Fig. 1. TGF-β1 signaling via Smad and non-Smad pathways.

Initiation of the TGF-β signaling cascade occurs upon ligand binding to TβRII and subsequent TβRI-TβRII hetero-tetrameric complex formation. The canonical Smad pathway involves activation of Smad2/3 through recruitment and phosphorylation by activated TβRI, and requires kinase activity of TβRI. TGF-β1 also activates various non-Smad pathways, including TAK1 and subsequently activates several downstream signaling cascades, including MKK4/7–JNK, MKK3/6–p38 MAPK, and nuclear factor-kappa B (NF-κB)-inducing kinase-IκB kinase. TGF-β1, transforming growth factor-β1; TβRI, TGF-β type I receptor; TβRII, TGF-β type 2 receptor; TAK1, TGF-β-activated kinase 1; TAB1, TAK1-binding protein 1; MKK, mitogen-activated protein kinase kinase; JNK, c-Jun N-terminal kinase.