Figure 1: Canonical and Noncanonical TGF-β signalling. Initiation of the TGF-β signalling cascade occurs via binding of active TGF-β ligand to the TGF-β type 2 receptor (TGF-βRII) [1, 5]. Once bound TGF-βRII is then able to activate its partner the TGF-β type 1 (TGF-βRI)/ALK5 receptor via phosphorylation [1, 14]. Phosphorylation of TGF-βRI results in a conformational change by which the kinase repressive N-terminal GS domain is flipped to act as a docking site for Receptor Smad (R-smad) proteins for example, Smad2 and 3 and in turn facilitates signal transduction by activation of the catalytic kinase domain [1, 16]. TGF-βRI phosphorylates Smad2 and 3, which associate with their co-smad Smad4 to form the active Smad complex, which accumulates in the nucleus via nucleoporin-mediated transport [5, 40]. Phosphorylation acts to inhibit the constant nucleocytoplasmic recycling of Smads resulting in nuclear accumulation [41]. Smads associate with DNA via binding at target gene DNA-Smad Binding Element’s (DNA-SBE), with a optimal conserved sequence of 5′-CAGAC-3′ [17, 42]. However, the Smad complex has only relatively weak DNA-binding affinity. Thus, association with numerous DNA-binding transcription factors for example, Zinc-fingers, homeobox and bHLH families, coactivators (e.g., CBP-300), corepressors (e.g., RBL1) and chromatin remodeling factors (e.g., Histone Deacetylase (HDAC)) allows the complex to achieve specific cell responses [17, 42, 43]. In addition activated TGF-βRI can also activate multiple noncanonical pathways. These Smad independent pathways can function autonomously to achieve a wide array of cellular responses in a transcription-independent manner [21]. In addition activation of the JNK, ERK, and CDK8/9 pathways regulate Smad linker phosphorylation to regulate Smad activity [22, 44].