kinase, which phosphorylates a type I receptor, leading to the phosphorylation of Smads.
61 Smad2 or 3 is activated by TGF-β signaling and Smad1, 5, or 8 in response to BMPs. Inhibitory Smads, namely Smad6 and 7, can compete with the latter Smads for binding to the type I receptors.
59 Smad pathways lead to activation of various transcription factors, including Snail transcription repressors, ZEB transcription factors, and basic helix-loop-helix (bHLH) factors.
62 Notably, Snail1 and 2 repress transcription of E-cadherin.
63 Snail1 is linked to disruption of the epithelial polarity
64 and remodeling of the cytoskeleton as well as cellular migration and invasion.
65 Likewise, Smads directly control many genes linked to the mesenchymal phenotype, like fibronectin, vimentin, and collagen α1.
58
ZEB1 and ZEB2 can repress or activate transcription, depending on the coactivators/repressors associated with them. These factors repress many genes linked to the epithelial phenotype, including E-cadherin (adherens and tight junctions, epithelial polarity), activate the expression of genes associated with a mesenchymal phenotype, such as α-SMA and vimentin, and have been associated with cell migration.
58
Other extracellular signals can also lead to activation of Snails and ZEBs. Indeed, HGF, FGF, or EGF signaling by the Ras-mitogen-activated protein kinase (MAPK) or PI3K-Akt pathways can cooperate with Snails in order to induce EMT.
59 It has also been shown in some cancers that Ras,
66 Notch, and Wnt
58 pathways can cooperate with TGF-β to induce Snail. Ras-MAPK and Wnt/β-catenin pathways also activate ZEB transcription factors.
62