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].