Figure 3.

TGF-β signaling in cardiac fibrosis. TGF-β could induce the signal transduction via the canonical (SMAD-dependent) and non-canonical (SMAD-independent) pathways. In the canonical pathway, TGF-β1 binds to and causes heterodimerization of TGF-β receptor type 1 (TβRI, also known as activin-like kinase (ALK) 5) and the type II receptor (TβRII), leading to the phosphorylation of SMAD2/SMAD3, which subsequently form a complex with SMAD4 and translocate into the nucleus, acting as a transcriptional factor to regulate the fibrotic gene expression (e.g., αSMA, collagen I, III or TNC). SMAD6/7 are inhibitory SMADs to inhibit transcription of SMAD2 and SMAD3. In canonical pathways, TGF-β1 can also induce SMAD-independent noncanonical signaling that involves several mitogen-activated protein kinases, including extracellular signal-regulated kinase (Erk), c-Jun-N-terminal kinase (JNK), TGF-β-activated kinase 1 (TAK1), Rho family of small GTPase, and p38 MAPK pathways.