⑵Binding to Smad2/3
In embryonic stem cells, YAP/TAZ was shown to interact directly with Smad2/3, and its interaction may occur in the cytoplasmic and nuclear compartments while regulating nuclear accumulation[22]. After YAP/TAZ downregulation, the interaction of Smads2/3 with YAP/TAZ was evident in tubular epithelial cells, reducing the accumulation of nuclear Smad2 and Smad3[22]. During fibrosis, Smad transcription factors are canonical mediators of profibrotic TGF-β responses[23]. An important step in TGF-β-induced fibroblast activation is the C-terminal phosphorylation of the profibrotic transcription factors Smad2 and Smad3. Phosphorylated Smad2/3 accumulates in the nucleus, where it drives the expression of TGF-β-sensitive profibrotic genes [24]. In turn, TGF-β induces YAP/TAZ to bind to the Smad2/3-4 complex and is recruited to the TGF-β response element to regulate the expression of target genes, while the loss of YAP/TAZ leads to the inhibition of TGF-β signaling[25,26].