Fig. 3
From: Signaling pathways involved in colorectal cancer progression
TGF-β signaling pathways in CRC. TGF-β receptors internalization occurs through clathrin-dependent or lipid-raft-dependent pathways. However, clathrin-dependent endocytosis of TGF-β receptors positively facilitates TGF-β signaling while internalization through lipid raft/caveolae exerts an inhibitory effect [70]. The internalized receptors are targeted to distinct destination through different functions of Rab5 GTPases. Binding of TGF-β ligands to TGFBR2 triggers initiation of TGF-β signaling. By binding TGF-β to TGFBR2, TGFBR2 recruits and phosphorylates TGFBR1, stimulating the protein kinase activity of TGFBR1, in which TGFBR1 is activated. Then, R-SMAD proteins or SMAD2 and SMAD3 are phosphorylated and activated by the activated TGFBR1, thereby allowing them to bind to SMAD4. As a result, the R-SMAD effectors make a complex with SMAD4 and SMAD. This complex migrates to the nucleus to regulate transcription of the target genes [28, 29]. In addition, SMAD7 has an inhibitory effect on the interaction of R-SMAD with TGFBR1 [30]. Multiple proteins contribute to the recruitment of R-SMAD proteins to the TGFBR1s and enhance SMAD activation, such as SARA [28]