Fig. 2

As the canonical signaling, the TGF-β ligand binds to the heterodimeric receptor which regulates the phosphorylation of SMAD2/3 proteins. Then, these proteins form complexes with SMAD4 and initiate transcription. TGF-β downstream pathway can promote tumorigenesis, cell proliferation, and migration by inducing the epithelial to mesenchymal transition (EMT). As one of the non-canonical signaling, TGF-β pathway also can activate RhoA signaling during EMT, and that inhibition of RhoA signaling blocks TGF-β-induced EMT. RhoA is mainly involved in activating stress fibers and cell contraction and its downstream signaling promotes cell junction dissolution. The activation of ROCK1 gene by RhoA increased TMEM16A channel activity owing to the phosphorylation of moesin at T558 in breast cancer cells. On the other hand, MiR-381 function as a tumor suppressor by directly targeting TMEM16A and regulating TGF-β pathway and subsequently EMT process in the development of progression of gastric cancer. The interaction between TMEM16A and TGF-β may have an indirect crosstalk in clarifying the mechanism of TMEM16A-induced EMT. Inhibitory/negative signals are indicated with inhibitory red arrows; Stimulatory/positive signals are indicated with green arrows