Figure 5.

TGFβ signaling in endoMT. The TGFβ signaling pathway plays a crucial role in endoMT. Cancer cells secrete TGFβ ligands, which bind to TGFβR1 (ALK5) and TGFβR2 receptors present on ECs. This ligand-receptor binding initiates the formation of TGFβR1-TGFβR2 heterodimers, leading to the autophosphorylation of TGFβR2. Phosphorylated TGFβR2, in turn, phosphorylates TGFβR1, resulting in the activation of the TGFβR1/2 complex. The activated TGFβR1/2 complex transmits signals through both SMAD-dependent and SMAD-independent pathways. In the SMAD-dependent pathway, cytoplasmic SMAD2/3 proteins are phosphorylated by the activated TGFβR1/2 complex. Phosphorylated SMAD2/3 proteins then translocate to the nucleus, where they bind to specific SMAD binding elements (SNAIL, SLUG, ZEB, TWIST, FSP1, COLS3). This binding regulates the expression of genes involved in endoMT. In the SMAD-independent pathway, the activated TGFβR1/2 complex can also propagate signals through the activation of ERK, p38MAPK, and JNK signaling pathways. These pathways contribute to TGFβ-mediated effects on endoMT, CVD, fibrosis, and cancer progression. Overall, TGFβ signaling activation induces endoMT and is involved in various pathological processes, including CVD, fibrosis, and cancer progression (All the figures were made in Biorender.com).